Trials and Tribble-ations of tissue T_RM cells

Abstract

CD8⁺ tissue-resident memory T cells (T_RM cells) in two mucosal tissues, the skin and the female reproductive tract, proliferate in situ to generate a secondary pool of T_RM cells that does not exit into the circulation.

An effective memory T cell response is based on tiered layers of defense that often begin with locally poised CD8⁺ T_RM cells. In this issue of Nature Immunology, Beura et al.¹ and Park et al.² describe the early and late effects of secondary infection on pre-existing T_RM cell pools in two mucosal tissues, the skin and the female reproductive tract (FRT), and show that CD8⁺ T_RM cells proliferate in situ to generate a secondary pool of T_RM cells that does not exit into the circulation. Although CD8⁺ memory T cells recruited from the circulation (T_CIRC cells) may also take up residence in the reinfected tissue, they do not outcompete the pre-existing T_RM cell population^1,2.

CD8⁺ memory T cells are a heterogeneous population of cells that can be conceptually segregated on the basis of their functional and spatial properties. Three memory T cell populations have been shown to circulate between the blood and organs: central memory T cells (T_CM cells), characterized by their high expression of lymph node (LN)-homing receptors, regenerative potential and interleukin 2 (IL-2) production; effector memory T cells (T_EM cells), distinguished by low expression of LN-homing receptors and high expression of CX3CR1, and which predominantly survey the blood and exert immediate cytotoxic functions; and peripheral memory T cells (T_PM cells), which are CX3CR1^int and preferentially patrol peripheral tissues via a distinct pattern of migration from blood to tissue to lymph. A fourth population of CD8⁺ memory T cells, the T_RM cells, derived from CX3CR1^lo/int and KLRG1^lo effector T cells and commonly distinguished by their increased expression of CD69 and CD103, do not recirculate in the host, but rather dwell long-term within tissues to provide rapid local protection. Such spatial compartmentalization of memory T cells provides a shield of protective immunity acting both outside-in and inside-out.

Poised at the front lines of defense, often within epithelial barriers, CD8⁺ T_RM cells serve as motile sentinels that patrol the tissue microenvironment for reinfection³ (Fig. 1). Intravital imaging by Park et al.² and Beura et al.¹ revealed different rates of motility of T_RM cells in the skin and FRT, with mean velocities of 2 μm min^–1 and 10 μm min^–1, respectively. Notably, in the FRT, CD8⁺ T cell velocity is slower down in the collagen-rich perimetrium than in the myometrium¹, possibly because of the unique tissue architectures and densities of the two regions. This is akin in some ways to the situation in the skin, where CD8⁺ T cell velocities are significantly faster in the dermis than in the epidermis³. Given the seemingly random motion of these motile CD8⁺ T_RM cells, it will be informative to learn whether they preferentially interact with cells that express survival-cue proteins such as IL-15 and TGF-β.

Fig. 1 |. Effects of secondary infection on a pre-existing T_RM cell population.

CD8⁺ T_RM cells (green) are motile sentinels that patrol and survey their tissue microenvironments for reinfection. When they recognize their target antigen (Ag) during reinfection, CD8⁺ T_RM cells arrest and undergo in situ proliferation to generate a secondary pool of T_RM cells that does not exit into the circulation. Antigen-specific (purple) and bystander (blue) CD8⁺ T_CIRC cells are also recruited into the infected tissue and adopt long-term tissue residency without displacing the pre-existing T_RM cells, thereby increasing the number and repertoire of T_RM cells in the tissue. Credit: Marina Spence/Springer Nature

A body of literature has informed on how T_CM cells and T_EM cells respond during secondary infection, but less is known about how T_RM cells respond in situ. The prevailing idea in the field was that T_RM cells had little self-renewal potential at steady state, and that upon reinfection T_CM cells dominated the recall response owing to their increased proliferative capacity. By elegantly delineating the responses of T_CIRC cells and T_RM cells, Park et al.² and Beura et al.¹ demonstrate that pre-existing T_RM cells undergo local proliferation in situ during reinfection. Whether there is a distinct subpopulation of T_RM cells with regenerative capacity remains to be explored. Importantly, the secondary pool of T_RM cells after reinfection is generated predominantly from the pre-existing, proliferating T_RM cells, rather than from the circulating memory T cells recruited into the inflamed tissue. One notable finding by Park et al.² is that homologous reinfection did not significantly boost the number of pre-existing T_RM cells, which suggests a numerically stable pool of T_RM cells that is robustly maintained, at least in the skin. Although there is evidence that CD103⁺ gut T_RM cells can circulate and acquire properties of splenic memory when adoptively transferred and restimulated⁴, the present data suggest that when reactivated in situ, T_RM cells maintain their cell fate identity and do not re-enter the circulation. Perhaps this occurs because the T_RM cells further upregulate CD69 after reactivation, thereby preventing S1P-mediated egress into the blood or lymph. As prior work has demonstrated that secondary or tertiary ‘experienced’ T_CIRC cells can become qualitatively different with each successive round of infection^5,6, it will be interesting to further investigate the quality, longevity and function of these secondary T_RM cells compared with those of primary T_RM cells.

Comprehensive studies are beginning to discern the tissue-specific requirements for T_RM cell formation and maintenance. For instance, T_RM cells in the skin, salivary gland and kidney require IL-15 for their homeostatic maintenance, whereas those in the FRT or small intestine do not^7,8. Additionally, T_RM cells in the lung and brain require cognate antigen for their establishment^9,10, unlike T_RM cells in skin, FRT and nasal tissue, where topical application of the skin irritant DNFB² and prime-and-pull strategies¹¹ are sufficient to stimulate circulating CD8⁺ T cells to adopt T_RM-cell-like phenotypes. Although Park et al. and Beura et al. both demonstrate that bystander CD8⁺ cells recruited during reinfection adopt tissue residency, the acquisition of CD103 expression on the infiltrating bystander cells occurred only in the skin^1,2. Perhaps such tissue-specific effects stem from differences in the bioavailability of TGF-β, a hallmark cytokine for the induction of CD103 expression^8,12.

The mucosal tissues are constantly exposed to different environmental challenges. Secondary heterologous infection in the lung can drive the migration of pre-existing CD8⁺ memory T cells into the bronchoalveolar spaces¹³. Whether these recruited memory T cells belong to lung T_RM cells or T_CIRC cells remains to be investigated, but this observation raises the question of whether successive waves of heterologous infection and inflammation can cause the pre-existing pool of T_RM cells to shrink, expand or change qualitatively. In a series of heterologous rechallenges via varying infection routes, Park et al. observed that despite the influx and seeding of new T_RM cells, the number of pre-existing T_RM cells remained mostly unaltered², which indicates that T_RM cells persist long-term and that the entire T_RM cell pool is expandable within tissues. This is consistent with previous observations that the memory T_CIRC cell population is a flexible compartment that can accommodate increased numbers of CD8⁺ memory T cells after heterologous prime-boost vaccinations¹⁴. Together, these results imply that the encounter of various pathogens throughout life contributes to the development of a diverse repository of T_RM cells, a goal that should be achieved by future vaccination strategies. ❐