Abstract
By using a primary in vitro response specific for Leishmania major, normal T cells from resistant CBA/CaH-T6J and susceptible BALB/c mice commit to a Th1 and a Th2 response, respectively. Since commitment occurred, we measured the production of gamma interferon (IFN-gamma), interleukin-1 (IL-1), IL-2, IL-4, IL-5, IL-10, and IL-12, prostaglandin E2 (PGE2), transforming growth factor beta (TGF-beta), and nitric oxide in the first 7 days of the response to identify factors that are critical for Th1 and Th2 development. While cells from resistant CBA mice produced more IFN-gamma, IL-10, and nitric oxide, cells from susceptible BALB/c mice produced more IL-1alpha, IL-5, PGE2, and TGF-beta. Although substantial amounts of IL-12 were detected, IL-12 did not associate with either Th1 or Th2 development. We did not anticipate that cells from resistant CBA mice would make more IL-10 in vitro. However, this also occurred in vivo since CBA mice produced substantial amounts of IL-10 following infection with L. major. Moreover, adding anti-IL-10 to primary in vitro responses enhanced production of IFN-gamma and nitric oxide by cells from CBA and BALB/c mice. Therefore, IL-10 cannot be regarded as a cytokine that associates with susceptibility to infection with L. major. Finally, the data presented here suggest that a collection of factors that can be produced by accessory cells influence Th commitment (e.g., IL-1, PGE2, and TGF-beta favor Th2 development).
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- Abu-Shakra M., Shoenfeld Y. Parasitic infection and autoimmunity. Autoimmunity. 1991;9(4):337–344. doi: 10.3109/08916939108997136. [DOI] [PubMed] [Google Scholar]
- Afonso L. C., Scharton T. M., Vieira L. Q., Wysocka M., Trinchieri G., Scott P. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science. 1994 Jan 14;263(5144):235–237. doi: 10.1126/science.7904381. [DOI] [PubMed] [Google Scholar]
- Baron J. L., Madri J. A., Ruddle N. H., Hashim G., Janeway C. A., Jr Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med. 1993 Jan 1;177(1):57–68. doi: 10.1084/jem.177.1.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barral-Netto M., Barral A., Brownell C. E., Skeiky Y. A., Ellingsworth L. R., Twardzik D. R., Reed S. G. Transforming growth factor-beta in leishmanial infection: a parasite escape mechanism. Science. 1992 Jul 24;257(5069):545–548. doi: 10.1126/science.1636092. [DOI] [PubMed] [Google Scholar]
- Behin R., Mauel J., Sordat B. Leishmania tropica: pathogenicity and in vitro macrophage function in strains of inbred mice. Exp Parasitol. 1979 Aug;48(1):81–91. doi: 10.1016/0014-4894(79)90057-2. [DOI] [PubMed] [Google Scholar]
- Belosevic M., Finbloom D. S., Van Der Meide P. H., Slayter M. V., Nacy C. A. Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol. 1989 Jul 1;143(1):266–274. [PubMed] [Google Scholar]
- Brown D. R., Fowell D. J., Corry D. B., Wynn T. A., Moskowitz N. H., Cheever A. W., Locksley R. M., Reiner S. L. Beta 2-microglobulin-dependent NK1.1+ T cells are not essential for T helper cell 2 immune responses. J Exp Med. 1996 Oct 1;184(4):1295–1304. doi: 10.1084/jem.184.4.1295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chakkalath H. R., Titus R. G. Leishmania major-parasitized macrophages augment Th2-type T cell activation. J Immunol. 1994 Nov 15;153(10):4378–4387. [PubMed] [Google Scholar]
- Chan J., Fujiwara T., Brennan P., McNeil M., Turco S. J., Sibille J. C., Snapper M., Aisen P., Bloom B. R. Microbial glycolipids: possible virulence factors that scavenge oxygen radicals. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2453–2457. doi: 10.1073/pnas.86.7.2453. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chatelain R., Varkila K., Coffman R. L. IL-4 induces a Th2 response in Leishmania major-infected mice. J Immunol. 1992 Feb 15;148(4):1182–1187. [PubMed] [Google Scholar]
- Cillari E., Dieli M., Maltese E., Milano S., Salerno A., Liew F. Y. Enhancement of macrophage IL-1 production by Leishmania major infection in vitro and its inhibition by IFN-gamma. J Immunol. 1989 Sep 15;143(6):2001–2005. [PubMed] [Google Scholar]
- Coffman R. L., Varkila K., Scott P., Chatelain R. Role of cytokines in the differentiation of CD4+ T-cell subsets in vivo. Immunol Rev. 1991 Oct;123:189–207. doi: 10.1111/j.1600-065x.1991.tb00611.x. [DOI] [PubMed] [Google Scholar]
- Corradin S. B., Fasel N., Buchmüller-Rouiller Y., Ransijn A., Smith J., Mauël J. Induction of macrophage nitric oxide production by interferon-gamma and tumor necrosis factor-alpha is enhanced by interleukin-10. Eur J Immunol. 1993 Aug;23(8):2045–2048. doi: 10.1002/eji.1830230851. [DOI] [PubMed] [Google Scholar]
- Descoteaux A., Turco S. J., Sacks D. L., Matlashewski G. Leishmania donovani lipophosphoglycan selectively inhibits signal transduction in macrophages. J Immunol. 1991 Apr 15;146(8):2747–2753. [PubMed] [Google Scholar]
- Ding A., Nathan C. F., Graycar J., Derynck R., Stuehr D. J., Srimal S. Macrophage deactivating factor and transforming growth factors-beta 1 -beta 2 and -beta 3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma. J Immunol. 1990 Aug 1;145(3):940–944. [PubMed] [Google Scholar]
- Farrell J. P., Kirkpatrick C. E. Experimental cutaneous leishmaniasis. II. A possible role for prostaglandins in exacerbation of disease in Leishmania major-infected BALB/c mice. J Immunol. 1987 Feb 1;138(3):902–907. [PubMed] [Google Scholar]
- Fruth U., Solioz N., Louis J. A. Leishmania major interferes with antigen presentation by infected macrophages. J Immunol. 1993 Mar 1;150(5):1857–1864. [PubMed] [Google Scholar]
- Green S. J., Nacy C. A., Meltzer M. S. Cytokine-induced synthesis of nitrogen oxides in macrophages: a protective host response to Leishmania and other intracellular pathogens. J Leukoc Biol. 1991 Jul;50(1):93–103. doi: 10.1002/jlb.50.1.93. [DOI] [PubMed] [Google Scholar]
- Hall L. R., Titus R. G. Sand fly vector saliva selectively modulates macrophage functions that inhibit killing of Leishmania major and nitric oxide production. J Immunol. 1995 Oct 1;155(7):3501–3506. [PubMed] [Google Scholar]
- Heinzel F. P., Rerko R. M., Ahmed F., Pearlman E. Endogenous IL-12 is required for control of Th2 cytokine responses capable of exacerbating leishmaniasis in normally resistant mice. J Immunol. 1995 Jul 15;155(2):730–739. [PubMed] [Google Scholar]
- Heinzel F. P., Sadick M. D., Mutha S. S., Locksley R. M. Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7011–7015. doi: 10.1073/pnas.88.16.7011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heinzel F. P., Schoenhaut D. S., Rerko R. M., Rosser L. E., Gately M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. doi: 10.1084/jem.177.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kuchroo V. K., Martin C. A., Greer J. M., Ju S. T., Sobel R. A., Dorf M. E. Cytokines and adhesion molecules contribute to the ability of myelin proteolipid protein-specific T cell clones to mediate experimental allergic encephalomyelitis. J Immunol. 1993 Oct 15;151(8):4371–4382. [PubMed] [Google Scholar]
- Launois P., Ohteki T., Swihart K., MacDonald H. R., Louis J. A. In susceptible mice, Leishmania major induce very rapid interleukin-4 production by CD4+ T cells which are NK1.1-. Eur J Immunol. 1995 Dec;25(12):3298–3307. doi: 10.1002/eji.1830251215. [DOI] [PubMed] [Google Scholar]
- Lehn M., Weiser W. Y., Engelhorn S., Gillis S., Remold H. G. IL-4 inhibits H2O2 production and antileishmanial capacity of human cultured monocytes mediated by IFN-gamma. J Immunol. 1989 Nov 1;143(9):3020–3024. [PubMed] [Google Scholar]
- Lichtman A. H., Chin J., Schmidt J. A., Abbas A. K. Role of interleukin 1 in the activation of T lymphocytes. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9699–9703. doi: 10.1073/pnas.85.24.9699. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liew F. Y., Cox F. E. Nonspecific defence mechanism: the role of nitric oxide. Immunol Today. 1991 Mar;12(3):A17–A21. doi: 10.1016/S0167-5699(05)80006-4. [DOI] [PubMed] [Google Scholar]
- Liew F. Y., Millott S., Li Y., Lelchuk R., Chan W. L., Ziltener H. Macrophage activation by interferon-gamma from host-protective T cells is inhibited by interleukin (IL)3 and IL4 produced by disease-promoting T cells in leishmaniasis. Eur J Immunol. 1989 Jul;19(7):1227–1232. doi: 10.1002/eji.1830190712. [DOI] [PubMed] [Google Scholar]
- Lytton S. D., Mozes E., Jaffe C. L. Effect of macrophage infection by Leishmania on the proliferation of an antigen-specific T-cell line, TPB1, to a non-parasite antigen. Parasite Immunol. 1993 Aug;15(8):489–492. doi: 10.1111/j.1365-3024.1993.tb00635.x. [DOI] [PubMed] [Google Scholar]
- Macatonia S. E., Hosken N. A., Litton M., Vieira P., Hsieh C. S., Culpepper J. A., Wysocka M., Trinchieri G., Murphy K. M., O'Garra A. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol. 1995 May 15;154(10):5071–5079. [PubMed] [Google Scholar]
- Marchand M., Daoud S., Titus R. G., Louis J., Boon T. Variants with reduced virulence derived from Leishmania major after mutagen treatment. Parasite Immunol. 1987 Jan;9(1):81–92. doi: 10.1111/j.1365-3024.1987.tb00490.x. [DOI] [PubMed] [Google Scholar]
- Mauël J., Corradin S. B., Buchmüller Rouiller Y. Nitrogen and oxygen metabolites and the killing of Leishmania by activated murine macrophages. Res Immunol. 1991 Sep;142(7):577–594. doi: 10.1016/0923-2494(91)90106-s. [DOI] [PubMed] [Google Scholar]
- Mauël J., Ransijn A., Corradin S. B., Buchmüller-Rouiller Y. Effect of PGE2 and of agents that raise cAMP levels on macrophage activation induced by IFN-gamma and TNF-alpha. J Leukoc Biol. 1995 Aug;58(2):217–224. doi: 10.1002/jlb.58.2.217. [DOI] [PubMed] [Google Scholar]
- Milano S., Arcoleo F., Dieli M., D'Agostino R., De Nucci G., D'Agostino P., Cillari E. Ex vivo evidence for PGE2 and LTB4 involvement in cutaneous leishmaniasis: relation with infection status and cytokine production. Parasitology. 1996 Jan;112(Pt 1):13–19. doi: 10.1017/s0031182000065033. [DOI] [PubMed] [Google Scholar]
- Moll H. Epidermal Langerhans cells are critical for immunoregulation of cutaneous leishmaniasis. Immunol Today. 1993 Aug;14(8):383–387. doi: 10.1016/0167-5699(93)90138-B. [DOI] [PubMed] [Google Scholar]
- Moore K. W., O'Garra A., de Waal Malefyt R., Vieira P., Mosmann T. R. Interleukin-10. Annu Rev Immunol. 1993;11:165–190. doi: 10.1146/annurev.iy.11.040193.001121. [DOI] [PubMed] [Google Scholar]
- Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
- Murray H. W., Rubin B. Y., Rothermel C. D. Killing of intracellular Leishmania donovani by lymphokine-stimulated human mononuclear phagocytes. Evidence that interferon-gamma is the activating lymphokine. J Clin Invest. 1983 Oct;72(4):1506–1510. doi: 10.1172/JCI111107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nacy C. A., Fortier A. H., Meltzer M. S., Buchmeier N. A., Schreiber R. D. Macrophage activation to kill Leishmania major: activation of macrophages for intracellular destruction of amastigotes can be induced by both recombinant interferon-gamma and non-interferon lymphokines. J Immunol. 1985 Nov;135(5):3505–3511. [PubMed] [Google Scholar]
- Phipps R. P., Stein S. H., Roper R. L. A new view of prostaglandin E regulation of the immune response. Immunol Today. 1991 Oct;12(10):349–352. doi: 10.1016/0167-5699(91)90064-Z. [DOI] [PubMed] [Google Scholar]
- Prina E., Jouanne C., de Souza Lão S., Szabo A., Guillet J. G., Antoine J. C. Antigen presentation capacity of murine macrophages infected with Leishmania amazonensis amastigotes. J Immunol. 1993 Aug 15;151(4):2050–2061. [PubMed] [Google Scholar]
- Reiner S. L., Zheng S., Wang Z. E., Stowring L., Locksley R. M. Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection. J Exp Med. 1994 Feb 1;179(2):447–456. doi: 10.1084/jem.179.2.447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sadick M. D., Heinzel F. P., Holaday B. J., Pu R. T., Dawkins R. S., Locksley R. M. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990 Jan 1;171(1):115–127. doi: 10.1084/jem.171.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sadick M. D., Locksley R. M., Tubbs C., Raff H. V. Murine cutaneous leishmaniasis: resistance correlates with the capacity to generate interferon-gamma in response to Leishmania antigens in vitro. J Immunol. 1986 Jan;136(2):655–661. [PubMed] [Google Scholar]
- Scharton-Kersten T., Afonso L. C., Wysocka M., Trinchieri G., Scott P. IL-12 is required for natural killer cell activation and subsequent T helper 1 cell development in experimental leishmaniasis. J Immunol. 1995 May 15;154(10):5320–5330. [PubMed] [Google Scholar]
- Scharton-Kersten T., Scott P. The role of the innate immune response in Th1 cell development following Leishmania major infection. J Leukoc Biol. 1995 Apr;57(4):515–522. doi: 10.1002/jlb.57.4.515. [DOI] [PubMed] [Google Scholar]
- Scharton T. M., 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 Aug 1;178(2):567–577. doi: 10.1084/jem.178.2.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott P. IFN-gamma modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J Immunol. 1991 Nov 1;147(9):3149–3155. [PubMed] [Google Scholar]
- Seder R. A., Paul W. E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994;12:635–673. doi: 10.1146/annurev.iy.12.040194.003223. [DOI] [PubMed] [Google Scholar]
- Shankar A. H., Morin P., Titus R. G. Leishmania major: differential resistance to infection in C57BL/6 (high interferon-alpha/beta) and congenic B6.C-H-28c (low interferon-alpha/beta) mice. Exp Parasitol. 1996 Nov;84(2):136–143. doi: 10.1006/expr.1996.0099. [DOI] [PubMed] [Google Scholar]
- Shankar A. H., Titus R. G. Leishmania major-specific, CD4+, major histocompatibility complex class II-restricted T cells derived in vitro from lymphoid tissues of naive mice. J Exp Med. 1993 Jul 1;178(1):101–111. doi: 10.1084/jem.178.1.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shankar A. H., Titus R. G. T cell and non-T cell compartments can independently determine resistance to Leishmania major. J Exp Med. 1995 Mar 1;181(3):845–855. doi: 10.1084/jem.181.3.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shankar A. H., Titus R. G. The influence of antigen-presenting cell type and interferon-gamma on priming and cytokine secretion of Leishmania major-specific T cells. J Infect Dis. 1997 Jan;175(1):151–157. doi: 10.1093/infdis/175.1.151. [DOI] [PubMed] [Google Scholar]
- Simon A. K., Seipelt E., Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8562–8566. doi: 10.1073/pnas.91.18.8562. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stenger S., Thüring H., Röllinghoff M., Bogdan C. Tissue expression of inducible nitric oxide synthase is closely associated with resistance to Leishmania major. J Exp Med. 1994 Sep 1;180(3):783–793. doi: 10.1084/jem.180.3.783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sypek J. P., Chung C. L., Mayor S. E., Subramanyam J. M., Goldman S. J., Sieburth D. S., Wolf S. F., Schaub R. G. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993 Jun 1;177(6):1797–1802. doi: 10.1084/jem.177.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Theodos C. M., Shankar A., Glasebrook A. L., Roeder W. D., Titus R. G. The effect of treating with anti-interleukin-1 receptor antibody on the course of experimental murine cutaneous leishmaniasis. Parasite Immunol. 1994 Nov;16(11):571–577. doi: 10.1111/j.1365-3024.1994.tb00312.x. [DOI] [PubMed] [Google Scholar]
- Titus R. G., Kelso A., Louis J. A. Intracellular destruction of Leishmania tropica by macrophages activated with macrophage activating factor/interferon. Clin Exp Immunol. 1984 Jan;55(1):157–165. [PMC free article] [PubMed] [Google Scholar]
- Titus R. G., Theodos C. M., Shankar A. H., Hall L. R. Interactions between Leishmania major and macrophages. Immunol Ser. 1994;60:437–459. [PubMed] [Google Scholar]
- Urioste S., Hall L. R., Telford S. R., 3rd, Titus R. G. Saliva of the Lyme disease vector, Ixodes dammini, blocks cell activation by a nonprostaglandin E2-dependent mechanism. J Exp Med. 1994 Sep 1;180(3):1077–1085. doi: 10.1084/jem.180.3.1077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vodovotz Y., Bogdan C., Paik J., Xie Q. W., Nathan C. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J Exp Med. 1993 Aug 1;178(2):605–613. doi: 10.1084/jem.178.2.605. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weaver C. T., Hawrylowicz C. M., Unanue E. R. T helper cell subsets require the expression of distinct costimulatory signals by antigen-presenting cells. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8181–8185. doi: 10.1073/pnas.85.21.8181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wenner C. A., Güler M. L., Macatonia S. E., O'Garra A., Murphy K. M. Roles of IFN-gamma and IFN-alpha in IL-12-induced T helper cell-1 development. J Immunol. 1996 Feb 15;156(4):1442–1447. [PubMed] [Google Scholar]