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Rapid early onset lymphocyte cell death in mice resistant, but not susceptible to Leishmania major infection

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Abstract

Leishmania major (Lm) infection in mice is a prototypical model for the role of immune deviation in disease resistance. Resistant strains of mice develop a Th1 response to Lm infection, distinguished by secretion of IL-12 and interferon γ. In contrast, susceptible strains display sustained IL-4 expression characteristic of a Th2 response. However, when mechanisms of cell death are blocked, mice display a susceptible phenotype even in the presence of a strong Th1 response, suggesting that cell death, and not cytokine bias, may be an importnt factor in disease resistance. Here, we investigated this hypothesis by comparing lymphocyte cellularity, cell death and Fas expression in resistant CBA and susceptible BALB/c mice during the course of Lm infection. We found that delayed onset of cell death and late Fas induction correlated with massive lymphocyte accumulation and susceptibility to leishmaniasis, while early cell death and rapid Fas induction occurred in resistant mice.

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References

  1. Pirmez C, Yamamura M, Uyemura K, Paes-Oliveira M, Conceicao-Silva F, Modlin RL. Cytokine patterns in the pathogenesis of human leishmaniasis. J Clin Invest 1993; 91: 1390–1395.

    PubMed  Google Scholar 

  2. Louzir H, Melby PC, Ben Salah A, et al. Immunologic determinants of disease evolution in localized cutaneous leishmaniasis due to Leishmania major. J Infect Dis 1998; 177: 1687–1695.

    PubMed  Google Scholar 

  3. Bogdan C, Rollinghoff M. The immune response to Leishmania: Mechanisms of parasite control and evasion. Int J Parasitol 1998; 28: 121–134.

    PubMed  Google Scholar 

  4. Mosmann TR. Regulation of Immune Responses by T cells with different cytokine secretion phenotypes: role of a new cytokine, cytokine synthesis inhibitory factor (IL10). International Archives of Allergy & Applied Immunology 1991; 94: 110–115.

    Google Scholar 

  5. Scott P. Differentiation, regulation, and death of T helper cell subsets during infection with Leishmania major. Immunol Res 1998; 17: 229–238.

    PubMed  Google Scholar 

  6. Reiner SL, Locksley RM. The Regulation of Immunity to Leishmania Major. Ann Rev Immunol 1995; 13: 151–177.

    Google Scholar 

  7. SolbachW, Lohoff M, Streck H, Rohwer P, Rollinghoff M. Kinetics of cell-mediated immunity developing during the course of Leishmania major infection in "healer" and "non-healer" mice: Progressive impairment of response to and generation of interleukin-2. Immunol 1987; 62: 485–492.

    Google Scholar 

  8. Weintraub J, Gottlieb M, Weinbaum FI. Leishmania tropica: Association of a B-cell mitogen with hypergammaglobulinemia in mice. Exp Parasitol 1982; 53: 87–94.

    PubMed  Google Scholar 

  9. Milon G, Titus RG, Cerottini J-C, Marchal G, Louis JA. Higher frequency of Leishmania major specific L3T4 + T cells in susceptible BALB/c as compared with resistant CBA mice. J Immunol 1986; 136: 1467–1471.

    PubMed  Google Scholar 

  10. Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med 1989; 169: 59–72.

    PubMed  Google Scholar 

  11. Howard JG. Immunological regulation and control of experimental leishmaniasis. Int Rev Exp Path 1986; 28: 79–116.

    PubMed  Google Scholar 

  12. Liew FY, O'Donnell CA. Immunology of leishmaniasis. Adv Parasitol 1993; 32: 162–259.

    Google Scholar 

  13. Sadick MD, Heinzel FP, Holaday BJ, Pu RT, Dawkins RS, Locksley RM. Cure of murine leishmaniasis with antiinterleukin 4 monoclonal antibody. Evidence for a T cell dependent, interferon gamma-independent mechanism. J Exp Med 1990; 171: 115–127.

    PubMed  Google Scholar 

  14. Scott P, Natovitz P, Coffman RL, Pearce E, Sher A. Immunoregulation of cutaneous leishmaniasis. T cell line that transfer protective immunity or exacerbation belongs to different T helper subsets and respond to distinct parasite antigens. J Exp Med 1996; 168: 1675–1684.

    Google Scholar 

  15. Wang ZE, Reiner SL, Zheng S, Dalton DK, Locksley RM. CD4+ effector cells default to the Th2 pathway in interferon gamma deficient mice infected with Leishmania major. J Exp Med 1994; 179: 1367–1371.

    PubMed  Google Scholar 

  16. Shankar A, Titus RG. T cell and non-T cell compartments can independently determine resistance to Leishmania major. J Exp Med 1995; 181: 845–855.

    PubMed  Google Scholar 

  17. Noben-Trauth N, Kropf P, Muller I. Susceptibility to Leishmania major infection in Interleukin-4–Deficient Mice. Science 1996; 271: 987–990.

    PubMed  Google Scholar 

  18. Huang F-P,XuD, Esfandiari E-O, SandsW, Wei X-q, Liew FY. Mice defective in Fas are highly susceptible to Leishmania major infection despite elevated IL-12 synthesis, strong Th1 responses, and enhanced nitric oxide production. J Immunol 1998; 160: 4143–4147.

    PubMed  Google Scholar 

  19. Conceicao-Silva F, Hahne M, Schroter M, Louis J, Tschopp J. The resolution of lesions induced by Leishmania major in mice requires a functional Fas (APO-1, CD95) pathway of cytotoxicity. Eur J Immunol 1998; 28: 237–245.

    PubMed  Google Scholar 

  20. Murphy ML, Engwerda CR, Gorak PM, Kaye PM. B7–2 blockade enhances T cell responses to Leishmania donovani. J Immunol 1997; 159: 4460–4469.

    PubMed  Google Scholar 

  21. Corry DB, Reiner SL, Linsley PS, Locksley RM. Differential effects of blockade of CD28–B7 on the development of Th1 or Th2 effector cells in experimental leishmaniasis. J Immunol 1994; 153: 4142–4148.

    PubMed  Google Scholar 

  22. Vieira LQ, Goldschmidt M, Nashleanas M, Pfieffer K, Mak T, Scott P. Mice lacking the TNF receptor p55 fail to resolve lesions caused by Infection with Leishmania major, but control parasite replication. J Immunol 1996; 157: 827–835.

    PubMed  Google Scholar 

  23. Zhou T, Edwards CK, Yang P, Wang Z, Bluethmann H, Mountz JD. Greatly acclerated lymphadenopathy and autoimmune diseasee in lpr mice lacking tumor necrosis factor receptor I. J Immunol 1996; 156: 2661–1665.

    PubMed  Google Scholar 

  24. Sytwu HK, Liblau RS, McDevitt HO. The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice. Immunity 1996; 5: 17–30.

    PubMed  Google Scholar 

  25. Moore KJ, Matlashewski G. Intracellular infection by Leishmania donovani inhibits macrophage apoptosis. J Immunol 1994; 152: 2930–2937.

    PubMed  Google Scholar 

  26. Zhang X, Brunner T, Carter L, et al. Unequal death in Th1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J Exp Med 1998; 185: 1837–1849.

    Google Scholar 

  27. Zhang X, Giangreco L, Broome HE, Dargen CM, Swain SL. Control of CD4 effector fate: TGFb1 and IL-2 synergize to prevent apoptosis and promote effector expansion. J Exp Med 1995; 185: 699–709.

    Google Scholar 

  28. Swain SL, Croft M, Dubey C, et al. From naive to memory T cells. Immunol Rev 1996; 150: 143–167.

    PubMed  Google Scholar 

  29. Vella AT, Dow S, Potter TA, Kappler J, Marrack P. Cytokineinduced survival of activated T cells in vitro and in vivo. Proc Natl Acad Sci USA 1998; 95: 3810–3815.

    PubMed  Google Scholar 

  30. Vella A, Teague TK, Ihle J, Kappler J, Marrack P. Interleukin 4 (IL-4) or IL-7 prevents the death of resting T cells: stat6 is probably not required for the effect of IL-4. J Exp Med 1997; 186: 325–330.

    PubMed  Google Scholar 

  31. Foote LC, Marshak-Rothstein A, Rothstein TL. Tolerant B lymphocytes acquire resistance to Fas-mediated apoptosis after treatment with interleukin 4 but not after treatment with specific antigen unless a surface immunoglobulin threshold is exceeded. J Exp Med 1998; 187: 847–853.

    PubMed  Google Scholar 

  32. Foote LC, Howard RG, Marshak-Rothstein A, Rothstein TL. IL-4 induces Fas resistance in B cells. J Immunol 1996; 157: 2749–2753.

    PubMed  Google Scholar 

  33. Zamorano J, Wang HY, Wang LM, Pierce JH, Keegan AD. IL-4 protects cells from apoptosis via the insulin receptor substrate pathway and a second independent signaling pathway. J Immunol 1996; 157: 4926–4934.

    PubMed  Google Scholar 

  34. Arkins S, Rebeiz N, Brunke-Reese DL, Biragyn A, Kelley KW. Interferon-gamma inhibits macrophage insulin-like growth factor-I synthesis at the transcriptional level. Mol Endocrinol 1995; 9: 350–360.

    PubMed  Google Scholar 

  35. Buck M, Houglum K, Chojkier M. Tumor necrosis factor-alpha inhibits collagen alpha1(I) gene expression and wound healing in a murine model of cachexia. Am J Pathol 1996; 149: 195–204.

    PubMed  Google Scholar 

  36. Cooney R, Iocono J, Maish G, Smith JS, Ehrlich P. Tumor necrosis factor mediates impaired wound healing in chronic abdominal sepsis. J Trauma 1997; 42: 415–420.

    PubMed  Google Scholar 

  37. Shi Z, Wakil AE, Rockey DC. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc Natl Acad Sci USA 1997; 94: 10663–10668.

    PubMed  Google Scholar 

  38. Varga J, Jimenez SA. Modulation of collagen gene expression: its relation to fibrosis in systemic sclerosis and other disorders. Ann Int Med 1995; 122: 60–62.

    PubMed  Google Scholar 

  39. Hubner G, Brauchle M, Smola H, Madlener M, Fassler R, Werner S. Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoidtreated mice. Cytokine 1996; 8: 548–556.

    PubMed  Google Scholar 

  40. Nestel FP, Price KS, Seemayer TA, Lapp WS. Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease. J Exp Med 1992; 175: 405–413.

    Google Scholar 

  41. Probert L, Akassoglou K, Kassiotis G, Pasparakis M, Alexopoupos L, Kollias G. TNF-alpha transgenic and knockout models of CNS inflammation and degeneration. J Neuroimmunol 1997; 72: 137–141.

    PubMed  Google Scholar 

  42. Isomaki P, Punnonen J. Pro-and anti-inflammatory cytokines in rheumatoid arthritis. Ann Med 1997; 29: 499–507.

    PubMed  Google Scholar 

  43. Titus RG, Ceredig R, Cerotinni J, Louis JA. Therapeutic effect of anti-L3T4 monoclonal antibody GK 1.5 on cutaneous leishmaniasis in genetically susceptible BALB/c mice. J Immunol 1985; 135: 2108–2114.

    PubMed  Google Scholar 

  44. Swihart K, Fruth U, Messmer N, et al. Mice from a genetically resistant background lacking the interferon gamma receptor are susceptible to infection with Leishmania major but mount a polarized T helper cell 1–type CD4+ T cell response. J Exp Med 1995; 181: 961–971.

    PubMed  Google Scholar 

  45. Titus RG, Lima GC, Engers HD, Louis JA. Exacerbation of murine cutaneous leishmaniasis by adoptive transfer of parasite-specific helper T cell populations capable of mediating Leishmania major-specific delayed type hypersensitivity. J Immunol 1984; 133: 1594–1600.

    PubMed  Google Scholar 

  46. Ahuja HS, Zhu Y, Zakeri Z. Association of cyclin-dependent kinase 5 and its activator p35 with apoptotic cell death. Develop Genet 1997; 21: 258–267.

    Google Scholar 

  47. Zakeri ZF, Ahuja HS. Apoptotic cell death in the limb and its relationship to pattern formation. Biochem Cell Biol 1994; 72: 603–613.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, 05405, USA

    Julie Desbarats, Jeffrey E. Stone, Gerald S. Davis, Linda M. Pfeiffer & M. Karen Newell

  2. Queens College and Graduate Center, Department of Biology, City University of New York, Flushing, New York, 11367, USA

    Lin Lin & Zahra F. Zakeri

  3. Department of Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, 80523, USA

    Richard G. Titus

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  1. Julie Desbarats
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Desbarats, J., Stone, J.E., Lin, L. et al. Rapid early onset lymphocyte cell death in mice resistant, but not susceptible to Leishmania major infection. Apoptosis 5, 189–196 (2000). https://doi.org/10.1023/A:1009601200580

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