Abstract
Cells comprising the CD4+ T-cell population are heterogeneous with regard to function, maturation, and the expression of membrane molecules such as the CD45RA antigen. Previous analyses of the CD4+ subsets defined by CD45RA antigen expression have shown that the ability to provide help for antibody production is restricted to cells within the CD4+CD45RA− subset. In the present studies, we have examined the ability of “naive” CD4+CD45RA+ cells and “memory” CD4+CD45RA− cells to provide help for the generation of alloreactive CD8+ cytotoxic T lymphocytes. When purified CD4+CD45RA+ or CD4+CD45RA− cells were cultured with autologous CD8+ cells and allogeneic E-stimulator cells, both subsets were consistently able to provide help for CD8+ cytotoxic T-cell development. In contrast, the ability to provide help for antibody production was restricted to cells in the CD4+CD45RA− subset. Differences in the mechanisms of the helper functions for these two systems were also identified. Whereas exogenous interleukin-2 (IL-2) could replace the help provided by either CD4+ subset for cytotoxic T-cell generation, IL-2 had only minimal effects on immunoglobulin production. Thus, our studies highlight the contrasting cellular requirements and mechanisms involved in “help” for B-cell differentiation versus cytotoxic T-lymphocyte generation, and they show that the helper/inducer functions of human CD4+ cells are not mediated solely by the CD4+CD45RA− subset.
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Gatenby PA, Kansas GS, Xian CY, Evans RL, Engleman EG: Dissection of immunoregulatory subpopulations of T lymphocytes within the helper and suppressor sublineages in man. J Immunol 129:1997–2000, 1982
Reinherz EL, Morimoto C, Fitzgerald KA, Hussey RE, Daley JF, Schlossman SF: Heterogeneity of human T4+ inducer T cells defined by a monoclonal antibody that delineates two functional subpopulations. J Immunol 128:463–470, 1982
Kansas GS, Wood GS, Fishwild DM, Engleman EG: Functional characterization of human T lymphocyte subsets distinguished by monoclonal anti-Leu-8. J Immunol 134:2995–3003, 1985
Tedder TF, Clement LT, Cooper MD: Human lymphocyte differentiation antigens HB-10 and HB-11. I. Ontogeny of antigen expression. J Immunol 134:2983–2988, 1985
Tedder TF, Cooper MD, Clement LT: Human lymphocyte differentiation antigens HB-10 and HB-11. II. Differential production of B cell growth and differentiation factors by distinct helper T cell subpopulations. J Immunol 134:2989–2994, 1985
Mormoto C, Letvin NL, Distaso JA, Aldrich WR, Schlossman SF: The isolation and characterization of the human suppressor inducer T cell subset. J Immunol 134:1508–1513, 1985
Smith SH, Brown MH, Rowe D, Callard RE, Beverly PCL: Functional subsets of human helper-inducer cells defined by a new monoclonal antibody, UCHL1. Immunology 58:63–71, 1986
Streuli M, Hall LR, Saga Y, Schlossman SF, Saito H: Differential usage of three exons generates at least five different mRNAs encoding human leukocyte common antigens. J Exp Med 166:1548–1557, 1987
Mossmann T, Coffman RL: Two types of mouse helper T cell clones. Implications for immune regulation. Immunol Today 8:223–227, 1987
Yefenof E, Sanders VM, Uhr JW, Vitetta ES: In vitro activation of murine antigen-specific memory B cells by a T-dependent antigen. J Immunol 137:85–90, 1987
Bartlett W, Michael A, MacCann J, Yuan D, Claassen E, Noelle RJ: Cognate interactions between helper T cells and B cells. II. Dissection of cognate help by using a class II-restricted antigen-specific, IL-2-dependent helper T cell clone. J Immunol 143:1745–1751, 1989
Landay A, Gartland GL, Clement LT: Characterization of a phenotypically distinct subpopulation of Leu-2+ cells that suppresses T cell proliferative responses. J Immunol 131:2757–2761, 1983
Clement LT, Yamashita N, Martin AM: The functionally distinct subpopulations of human helper/inducer T lymphocytes defined by anti-CD45RA antibodies derive sequentially from a differentiation pathway that is regulated by activation-dependent post-thymic differentiation. J Immunol 141:1464–1470, 1988
Yamashita N, Clement LT: Phenotypic characterization of the post-thymic differentiation of human alloantigen-specific CD8+ cytotoxic T lymphocytes. J Immunol 143:1518–1523, 1989
Clement LT, Dagg MK, Landay A: Characterization of human lymphocyte subpopulations: Alloreactive cytotoxic T lymphocyte precursor and effector cells are phenotypically distinct from Leu-2+ suppressor cells. J Clin Immunol 4:395–402, 1984
Hakkbar AN, Terry L, Timms A, Beverly PCL, Janossy G: Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J Immunol 140:2171–2176, 1988
Kalish RS, Morimoto C, Schlossman SF, Generation of CD8 (T8) cytotoxic cells has a preferential requirement for CD4 + 2H4− inducer cells. Cell Immunol 111:379–385, 1988
Wee SL, Chen LK, Strassmann G, Bach FH: Helper cell-independent cytotoxic clones in man. J Exp Med 156:1854–1862, 1982
Singer A, Munitz TI, Golding H, Rosenberg AS, Mizuochi T: Recognition requirements for the activation, differentiation, and function of T helper cells specific for class I MHC alloantigens. Immunol Rev 98:143–162, 1987
Mizuochi T, Hugin AW, Morse HC, Singer A, Buller RML: Role of lymphokine-secreting CD8+ T cells in cytotoxic T lymphocyte responses against vaccinia virus. J Immunol 142:270–275, 1989
Sanders ME, Makgoba MW, Shaw S: Human naive and memory T cells: Reinterpretation of helper-inducer and suppressor-inducer subsets. Immunol Today 9:195–199, 1988
Serra HM, Krowka JF, Ledbetter JA, Pilarski LM: Loss of CD45R (Lp220) represents a post-thymic T cell differentiation event. J Immunol 140:1441–1445, 1988
Hirohata S, Lipsky PE: T cell regulation of human B cell proliferation and differentiation. Regulatory influences of CD45R + and CD45R - T4 cell subsets. J Immunol 142:2597–2604, 1989
Moore K, Nesbitt AM: Identification and isolation of OKT4+ suppressor cells with the monoclonal antibody WR16. Immunology 58:659–667, 1986
Gillis S, Gillis AE, Henney CS: Monoclonal antibody directed against interleukin 2. I. Inhibition of T lymphocyte mitogenesis and the in vitro differentiation of alloreactive cytotoxic T cells. J Exp Med 154:983–994, 1981
Wagner H, Hardt C, Rouse BT, Roellinghoff M, Scheurich P, Pfizenmaier K: Dissection of the proliferative and differentiation signals controlling murine cytotoxic T lymphocyte responses. J Exp Med 155:1876–1885, 1982
Chen L, Tourvielle B, Burns GF, Bach FH, Mathieu-Mahul D, Sasportes, M, Bensussan A: Interferon: A cytotoxic T lymphocyte differentiation signal. Eur J Immunol 16:767–771, 1986
Maraskovsky E, Chen WF, Shortman K: IL-2 and IFN-g are two necessary lymphokines in the development of cytolytic T cells. J Immunol 143:1210–1214, 1989
Widmer MB, Grabstein KH: Regulation of cytolytic T-lymphocyte generation by B-cell stimulatory factor. Nature (London) 326:795–797, 1987
Pfeifer JD, Mckenzie DT, Swain SL, Dutton RW: B cell stimulatory factor 1 (interleukin 4) is sufficient for the proliferation and differentiation of lectin-stimulated cytolytic T lymphocyte precursors. J Exp Med 166:1464–1474, 1987
Takatsu K, Kikuchi Y, Takahashi T, Honjo T, Matsumoto M, Harada N, Yamaguchi N, Tominaga A: Interleukin 5, a T-cell derived B-cell differentiation factor also induces cytotoxic T lymphocytes. Proc Natl Acad Sci USA 84:4234–4239, 1987
Takai Y, Wong GG, Clark SC, Burakoff SJ, Hermann SH: B cell stimulatory factor-2 is involved in the differentiation of cytotoxic T lymphocytes. J Immunol 140:508–512, 1988
Okada M, Kitahara M, Kishimoto S, Matsuda T, Hirano T, Kishimoto T: IL-6/BSF-2 functions as a killer helper factor in the in vitro induction of cytotoxic T cells. J Immunol 141:1543–1549, 1988
Uyttenhove C, Coulie PG, van Snick J: T cell growth and differentiation induced by interleukin-HP1/IL-6, the murine hybridoma/plasmacytoma growth factor. J Exp Med 167:1417–1422, 1988
Rosenberg SA, Lotze MT: Cancer immunotherapy using interleukin-2 and interleukin-2-activated lymphocytes. Annu Rev Immunol 4:681–704, 1986
Leist TP, Kohler M, Eppler M, Zinkernagel RM: Effects of treatment with IL-2 receptor specific monoclonal antibody in mice. Inhibition of cytotoxic T cell responses but not of T help. J Immunol 143:628–634, 1989
Sanders ME, Makgoba MW, Sharrow SO, Stephany D, Springer TA, Young HA, Shaw S: Human memory lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-g production. J Immunol 140:1401–1408, 1988
Clement LT, Roberts RL, Martin AM: Characterization of a monocyte differentiation factor distinct from gamma-interferon, tumor necrosis factor, or G,M-colony stimulating factor that regulates the growth and functional capabilities of the U937 monocytic cell line. J Leuk Biol 44:101–110, 1988
Paliard X, de Waal Malefijt R, Yssel H, Blanchard D, Chretien I, Abrams J, de Vries J, Spits H: Simultaneous production of IL-2, IL-4, and IFN-g by activated human CD4+ and CD8+ T cell clones. J Immunol 141:849–855, 1988
Kashahara T, Hooks JJ, Dougherty SF, Oppenheim JJ: Interleukin 2-mediated immune interferon production by human T cells and T cel subsets. J Immunol 130:1784–1789, 1983
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Yamashita, N., Bullington, R. & Clement, L.T. Equivalent helper functions of human “naive” and “memory” CD4+ T cells for the generation of alloreactive cytotoxic T lymphocytes. J Clin Immunol 10, 237–246 (1990). https://doi.org/10.1007/BF00916699
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DOI: https://doi.org/10.1007/BF00916699