Abstract
Two types of T helper (Th) cells have been defined on the basis of their cytokine secretion patterns. The decision of a naive T cell to differentiate into Th1 or Th2 is crucial, since to a first approximation it determines whether a cell-mediated or humoral immune response is triggered against a particular pathogen, which profoundly influences disease outcome. Here we show that the internal behaviour of the T helper system, which emerges from regulatory mechanisms ‘built into’ the T helper system, itself can usually select the appropriate T helper response. This phenomenon arises from an initial Th1 bias together with the induction of Th1 → Th2 switches when Th1 effectors do not lead to efficient antigen clearance. The occurrence of these shifts is based on the antigen dose dependence of T helper differentiation, which is a consequence of asymmetries in cross-suppression. Critical for this feature is the rate with which Th2 cells undergo antigen-induced cell death.
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Bancroft, A. J., K. J. Else and R. K. Grencis (1994). Low-level infection with Trichuris muris significantly affects the polarization of the CD4 response. Eur. J. Immunol. 24, 3313–3318.
Behn, U., H. Dambeck and G. Metzner (2000). Modeling Th1-Th2 regulation, allergy and hyposensitization, in Dynamical Modeling in Biotechnology: Ecology, DNA and the Immune System, F. Bagnoli, S. Ruffo and P. Lio (Eds), Singapore: World Scientific.
Bird, J. J., D. R. Brown, A. C. Mullen, N. H. Moskowitz, M. A. Mahowald, J. R. Sider, T. F. Gajewski, C. R. Wang and S. L. Reiner (1998). Helper T cell differentiation is controlled by the cell cycle. Immunity 9, 229–237.
Borghans, J. A. M. and R. J. De Boer (2000). Diversity in the immune system, in Design Principles for the Immune System and Other Distributed Autonomous Systems, I. R. Cohen and L. A. Segel (Eds), Oxford University Press.
Bretscher, P. A., G. Wei, J. N. Menon and H. Bielefeldt-Ohmann (1992). Establishment of stable, cell-mediated immunity that makes “susceptible” mice resistant to Leishmania major. Science 257, 539–542.
Carneiro, J., J. Stewart, A. Coutinho and G. Coutinho (1995). The ontogeny of class-regulation of CD4+ T lymphocyte populations. Int. Immnol. 7, 1265–1277.
Doherty, T. M. and R. L. Coffman (1996). Leishmania major: effect of infectious dose on T cell subset development in BALB/c mice. Exp. Parasitol. 84, 124–135.
Fishman, M. A. and A. S. Perelson (1993). Modeling T cell-antigen presenting cell interactions. J. Theor. Biol. 160, 311–342.
Fishman, M. A. and A. S. Perelson (1994). Th1/Th2_cross regulation. J. Theor. Biol. 170, 25–56.
Fishman, M. and A. S. Perelson (1999). Th1/Th2 differentiation and cross-regulation. Bull. Math. Biol. 61, 403–436.
Grakoui, A., D. L. Donermeyer, O. Kanagawa, K. M. Murphy and P. M. Allen (1999). TCR-independent pathways mediate the effects of antigen dose and altered peptide ligands on Th cell polarization. J. Immunol. 162, 1923–1930.
Hosken, N. A., K. Shibuya, A. W. Heath, K. M. Murphy and A. O’Garra (1995). The effect of antigen dose on CD4+ T helper phenotype development in a T cell receptor-alpha beta-transgenic model. J. Exp. Med. 182, 1579–1584.
Ju, S. T., K. Matsui and M. Ozdemerli (1999). Molecular and cellular mechanisms regulating T and B cell apoptosis through Fas/FasL interaction. Int. Rev. Immunol. 18, 485–513.
Lederer, J. A., V. L. Perez, L. DesRoches, S. M. Kim, A. K. Abbas and A. H. Lichtman (1996). Cytokine transcriptional events during helper T cell subset differentiation. J. Exp. Med. 184, 397–406.
Medzhitov, R. and C. A. Janeway (1997). Innate immunity: impact on the adaptive immune response. Curr. Opin. Immunol. 9, 4–9.
Menon, J. N. and P. A. Bretschner (1998). Parasite dose determines the Th1/Th2 nature of response to Leishmania major independently of infection route and strain of host or parasite. Eur. J. Immunol. 28, 4020–4028.
Mosmann, T. R. and S. Sad (1996). The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol. Today 17, 138–146.
Muraille, E., O. Leo and M. Kaufman (1995). The role of antigen presentation in the regulation of class-specific (Th1/Th2) immune responses. J. Biol. Syst. 3, 397–408.
Rogers, P. R. and M. Croft (1999). Peptide dose, affinity, and time of differentiation can contribute to the Th1/Th2 cytokine balance. J. Immunol. 163, 1205–1213.
Romagnani, S. (1997). The Th1/Th2 paradigm. Immunol. Today 18, 263–266.
Sarzotti, M., D. S. Robbins and P. M. Hoffman (1996). Induction of protective CTL responses in newborn mice by a murine retrovirus. Science 271, 1726–1728.
Seder, R. A. and W. E. Paul (1994). Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu. Rev. Immunol. 12, 635–673.
Segel, L. A. and R. Lev Bar-Or (1999). On the role of feedback in promoting conflicting goals of the adaptive immune system. J. Immunol. 163, 1324–1349.
Varadhachary, A. S., M. E. Peter, S. N. Perdow, P. H. Krammer and P. Salgame (1999). Selective up-regulation of phosphatidylinositol 3′-kinase activity in Th2 cells inhibits caspase-8 cleavage at the death-inducing complex: A mechanism for Th2 resistance from Fas-mediated apoptosis. J. Immunol. 163, 4772–4779.
Yates, A., C. C. Bergmann, J. L. van Hemmen, J. Stark and R. Callard (2000). Cytokine-modulated regulation of helper T cell populations. J. Theor. Biol. 206, 539–560.
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Bergmann, C., van Hemmen, J.L. & Segel, L.A. Th1 or Th2: How an appropriate T helper response can be made. Bull. Math. Biol. 63, 405–430 (2001). https://doi.org/10.1006/bulm.2000.0215
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DOI: https://doi.org/10.1006/bulm.2000.0215