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. 1993 Aug;79(4):556–561.

Loss of Th1-associated function in peripheral T cells but not thymocytes in tolerance to major histocompatibility complex alloantigen.

P J Wood 1, I A Cossens 1
PMCID: PMC1421924  PMID: 8406580

Abstract

Mice of the strains A.TH and A.TL were rendered neonatally tolerant to class II major histocompatibility complex (MHC) by the injection of (A.TH x A.TL)F1 spleen and bone marrow cells within 24 hr of birth. Spleen and thymus cells from adult tolerant mice bearing long-term surviving skin grafts were compared with those from normal mice for their in vitro reactivity towards the tolerogen. In a primary mixed lymphocyte reaction (MLR), spleen cells from normal mice proliferated in response to 'tolerogen', generated cytotoxic cells and produced interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) but no IL-4 or IL-5. In contrast, although spleen cells from tolerant mice proliferated and produced IL-2, they failed to generate cytotoxic cells or produce IFN-gamma but produced large amounts of IL-4 and IL-5. The loss of the ability of tolerant cells to generate cytotoxicity or IFN-gamma was profound in that no activity was detected in a secondary MLR and mRNA for IFN-gamma could not be detected by reverse transcription polymerase chain reaction (RT-PCR). To see whether the alteration in function occurred centrally or peripherally, thymus cells from normal and tolerant mice were tested for function. Normal thymocytes produced IFN-gamma, IL-4 and IL-5 in a primary MLR and generated cytotoxic cells in a secondary MLR. In contrast to spleen cells, thymus cells from tolerant mice retained their ability to generate IFN-gamma or cytotoxic cells in response to tolerogen. Overall the results point to a profound switch in peripheral tolerogen-specific responses from a Th 1-biased response in normal mice to a Th2-biased response in tolerant mice and suggest that the alteration in function is post thymic.

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Selected References

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  1. Abramowicz D., Doutrelepont J. M., Lambert P., Van der Vorst P., Bruyns C., Goldman M. Increased expression of Ia antigens on B cells after neonatal induction of lymphoid chimerism in mice: role of interleukin 4. Eur J Immunol. 1990 Mar;20(3):469–476. doi: 10.1002/eji.1830200303. [DOI] [PubMed] [Google Scholar]
  2. Abromson-Leeman S. R., Cantor H. Specificity of T cell clones for antigen and autologous major histocompatibility complex products determines specificity for foreign major histocompatibility complex products. J Exp Med. 1983 Aug 1;158(2):428–437. doi: 10.1084/jem.158.2.428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ashwell J. D., Chen C., Schwartz R. H. High frequency and nonrandom distribution of alloreactivity in T cell clones selected for recognition of foreign antigen in association with self class II molecules. J Immunol. 1986 Jan;136(2):389–395. [PubMed] [Google Scholar]
  4. Ben-Sasson S. Z., Le Gros G., Conrad D. H., Finkelman F. D., Paul W. E. IL-4 production by T cells from naive donors. IL-2 is required for IL-4 production. J Immunol. 1990 Aug 15;145(4):1127–1136. [PubMed] [Google Scholar]
  5. Bendelac A., Schwartz R. H. CD4+ and CD8+ T cells acquire specific lymphokine secretion potentials during thymic maturation. Nature. 1991 Sep 5;353(6339):68–71. doi: 10.1038/353068a0. [DOI] [PubMed] [Google Scholar]
  6. Bottomly K., Luqman M., Greenbaum L., Carding S., West J., Pasqualini T., Murphy D. B. A monoclonal antibody to murine CD45R distinguishes CD4 T cell populations that produce different cytokines. Eur J Immunol. 1989 Apr;19(4):617–623. doi: 10.1002/eji.1830190407. [DOI] [PubMed] [Google Scholar]
  7. Budd R. C., Cerottini J. C., MacDonald H. R. Selectively increased production of interferon-gamma by subsets of Lyt-2+ and L3T4+ T cells identified by expression of Pgp-1. J Immunol. 1987 Jun 1;138(11):3583–3586. [PubMed] [Google Scholar]
  8. Carnaud C., Ishizaka S. T., Stutman O. Early loss of precursors of CTL and IL 2-producing cells in the development of neonatal tolerance to alloantigens. J Immunol. 1984 Jul;133(1):45–51. [PubMed] [Google Scholar]
  9. Chang J. C., Zhang L., Edgerton T. L., Kaplan A. M. Heterogeneity in direct cytotoxic function of L3T4 T cells. TH1 clones express higher cytotoxic activity to antigen-presenting cells than TH2 clones. J Immunol. 1990 Jul 15;145(2):409–416. [PubMed] [Google Scholar]
  10. 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]
  11. Dauphinée M. J., Kipper S. B., Wofsy D., Talal N. Interleukin 2 deficiency is a common feature of autoimmune mice. J Immunol. 1981 Dec;127(6):2483–2487. [PubMed] [Google Scholar]
  12. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  13. Ideyama S., Hosono M., Imamura S., Tomana M., Katsura Y. Intrathymic induction of neonatal tolerance to Mls-1a determinant: clonal deletion and clonal anergy by haematolymphoid cells. Immunology. 1991 Oct;74(2):240–245. [PMC free article] [PubMed] [Google Scholar]
  14. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  15. Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
  16. Maizels R. M., Lawrence R. A. Immunological tolerance: The key feature in human filariasis? Parasitol Today. 1991 Oct;7(10):271–276. doi: 10.1016/0169-4758(91)90093-4. [DOI] [PubMed] [Google Scholar]
  17. Mohler K. M., Streilein J. W. Lymphokine production by MLR-reactive reaction lymphocytes obtained from normal mice and mice rendered tolerant of class II MHC antigens. Transplantation. 1989 Apr;47(4):625–633. doi: 10.1097/00007890-198904000-00013. [DOI] [PubMed] [Google Scholar]
  18. Mosmann T. R., Schumacher J. H., Street N. F., Budd R., O'Garra A., Fong T. A., Bond M. W., Moore K. W., Sher A., Fiorentino D. F. Diversity of cytokine synthesis and function of mouse CD4+ T cells. Immunol Rev. 1991 Oct;123:209–229. doi: 10.1111/j.1600-065x.1991.tb00612.x. [DOI] [PubMed] [Google Scholar]
  19. Nossal G. J. Cellular mechanisms of immunologic tolerance. Annu Rev Immunol. 1983;1:33–62. doi: 10.1146/annurev.iy.01.040183.000341. [DOI] [PubMed] [Google Scholar]
  20. Nossal G. J., Pike B. L. Functional clonal deletion in immunological tolerance to major histocompatibility complex antigens. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3844–3847. doi: 10.1073/pnas.78.6.3844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Peltz G. A role for CD4+ T-cell subsets producing a selective pattern of lymphokines in the pathogenesis of human chronic inflammatory and allergic diseases. Immunol Rev. 1991 Oct;123:23–35. doi: 10.1111/j.1600-065x.1991.tb00604.x. [DOI] [PubMed] [Google Scholar]
  22. Powell T. J., Jr, Streilein J. W. Neonatal tolerance induction by class II alloantigens activates IL-4-secreting, tolerogen-responsive T cells. J Immunol. 1990 Feb 1;144(3):854–859. [PubMed] [Google Scholar]
  23. Puré E., Inaba K., Metlay J. Lymphokine production by murine T cells in the mixed leukocyte reaction. J Exp Med. 1988 Aug 1;168(2):795–800. doi: 10.1084/jem.168.2.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rosenberg A. S., Finbloom D. S., Maniero T. G., Van der Meide P. H., Singer A. Specific prolongation of MHC class II disparate skin allografts by in vivo administration of anti-IFN-gamma monoclonal antibody. J Immunol. 1990 Jun 15;144(12):4648–4650. [PubMed] [Google Scholar]
  25. Schurmans S., Brighouse G., Kramer G., Wen L., Izui S., Merino J., Lambert P. H. Transient T and B cell activation after neonatal induction of tolerance to MHC class II or Mls alloantigens. J Immunol. 1991 Apr 1;146(7):2152–2160. [PubMed] [Google Scholar]
  26. Stobo J. D., Paul W. E. Functional heterogeneity of murine lymphoid cells. II. Acquisition of mitogen responsiveness and of theta antigen during the ontogeny of thymocytes and "T" lymphocytes. Cell Immunol. 1972 Aug;4(4):367–380. doi: 10.1016/0008-8749(72)90039-1. [DOI] [PubMed] [Google Scholar]
  27. Streilein J. W., Mohler K., Wood P. J. Mechanisms of neonatal transplantation tolerance. Transplant Proc. 1987 Dec;19(6 Suppl 7):82–87. [PubMed] [Google Scholar]
  28. Streilein J. W. Neonatal tolerance of H-2 alloantigens. Procuring graft acceptance the "old-fashioned" way. Transplantation. 1991 Jul;52(1):1–10. doi: 10.1097/00007890-199107000-00001. [DOI] [PubMed] [Google Scholar]
  29. Swain S. L., Bradley L. M., Croft M., Tonkonogy S., Atkins G., Weinberg A. D., Duncan D. D., Hedrick S. M., Dutton R. W., Huston G. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol Rev. 1991 Oct;123:115–144. doi: 10.1111/j.1600-065x.1991.tb00608.x. [DOI] [PubMed] [Google Scholar]
  30. Swain S. L., McKenzie D. T., Weinberg A. D., Hancock W. Characterization of T helper 1 and 2 cell subsets in normal mice. Helper T cells responsible for IL-4 and IL-5 production are present as precursors that require priming before they develop into lymphokine-secreting cells. J Immunol. 1988 Nov 15;141(10):3445–3455. [PubMed] [Google Scholar]
  31. Wood P. J., Streilein J. W. Ontogeny of acquired immunological tolerance to H-2 alloantigens. Eur J Immunol. 1982 Mar;12(3):188–194. doi: 10.1002/eji.1830120304. [DOI] [PubMed] [Google Scholar]
  32. Wood P. J., Strome P. G., Streilein J. W. Characterization of cytotoxic cells in mice rendered neonatally tolerant of MHC alloantigens: evidence for repertoire modification. J Immunol. 1987 Jun 1;138(11):3661–3668. [PubMed] [Google Scholar]
  33. Wood P. J., Strome P. G., Streilein J. W. Clonal analysis of helper and effector T-cell function in neonatal transplantation tolerance: clonal deletion of helper cells determines lack of in vitro responsiveness. Immunogenetics. 1984;20(2):185–196. doi: 10.1007/BF00364489. [DOI] [PubMed] [Google Scholar]
  34. Wu S. Ontogeny of cell-mediated immunity of murine thymocytes and spleen cells. In vitro mixed leukocyte culture and cell-mediated lympholysis reactions. Differentiation. 1978;11(3):169–174. doi: 10.1111/j.1432-0436.1978.tb00980.x. [DOI] [PubMed] [Google Scholar]
  35. Yamamura M., Uyemura K., Deans R. J., Weinberg K., Rea T. H., Bloom B. R., Modlin R. L. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. doi: 10.1126/science.254.5029.277. [DOI] [PubMed] [Google Scholar]
  36. von Boehmer H., Hengartner H., Nabholz M., Lernhardt W., Schreier M. H., Haas W. Fine specificity of a continuously growing killer cell clone specific for H-Y antigen. Eur J Immunol. 1979 Aug;9(8):592–597. doi: 10.1002/eji.1830090804. [DOI] [PubMed] [Google Scholar]

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