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. Author manuscript; available in PMC: 2017 Nov 1.
Published in final edited form as: Cell Immunol. 2016 Jul 16;309:50–54. doi: 10.1016/j.cellimm.2016.07.010

Memory T cells in cutaneous leishmaniasis

Nelson D Glennie 1, Phillip Scott 1,*
PMCID: PMC5127769  NIHMSID: NIHMS807615  PMID: 27493096

Abstract

Leishmania causes a spectrum of diseases that range from self-healing to fatal infections. Control of leishmania is dependent upon generating CD4+ Th1 cells that produce IFNγ, leading to macrophage activation and killing of the intracellular parasites. Following resolution of the disease, short-lived effector T cells, as well as long-lived central memory T cells and skin resident memory T cells, are retained and able to mediate immunity to a secondary infection. However, there is no vaccine for leishmaniasis, and the drugs used to treat the disease can be toxic and ineffective. While a live infection generates immunity, a successful vaccine will depend upon generating memory T cells that can be maintained without the continued presence of parasites. Since both central memory and skin resident memory T cells are long-lived, they may be the appropriate targets for a leishmaniasis vaccine.

Keywords: Leishmania, Memory T cells, Vaccine

1. Introduction

Leishmaniasis, caused by several different intracellular protozoan parasites, remains a serious global public health problem, and is characterized by diverse clinical entities ranging from self-healing cutaneous lesions, to severe, disfiguring chronic lesions, to fatal disease. Drug treatment for leishmaniasis is notoriously poor and, despite decades of research, there is no vaccine for this disease. Antibodies play no protective role, and indeed may exacerbate disease. Instead, IFNγ produced by CD4+ T cells is required to activate infected macrophages to kill the parasites, and the inability to develop a successful vaccine is largely due to a lack of knowledge on how to generate long-lived memory CD4+ T cells [1].

The life cycle of leishmania is relatively simple [1]. The parasites are transmitted by sand flies that harbor the flagellated promastigote form of the parasite. When feeding, sand flies deposit promastigotes in the skin, and phagocytic cells rapidly take up the parasites. While the initial cells that become infected include neutrophils, macrophages, and monocytes, it is primarily within macrophages that the parasites survive and replicate as non-flagellated amastigotes. Surprisingly, unlike other intracellular parasites, such as toxoplasma or Trypanosoma cruzi, leishmania survives and replicates within the phagolysome, having evolved the ability to survive in an environment meant to destroy most microbes. After several rounds of replication, the amastigotes rupture the infected cell and invade other neighboring macrophages. The parasites only differentiate back into promastigotes when taken up by sand flies, and thus a successful vaccine needs to be directed at antigens expressed by amastigotes.

Existing vaccines primarily depend upon generating protective antibodies [2,3]. Given that antibodies are not protective in leishmaniasis, a trait shared by other diseases without vaccines such as tuberculosis and leprosy, it has been more challenging to induce long-term protection by immunization. Many experimental vaccines have been developed and large human vaccine trials have been performed over the last 25 years, and yet no human leishmaniasis vaccine exists [4,5]. It has been suggested that a major problem is that long-term memory T cells fail to develop in leishmaniasis, and thus any vaccine developed will require continual boosting to maintain resistance [6]. In this review we will consider the type of immune responses that need to be generated for protection, and discuss the current understanding of memory T cells in leishmaniasis.

2. Protective mechanisms in cutaneous leishmaniasis

The production of reactive oxygen species (ROS) during phagocytosis, called the respiratory burst, is an innate response that allows macrophages and neutrophils to kill microbes before the development of an adaptive response. Those microbes that survive innate killing become pathogens that require a greater response for elimination, which can be induced by the action of IFNγ. This IFNγ response leads to increased production of ROS, as well as activation of inducible nitric oxide synthase, leading to the release of nitric oxide (NO). Leishmania parasites are killed by both ROS and NO, although NO may be more important in the mouse than in the human [7], and different myeloid cells may be better able to kill by one mechanism than the other. For example, inflammatory monocytes exhibit a high level of ROS and can kill leishmania without being activated, while macrophages require IFNγ activation for killing [7,8]. Under some circumstances neutrophils cooperate with macrophages to kill the parasites [9], although in other situations neutrophils appear to inhibit parasite control [10]. Furthermore, while it is clear that NO is required for the ability of mouse macrophages to kill leishmania, the role of NO in human cells remains controversial [7,11,12]. Nonetheless, in both mice and humans IFNγ is absolutely required to control the parasites sufficiently and control the disease.

Many cell types can produce IFNγ, including NK cells, ILCs, γδ T cells, CD4 T cells and CD8 T cells. However, while all IFNγ producing cells may contribute to an effective response, only CD4+ T cells can provide resistance to leishmania infection in reconstituted RAG mice [13,14]. The critical attribute of these cells appears to be their MHC restriction, since it was recently found that adoptive transfer of Class II restricted, but double negative (CD4−, CD8−) T cells, also provides resistance to leishmania [15]. Nevertheless, while not protective by themselves, other IFNγ producing cells can play important roles in augmenting protection. NK cells (and possibly other innate lymphoid cells) accelerate the development of a Th1 response when CD4 + T cells are being primed in the draining lymph nodes [16–18]. Similarly, following a low dose challenge, IFNγ from CD8 T cells promotes the CD4+ Th1 response [19].

It is important to note that control of the parasites and the development of disease are often dissociated. This is most evident in Leishmania braziliensis patients with mucosal disease, where the severe lesions are chronic and debilitating, but contain few parasites. Conversely, while RAG mice are unable to control parasite replication, they develop only minor swelling at the site of infection [13,14,20]. Adoptive transfer of CD4+ T cells to these immunocompromised mice is sufficient to allow for parasite control, but may lead to the development of larger lesions, although these lesions generally resolve, depending on the leishmania species [13,14,20]. On the other hand, when RAG mice are reconstituted with CD8+ T cells they not only fail to control the parasites, but also develop a severe inflammatory response, as well as the development of metastatic lesions [13,14]. This is a surprising result, since under certain circumstances CD8 T cells can promote protection [19,21,22]. It turns out that whether CD8 T cells promote resistance or increased disease relates directly to whether they primarily produce IFNγ or are cytolytic, as increased cytolytic activity promotes a pathologic inflammatory response [14,23].

Although there is a shared pathway for resistance to leishmania that requires IFNγ, there are many different strains and species of the parasites, and these can induce distinct immune responses, and have different sensitivities to activated macrophage killing. This is particularly true of species in South America, which can produce chronic infections in mice normally resistant to Leishmania major [24]. One example is Leishmania amazonensis, which induces a chronic disease in C57BL/6 mice [25]. L. amazonensis parasites induce a weaker CD4+ Th1 response than L. major infection, and are also able to resist killing by activated macrophages that can kill L. major [26]. Even within the same leishmania species, different strains can lead to diverse outcomes following infection [27]. From this, one might conclude that vaccines and the memory T cells they generate might be effective against one species or strain of leishmania, but may be less effective against another. On the other hand, several studies have shown cross-protection between species, providing some evidence that a single vaccine may work for different leishmania parasites, and even protect against the visceral form of the disease [28,29].

3. Circulating memory T cells in cutaneous leishmaniasis

Following resolution of a primary infection mice are highly resistant to reinfection with leishmania, a fact that led to the belief that it would be relatively straight-forward to develop a vaccine for leishmaniasis. This resistance is primarily dependent upon CD4+ T cells, although immune mice also contain a population of IFNγ-producing CD8+ T cells that contribute to immunity, since depletion of either CD4+ or CD8+ T cells in immune mice decreases resistance to reinfection [21,22]. The strong resistance observed in healed mice is dependent in part on the persistence of a low number of parasites [30,31]. Thus, the few parasites that are left maintain a pool of effector CD4+ T cells that can rapidly respond to a challenge. This raises the question of whether memory T cells develop during a leishmania infection, and if so what type of memory T cells contribute to protection.

Memory T cells have classically been divided into two subsets, central memory (TCM) and effector memory (TEM) cells, based on surface marker expression, tissue tropism, proliferative capacity, and effector function [32]. Central memory T cells express CD62L and CCR7, which allow them to efficiently traffic through the blood and lymph nodes. Upon restimulation, TCM cells rapidly proliferate and thus provide a pool of differentiated, antigen-specific cells to combat a secondary infection. In contrast, TEM cells lack CD62L and CCR7, circulate through blood and non-lymphoid tissues, and exhibit effector functions, such as cytokine production and cytotoxicity, upon restimulation. TEM cells are often distinguished from closely related T effector cells (TEff) by their ability to persist after antigen is cleared, but can also be identified by IL-7R expression on CD8 T cells [33], and additionally by the absence of Ly6C expression on CD4 T cells [34].

Memory CD4 and CD8 T cells share many defining features, but important distinctions have been identified between the two, specifically in lineage development and recall function. After viral infection, CD8 T cells appear to follow a temporally regulated pathway of differentiation from effector, to effector memory, to central memory cells [35], though there may be some heterogeneity in how these populations arise [36]. During recall, CD8 T cells can produce cytokines such as IFNγ, but are best known for their cytotoxic activity. In contrast, CD4 memory T cell generation is thought to be more plastic and highly heterogeneous, varying based on factors such as the nature of the pathogen, amount of antigen exposure, and the cytokine milieu [37–40]. Activated memory CD4 cells also perform a wide variety of functions, largely mediated by their ability to produce a diverse array of cytokines. Because CD4 T cells are the predominant mediator of protection against leishmaniasis [41], this review will focus on the memory CD4 T cell subsets required for resistance.

During a primary infection, effector T cells proliferate in the draining lymph nodes, and migrate to the site of infection to mediate protection (Fig. 1). Some of these effector T cells remain once the infection resolves, as a population of short-lived Ly6C+ effector cells have been well characterized [42]. These cells closely resemble phenotypically the CD4 TEff cells generated after viral infection [34], produce IFNγ at a high frequency, and can transfer protection, but they fail to persist in the absence of antigen. However, a population of long-lived CD62L+ TCM cells have also been identified [43]. These cells proliferate rapidly in response to restimulation, produce IL-2, and do not require persistent antigen for survival. Intriguingly, CD62L+ memory cells can also transfer resistance, but this protection is delayed compared to CD62L− cells. This result indicates that TCM cells are important, but may first need to differentiate into new TEff cells to provide immunity (Fig. 2).

Fig. 1.

Fig. 1

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T cell responses following infection with leishmania. Leishmania are deposited in the skin by infected sand flies and rapidly invade phagocytic cells, including dendritic cells (DC). DCs migrate from the skin to the draining lymph node (1) where they stimulate naïve T cells, which proliferate and differentiate into effector T (Teff) cells (2) or central memory (Tcm) cells (3). Teff cells leave the lymph nodes and migrate to the site of infection (4), where they produce IFNγ leading to parasite control. Some of the Teff cells will also migrate through distant skin sites, where some will become resident memory T (Trm) cells (5).

Fig. 2.

Fig. 2

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T cell responses following a secondary infection with leishmania. When mice that have resolved a primary infection are challenged with leishmania, Trm cells are activated (1) and produce cytokines and chemokines that lead to recruitment of Teff cells from the blood (2), as well as other cells including inflammatory monocytes (iMO) (3). DCs also migrate from the skin to the draining lymph node (4) where they stimulate Tcm cells, which proliferate and differentiate into effector T (Teff) cells (5), thus rapidly increasing the population of Teff cells that are able to control the infection.

Since leishmania is a chronic infection, TCM cells must be generated while the parasite is still present. In fact, antigen-specific CD62L+CCR7+ cells can be identified within the first couple weeks of infection, indicating that subsets of TCM and TEff are generated concurrently. This cell fate decision appears to be affected by the timing of antigen experience and the number of proliferative cycles a cell has gone through [44]. The role for TEM cells in leishmania infection is less defined, and may not be particularly relevant in a chronic infection. Nonetheless, there is evidence that leishmania infection generates a population of antigen experienced CD62L− IL-7R+Ly6C− cells [44], though their role in protection remains unclear as they may not be able to migrate to the infection site or proliferate effectively [42].

4. Resident memory T cells in cutaneous leishmaniasis

Tissue resident memory (TRM) T cells have been established as a third population of memory T cells that are critical for protection against a number of pathogens. TRM cells occupy barrier surfaces such as the lung, gut, and skin [45–47], and phenotypically resemble TEM cells in that they are low for CD62L and CCR7 expression [48]. Global analysis has revealed that TRM indeed have a unique gene signature, displaying a wide array of migration, adhesion, and activation markers [49,50].

TRM cells have been shown to increase protection against a variety of pathogens, in a number of tissues, and in a variety of different ways. Many of the initial studies were done on CD8 memory cells, but it is becoming clear that there are a variety of roles for CD4 TRM cells as well. In the skin, herpes simplex virus-specific CD8 TRM cells provide enhanced local protection [51]. Moreover, skin infection with modified vaccinia virus generates CD8 TRM cells that are globally distributed throughout the skin and provide protection superior to that of circulating memory [52]. CD8 TRM generated by lymphatic choriomeningitis virus infection in the female reproductive tract robustly protect against rechallenge by recruiting circulating TEff more rapidly [53], and can also increase local humoral responses, dendritic cell maturation, and natural killer cell activation [54].

At steady state many CD4 T cells circulate through tissues such as the skin, but CD4 cells also form skin resident populations, particularly after inflammation [55,56]. CD4 TRM cells in the lung provide increase protection against influenza [57], and appear to do so by orchestrating the establishment of local CD8 cells [58]. Furthermore, CD4 cells in the vaginal mucosa can interact with local macrophages to protect against herpes simplex virus-2 [59]. However, CD4 TRM cells are not always beneficial and have also been implicated in psoriasis [60] and asthma [61].

TRM cells have now been shown to play a critical role in protection against leishmaniasis [62]. TRM cells are generated early in infection, and appear to infiltrate the skin globally, as they can be detected in many sites distal to the primary site of infection. Importantly, these cells are long lived and establish residence in the absence of persistent parasites, as demonstrated by their ability to remain in skin when grafted onto a naive host [62], or after parabiotic surgery (Glennie & Scott, unpublished data). Upon restimulation, these cells produce IFNγ which results in a more rapid recruitment of TEff cells to the skin in a CXCR3 dependent manner, which in turn results in better parasite control. In concert with circulating T cells, TRM cells play a critical role in promoting optimal immunity to infection. Moreover, it is possible that the rapid production of cytokines by TRM in the skin may promote additional protective responses even in the absence of TEff cells. These potential responses, such as the direct activation of infected cells, maturation of dendritic cells, or recruitment of phagocytes should continue to be explored.

5. Implications for the development of a cutaneous leishmaniasis vaccine

Cutaneous leishmaniasis poses a conundrum for vaccine development. On the one hand, control of a primary infection is highly protective, a prospect that bodes well for any potential vaccine. On the other hand, the parasite is never fully cleared, and forcing elimination of the parasite reduces immunity to reinfection [30,31]. While a live vaccine that provides persistent antigen might provide protection, it could be difficult to deliver such a vaccine due to ethical and logistical concerns. Encouragingly, it is not required that a cutaneous leishmaniasis vaccine provides sterile immunity, as it is apparent that low levels of parasites can be maintained without pathology. Therefore, the goal of a cutaneous leishmaniasis vaccine might not be to completely eliminate the parasites but instead reduce the parasite load below a certain threshold, and in particular decrease the incidence of the most pathologic outcomes of disease such as mucosal, disseminated, and diffuse cutaneous leishmaniasis.

Circulating CD4 TEff cells are critical mediators of immunity and thus will be important to target in a vaccine. Unfortunately, these T cells require parasites to persist, and therefore maintaining them will demand a strategy that supplies continuous antigen either through a live-attenuated pathogen, frequent boosts, or some other persistent delivery platform. The development of a safe live-attenuated parasite that maintains TEff, TCM, and TRM may be the simplest path to an effective vaccine, but has proven difficult to develop. Another barrier to the generation of a CD4 T cell vaccine has been the lack of well-defined immunodominant CD4 epitopes, as most immunization strategies have required complex polyprotein constructs to induce responses [4,63]. The recent identification of a protein, phosphoenolpyruvate carboxykinase, that reacts with approximately 20% of L. major-specific CD4 T cells and has broad cross-reactivity may help resolve this need, and will also be an invaluable tool for assessing CD4 responses [29]. CD8 T cells have been shown to be protective in some vaccine and mouse models [64], but also might be problematic as CD8 cytotoxic lymphocytes are associated with increased pathology in Leishmania braziliensis [23,65].

Fortunately, there are at least two populations of memory T cells that are maintained in the absence of persistent parasites: TCM and TRM cells. CCR7+ CD4 memory cells that show increased proliferative capacity in response to leishmania antigen have been identified in cutaneous leishmaniasis patients that have healed [66], suggesting that TCM cells are generated by infection in humans and may be a good target in a vaccine.

TRM have never been targeted in a leishmania vaccine, and may be the missing link for optimal vaccine-induced protection. Indeed, when challenged by sand fly bite instead of needle injection, only immune mice and not vaccinated mice are protected against L. major [67]. Since immune mice contain a population of TRM cells, this result may demonstrate the importance of TRM for a vaccine. Further, since all species of the parasite are transmitted through the skin by sand fly bite, TRM cells may be able to provide significant cross-protection, even against the visceral form of the disease. Skin-scarification has been shown to induce increased proliferation of T cells in skin-draining lymph nodes, as well as increased homing to peripheral tissue [68], suggesting that a delivery strategy involving epidermal abrasion may generate TRM cells more effectively than other delivery methods. Since TRM cells can respond rapidly, a vaccine that combines the induction of TRM cells and circulating TCM responses may offer the best hope of an effective vaccine for cutaneous leishmaniasis.

Acknowledgments

This work was supported by NIH grant AI 110869.

References

  • 1.Scott P, Novais FO. Cutaneous leishmaniasis: immune responses in protection and pathogenesis. Nat Rev Immunol. 2016 doi: 10.1038/nri.2016.72. http://dx.doi.org/10.1038/nri.2016.72. [DOI] [PubMed]
  • 2.Plotkin SA. Correlates of protection induced by vaccination. Clin Vaccine Immunol. 2010;17:1055–1065. doi: 10.1128/CVI.00131-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Coffman RL, Sher A, Seder RA. Vaccine adjuvants: putting innate immunity to work. Immunity. 2010;33:492–503. doi: 10.1016/j.immuni.2010.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.V. Working Group on Research Priorities for Development of Leishmaniasis. Costa CH, Peters NC, Maruyama SR, de Brito EC, Jr, Santos IK. Vaccines for the leishmaniases: proposals for a research agenda. PLoS Negl Trop Dis. 2011;5:e943. doi: 10.1371/journal.pntd.0000943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Kumar R, Engwerda C. Vaccines to prevent leishmaniasis. Clin Transl Immunol. 2014;3:e13. doi: 10.1038/cti.2014.4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Tubo NJ, Jenkins MK. CD4+ T Cells: guardians of the phagosome. Clin Microbiol Rev. 2014;27:200–213. doi: 10.1128/CMR.00097-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Novais FO, Nguyen BT, Beiting DP, Carvalho LP, Glennie ND, Passos S, Carvalho EM, Scott P. Human classical monocytes control the intracellular stage of Leishmania braziliensis by reactive oxygen species. J Infect Dis. 2014;209:1288–1296. doi: 10.1093/infdis/jiu013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Goncalves R, Zhang X, Cohen H, Debrabant A, Mosser DM. Platelet activation attracts a subpopulation of effector monocytes to sites of Leishmania major infection. J Exp Med. 2011;208:1253–1265. doi: 10.1084/jem.20101751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Novais FO, Santiago RC, Bafica A, Khouri R, Afonso L, Borges VM, Brodskyn C, Barral-Netto M, Barral A, de Oliveira CI. Neutrophils and macrophages cooperate in host resistance against Leishmania braziliensis infection. J Immunol. 2009;183:8088–8098. doi: 10.4049/jimmunol.0803720. [DOI] [PubMed] [Google Scholar]
  • 10.Afonso L, Borges VM, Cruz H, Ribeiro-Gomes FL, DosReis GA, Dutra AN, Clarencio J, de Oliveira CI, Barral A, Barral-Netto M, Brodskyn CI. Interactions with apoptotic but not with necrotic neutrophils increase parasite burden in human macrophages infected with Leishmania amazonensis. J Leukoc Biol. 2008;84:389–396. doi: 10.1189/jlb.0108018. [DOI] [PubMed] [Google Scholar]
  • 11.Carneiro PP, Conceicao J, Macedo M, Magalhaes V, Carvalho EM, Bacellar O. The role of nitric oxide and reactive oxygen species in the killing of Leishmania braziliensis by monocytes from patients with cutaneous leishmaniasis. PLoS One. 2016;11:e0148084. doi: 10.1371/journal.pone.0148084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Vouldoukis I, Riveros-Moreno V, Dugas B, Ouaaz F, Becherel P, Debre P, Moncada S, Mossalayi MD. The killing of Leishmania major by human macrophages is mediated by nitric oxide induced after ligation of the Fc epsilon RII/CD23 surface antigen. Proc Natl Acad Sci USA. 1995;92:7804–7808. doi: 10.1073/pnas.92.17.7804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Belkaid Y, Von Stebut E, Mendez S, Lira R, Caler E, Bertholet S, Udey MC, Sacks D. CD8+ T cells are required for primary immunity in C57BL/6 mice following low-dose, intradermal challenge with Leishmania major. J Immunol. 2002;168:3992–4000. doi: 10.4049/jimmunol.168.8.3992. [DOI] [PubMed] [Google Scholar]
  • 14.Novais FO, Carvalho LP, Graff JW, Beiting DP, Ruthel G, Roos DS, Betts MR, Goldschmidt MH, Wilson ME, de Oliveira CI, Scott P. Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis. PLoS Pathog. 2013;9:e1003504. doi: 10.1371/journal.ppat.1003504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Mou Z, Liu D, Okwor I, Jia P, Orihara K, Uzonna JE. MHC class II restricted innate-like double negative T cells contribute to optimal primary and secondary immunity to Leishmania major. PLoS Pathog. 2014;10:e1004396. doi: 10.1371/journal.ppat.1004396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Laouar Y, Sutterwala FS, Gorelik L, Flavell RA. Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat Immunol. 2005;6:600–607. doi: 10.1038/ni1197. [DOI] [PubMed] [Google Scholar]
  • 17.Prajeeth CK, Haeberlein S, Sebald H, Schleicher U, Bogdan C. Leishmania-infected macrophages are targets of NK cell-derived cytokines but not of NK cell cytotoxicity. Infect Immun. 2011;79:2699–2708. doi: 10.1128/IAI.00079-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Scharton TM, Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J Exp Med. 1993;178:567–577. doi: 10.1084/jem.178.2.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Uzonna JE, Joyce KL, Scott P. Low dose Leishmania major promotes a transient T helper cell type 2 response that is down-regulated by interferon gamma-producing CD8+ T cells. J Exp Med. 2004;199:1559–1566. doi: 10.1084/jem.20040172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Soong L, Chang CH, Sun J, Longley BJ, Jr, Ruddle NH, Flavell RA, McMahon-Pratt D. Role of CD4+ T cells in pathogenesis associated with Leishmania amazonensis infection. J Immunol. 1997;158:5374–5383. [PubMed] [Google Scholar]
  • 21.Muller I, Kropf P, Etges RJ, Louis JA. Gamma interferon response in secondary Leishmania major infection: role of CD8+ T cells. Infect Immun. 1993;61:3730–3738. doi: 10.1128/iai.61.9.3730-3738.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Muller I, Kropf P, Louis JA, Milon G. Expansion of gamma interferon-producing CD8+ T cells following secondary infection of mice immune to Leishmania major. Infect Immun. 1994;62:2575–2581. doi: 10.1128/iai.62.6.2575-2581.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.da Santos SC, Boaventura V, Ribeiro Cardoso C, Tavares N, Lordelo MJ, Lordelo MJ, Noronha A, Costa J, Borges VM, de Oliveira CI, Van Weyenbergh J, Van Weyenbergh J, Barral A, Barral-Netto M, Brodskyn CI. CD8(+) granzyme B (+)-mediated tissue injury vs. CD4(+)IFNgamma(+)-mediated parasite killing in human cutaneous leishmaniasis. J Invest Dermatol. 2013;133:1533–1540. doi: 10.1038/jid.2013.4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.McMahon-Pratt D, Alexander J. Does the Leishmania major paradigm of pathogenesis and protection hold for New World cutaneous leishmaniases or the visceral disease? Immunol Rev. 2004;201:206–224. doi: 10.1111/j.0105-2896.2004.00190.x. [DOI] [PubMed] [Google Scholar]
  • 25.Khouri R, Bafica A, da Silva PM, Noronha A, Kolb JP, Wietzerbin J, Barral A, Barral-Netto M, Van Weyenbergh J. IFN-beta impairs superoxide-dependent parasite killing in human macrophages: evidence for a deleterious role of SOD1 in cutaneous leishmaniasis. J Immunol. 2009;182:2525–2531. doi: 10.4049/jimmunol.0802860. [DOI] [PubMed] [Google Scholar]
  • 26.Scott P, Sacks D, Sher A. Resistance to macrophage-mediated killing as a factor influencing the pathogenesis of chronic cutaneous leishmaniasis. J Immunol. 1983;131:966–971. [PubMed] [Google Scholar]
  • 27.Anderson CF, Mendez S, Sacks DL. Nonhealing infection despite Th1 polarization produced by a strain of Leishmania major in C57BL/6 mice. J Immunol. 2005;174:2934–2941. doi: 10.4049/jimmunol.174.5.2934. [DOI] [PubMed] [Google Scholar]
  • 28.Romano A, Doria NA, Mendez J, Sacks DL, Peters NC. Cutaneous infection with Leishmania major mediates heterologous protection against visceral infection with Leishmania infantum. J Immunol. 2015;195:3816–3827. doi: 10.4049/jimmunol.1500752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Mou Z, Li J, Boussoffara T, Kishi H, Hamana H, Ezzati P, Hu C, Yi W, Liu D, Khadem F, Okwor I, Jia P, Shitaoka K, Wang S, Ndao M, Petersen C, Chen J, Rafati S, Louzir H, Muraguchi A, Wilkins JA, Uzonna JE. Identification of broadly conserved cross-species protective Leishmania antigen and its responding CD4+ T cells. Sci Transl Med. 2015;7:310ra167. doi: 10.1126/scitranslmed.aac5477. [DOI] [PubMed] [Google Scholar]
  • 30.Uzonna JE, Wei G, Yurkowski D, Bretscher P. Immune elimination of Leishmania major in mice: implications for immune memory, vaccination, and reactivation disease. J Immunol. 2001;167:6967–6974. doi: 10.4049/jimmunol.167.12.6967. [DOI] [PubMed] [Google Scholar]
  • 31.Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature. 2002;420:502–507. doi: 10.1038/nature01152. [DOI] [PubMed] [Google Scholar]
  • 32.Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708–712. doi: 10.1038/44385. [DOI] [PubMed] [Google Scholar]
  • 33.Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat Immunol. 2003;4:1191–1198. doi: 10.1038/ni1009. [DOI] [PubMed] [Google Scholar]
  • 34.Marshall HD, Chandele A, Jung YW, Meng H, Poholek AC, Parish IA, Rutishauser R, Cui W, Kleinstein SH, Craft J, Kaech SM. Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4(+) cell properties during viral infection. Immunity. 2011;35:633–646. doi: 10.1016/j.immuni.2011.08.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R, von Andrian UH, Ahmed R. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol. 2003;4:225–234. doi: 10.1038/ni889. [DOI] [PubMed] [Google Scholar]
  • 36.Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012;12:749–761. doi: 10.1038/nri3307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Jaigirdar SA, MacLeod MK. Development and function of protective and pathologic memory CD4 T cells. Front Immunol. 2015;6:456. doi: 10.3389/fimmu.2015.00456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol. 2002;2:251–262. doi: 10.1038/nri778. [DOI] [PubMed] [Google Scholar]
  • 39.MacLeod MK, Kappler JW, Marrack P. Memory CD4 T cells: generation, reactivation and re-assignment. Immunology. 2010;130:10–15. doi: 10.1111/j.1365-2567.2010.03260.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Zaph C, Rook KA, Goldschmidt M, Mohrs M, Scott P, Artis D. Persistence and function of central and effector memory CD4+ T cells following infection with a gastrointestinal helminth. J Immunol. 2006;177:511–518. doi: 10.4049/jimmunol.177.1.511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Liew FY, Millott S, Lelchuk R, Cobbold S, Waldmann H. Effect of CD4 monoclonal antibody in vivo on lesion development, delayed-type hypersensitivity and interleukin 3 production in experimental murine cutaneous leishmaniasis. Clin Exp Immunol. 1989;75:438–443. [PMC free article] [PubMed] [Google Scholar]
  • 42.Peters NC, Pagan AJ, Lawyer PG, Hand TW, Henrique Roma E, Stamper LW, Romano A, Sacks DL. Chronic parasitic infection maintains high frequencies of short-lived Ly6C+CD4+ effector T cells that are required for protection against re-infection. PLoS Pathog. 2014;10:e1004538. doi: 10.1371/journal.ppat.1004538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Zaph C, Uzonna J, Beverley SM, Scott P. Central memory T cells mediate long-term immunity to Leishmania major in the absence of persistent parasites. Nat Med. 2004;10:1104–1110. doi: 10.1038/nm1108. [DOI] [PubMed] [Google Scholar]
  • 44.Colpitts SL, Scott P. The early generation of a heterogeneous CD4+ T cell response to Leishmania major. J Immunol. 2010;185:2416–2423. doi: 10.4049/jimmunol.1000483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK, Kupper TS. The vast majority of CLA+ T cells are resident in normal skin. J Immunol. 2006;176:4431–4439. doi: 10.4049/jimmunol.176.7.4431. [DOI] [PubMed] [Google Scholar]
  • 46.Hogan RJ, Zhong W, Usherwood EJ, Cookenham T, Roberts AD, Woodland DL. Protection from respiratory virus infections can be mediated by antigen-specific CD4(+) T cells that persist in the lungs. J Exp Med. 2001;193:981–986. doi: 10.1084/jem.193.8.981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Masopust D, Vezys V, Wherry EJ, Barber DL, Ahmed R. Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J Immunol. 2006;176:2079–2083. doi: 10.4049/jimmunol.176.4.2079. [DOI] [PubMed] [Google Scholar]
  • 48.Masopust D, Vezys V, Marzo AL, Lefrancois L. Preferential localization of effector memory cells in nonlymphoid tissue. Science. 2001;291:2413–2417. doi: 10.1126/science.1058867. [DOI] [PubMed] [Google Scholar]
  • 49.Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, Vega-Ramos J, Lauzurica P, Mueller SN, Stefanovic T, Tscharke DC, Heath WR, Inouye M, Carbone FR, Gebhardt T. The developmental pathway for CD103(+) CD8+ tissue-resident memory T cells of skin. Nat Immunol. 2013;14:1294–1301. doi: 10.1038/ni.2744. [DOI] [PubMed] [Google Scholar]
  • 50.Mackay LK, Minnich M, Kragten NA, Liao Y, Nota B, Seillet C, Zaid A, Man K, Preston S, Freestone D, Braun A, Wynne-Jones E, Behr FM, Stark R, Pellicci DG, Godfrey DI, Belz GT, Pellegrini M, Gebhardt T, Busslinger M, Shi W, Carbone FR, van Lier RA, Kallies A, van Gisbergen KP. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science. 2016;352:459–463. doi: 10.1126/science.aad2035. [DOI] [PubMed] [Google Scholar]
  • 51.Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, Carbone FR. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol. 2009;10:524–530. doi: 10.1038/ni.1718. [DOI] [PubMed] [Google Scholar]
  • 52.Jiang X, Clark RA, Liu L, Wagers AJ, Fuhlbrigge RC, Kupper TS. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature. 2012;483:227–231. doi: 10.1038/nature10851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Schenkel JM, Fraser KA, Vezys V, Masopust D. Sensing and alarm function of resident memory CD8(+) T cells. Nat Immunol. 2013;14:509–513. doi: 10.1038/ni.2568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Schenkel JM, Fraser KA, Beura LK, Pauken KE, Vezys V, Masopust D. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science. 2014;346:98–101. doi: 10.1126/science.1254536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Bromley SK, Yan S, Tomura M, Kanagawa O, Luster AD. Recirculating memory T cells are a unique subset of CD4+ T cells with a distinct phenotype and migratory pattern. J Immunol. 2013;190:970–976. doi: 10.4049/jimmunol.1202805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Collins N, Jiang X, Zaid A, Macleod BL, Li J, Park CO, Haque A, Bedoui S, Heath WR, Mueller SN, Kupper TS, Gebhardt T, Carbone FR. Skin CD4(+) memory T cells exhibit combined cluster-mediated retention and equilibration with the circulation. Nat Commun. 2016;7:11514. doi: 10.1038/ncomms11514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Teijaro JR, Turner D, Pham Q, Wherry EJ, Lefrancois L, Farber DL. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J Immunol. 2011;187:5510–5514. doi: 10.4049/jimmunol.1102243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Laidlaw BJ, Zhang N, Marshall HD, Staron MM, Guan T, Hu Y, Cauley LS, Craft J, Kaech SM. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity. 2014;41:633–645. doi: 10.1016/j.immuni.2014.09.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Iijima N, Iwasaki A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science. 2014;346:93–98. doi: 10.1126/science.1257530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Cheuk S, Wiken M, Blomqvist L, Nylen S, Talme T, Stahle M, Eidsmo L. Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis. J Immunol. 2014;192:3111–3120. doi: 10.4049/jimmunol.1302313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Hondowicz BD, An D, Schenkel JM, Kim KS, Steach HR, Krishnamurty AT, Keitany GJ, Garza EN, Fraser KA, Moon JJ, Altemeier WA, Masopust D, Pepper M. Interleukin-2-dependent allergen-specific tissue-resident memory cells drive asthma. Immunity. 2016;44:155–166. doi: 10.1016/j.immuni.2015.11.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Glennie ND, Yeramilli VA, Beiting DP, Volk SW, Weaver CT, Scott P. Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection. J Exp Med. 2015;212:1405–1414. doi: 10.1084/jem.20142101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Duthie MS, Favila M, Hofmeyer KA, Tutterrow YL, Reed SJ, Laurance JD, Picone A, Guderian J, Bailor HR, Vallur AC, Liang H, Mohamath R, Vergara J, Howard RF, Coler RN, Reed SG. Strategic evaluation of vaccine candidate antigens for the prevention of Visceral Leishmaniasis. Vaccine. 2016;34:2779–2786. doi: 10.1016/j.vaccine.2016.04.067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Novais FO, Scott P. CD8+ T cells in cutaneous leishmaniasis: the good, the bad, and the ugly. Semin Immunopathol. 2015;37:251–259. doi: 10.1007/s00281-015-0475-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Novais F, Carvalho L, Graff J, Beiting D, Ruthel G, Roos D, Betts M, Goldschmidt M, Wilson M, de Oliveira C, Scott P. Cytotoxic T cells mediate pathology and metastasis in cutaneous leishmaniasis. PLoS Pathog. 2013;9 doi: 10.1371/journal.ppat.1003504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Keshavarz Valian H, Nateghi Rostami M, Tasbihi M, Miramin Mohammadi A, Eskandari SE, Sarrafnejad A, Khamesipour A. CCR7+ central and CCR7-effector memory CD4+ T cells in human cutaneous leishmaniasis. J Clin Immunol. 2013;33:220–234. doi: 10.1007/s10875-012-9788-7. [DOI] [PubMed] [Google Scholar]
  • 67.Peters NC, Kimblin N, Secundino N, Kamhawi S, Lawyer P, Sacks DL. Vector transmission of leishmania abrogates vaccine-induced protective immunity. PLoS Pathog. 2009;5:e1000484. doi: 10.1371/journal.ppat.1000484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Liu L, Zhong Q, Tian T, Dubin K, Athale SK, Kupper TS. Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity. Nat Med. 2010;16:224–227. doi: 10.1038/nm.2078. [DOI] [PMC free article] [PubMed] [Google Scholar]

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