Abstract
An overwhelming virus infection that spreads within a few days throughout the host can cause deletion of the specific cytotoxic T lymphocytes (CTL). This phenomenon is known as ‘clonal exhaustion’. Current explanations for this phenomenon are ‘clonal’, and consider either the terminal differentiation of the virus-specific CTL to an effector phenotype, or the lack of help and antigen presentation for a specific CTL clone. The virus remains controlled by some other form of immunity in the exhausted state. Candidates are innate immunity (especially NK cells andmacrophages) and a T helper type 2 based immune response. Surprisingly, the role of this other form of immunity in causing exhaustion has been ignored so far. Develo** a mathematical model, we here investigate the possibility that this inter-clonal immunity is responsible for exhaustion by down regulating the CTL response. The model is based on previously published exhaustion data for Lymphocytic choriomeningitis virus as an in vivo model. We demonstrate that several complicated experiments on clonal exhaustion are consistentwith inter-clonal regulation. By interpreting the available data with a mathematical model, we compare this novel mechanism with the mechanisms suggested previously.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Ahmed, R., A. Salmi, L. D. Butler, J. M. Chiller and M. B. A. Oldstone (1984). Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. J. Exp. Med. 160, 521–540.
Aichele, P., K. Brduscha-Riem, R. M. Zinkernagel, H. Hengartner and H. Pircher (1995). T cell priming versus T cell tolerance induced by synthetic peptides. J. Exp. Med. 182, 261–266.
Aichele, P., D. Kyburz, P. S. Ohashi, B. Odermatt, R. M. Zinkernagel, H. Hengartner and H. Pircher (1994). Peptide-induced T-cell tolerance to prevent autoimmune diabetes in a transgenic mouse model. Proc. Natl Acad. Sci. U.S.A. 91, 444–448.
Alexander-Miller, M. A., G. R. Leggatt, A. Sarin and J. A. Berzofsky (1996). Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL. J. Exp. Med. 184, 485–492.
Allan, W., Z. Tabi, A. Cleary and P. C. Doherty (1990). Cellular events in the lymph node and lung of mice with influenza. Consequences of depleting CD4+ T cells. J. Immunol. 144, 3980–3986.
Baldridge, J. R., T. S. McGraw, A. Paoletti and M. J. Buchmeier (1997). Antibody prevents the establishment of persistent arenavirus infection in synergy with endogenous T cells. J. Virol. 71, 755–758.
Battegay, M., D. Moskophidis, A. Rahemtulla, H. Hengartner, T. W. Mak and R. M. Zinkernagel (1994). Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice. J. Virol. 68, 4700–4704.
Bocharov, G. A. (1998). Modelling the dynamics of LCMV infection in mice: conventional and exhaustive CTL responses. J. Theor. Biol. 192, 283–308.
Brundler, M. A., P. Aichele, M. Bachmann, D. Kitamura, K. Rajewsky and R. M. Zinkernagel (1996). Immunity to viruses in B cell-deficient mice: influence of antibodies on virus persistence and on T cell memory. Eur. J. Immunol. 26, 2257–2262.
Cardin, R. D., J. W. Brooks, S. R. Sarawar and P. C. Doherty (1996). Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. J. Exp. Med. 184, 863–871.
De Boer, R. and A. Perelson (1995). Towards a general function describing T cell proliferation. J. Theor. Biol. 175, 567–576.
Effros, R. B. and G. Pawelec (1997). Replicative senescence of T cells: does the Hayflick Limit lead to immune exhaustion? Immunol. Today 18, 450–454.
Eigler, A., B. Sinha, G. Hartmann and S. Endres (1997). Taming TNF: strategies to restrain this proinflammatory cytokine. Immunol. Today 18, 487–492.
Gallimore, A., A. Glithero, A. Godkin, A. C. Tissot, A. Pluckthun, T. Elliott, H. Hengartner and R. Zinkernagel (1998). Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J. Exp. Med. 187, 1383–1393.
Grossman, Z. (1986). A new approach to the evolution of the blastic crisis from chronic myelocytic leukemia: dynamic interplay of cellular alterations and a changing microenvironment. EMBO J. 5, 671–677.
Grossman, Z., C. L. Greenblatt and I. R. Cohen (1986). Parasite immunology and lymphocyte population dynamics. J. Theor. Biol. 121, 129–139.
Guidotti, L. G. and F. V. Chisari (1996). To kill or to cure: options in host defense against viral infection. Curr. Opin. Immunol. 8, 478–483.
Horwitz, D. A., J. D. Gray, K. Ohtsuka, M. Hirokawa and T. Takahashi (1997). The immunoregulatory effects of NK cells: the role of TGF-β and implications for autoimmunity. Immunol. Today 18, 538–542.
Kaech, S. M. and R. Ahmed (2001). Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat. Immunol. 2, 415–422.
Kagi, D. and H. Hengartner (1996). Different roles for cytotoxic T cells in the control of infections with cytopathic versus noncytopathic viruses. Curr. Opin. Immunol. 8, 472–477.
Kos, F. J. and E. G. Engleman (1996). Immune regulation: a critical link between NK cells and CTLs. Immunol. Today 17, 174–176.
Lehmann-Grube, F., I. Krenz, T. Krahnert, R. Schwachenwald, D. Moskophidis, J. Lohler and C. J. Villeda Posada (1987). Mechanism of recovery from acute virus infection. IV. Questionable role of mononuclear phagocytes in the clearance of lymphocytic choriomeningitis virus from spleens of mice. J. Immunol. 138, 2282–2289.
Matloubian, M., R. J. Concepcion and R. Ahmed (1994). CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J. Virol. 68, 8056–8063.
Matzinger, P. (1994). Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045.
Mitchison, N. A. (1964). Induction of immunological paralysis in two zones of dosage. Roy. Soc. Proc. 161, 275–292.
Mo, X. Y., R. A. Tripp, M. Y. Sangster and P. C. Doherty (1997). The cytotoxic T-lymphocyte response to Sendai virus is unimpaired in the absence of λ interferon. J. Virol. 71, 1906–1910.
Moskophidis, D., M. Battegay, M. A. Bruendler, E. Laine, I. Gresser and R. M. Zinkernagel (1994a). Resistance of lymphocytic choriomeningitis virus to α/β interferon and to λ interferon. J. Virol. 68, 1951–1955.
Moskophidis, D., M. Battegay, M. Van den Broek, E. Laine, U. Hoffmann-Rohrer and R. M. Zinkernagel (1995). Role of virus and host variables in virus persistence or immunopathological disease caused by a non-cytolytic virus. J. Gen. Virol. 76, 381–391.
Moskophidis, D., E. Laine and R. M. Zinkernagel (1993a). Peripheral clonal deletion of antiviral memory CD8+ T cells. Eur. J. Immunol. 23, 3306–3311.
Moskophidis, D., F. Lechner, H. Hengartner and R. M. Zinkernagel (1994b). MHC class I and non-MHC-linked capacity for generating an anti-viral CTL response determines susceptibility to CTL exhaustion and establishment of virus persistence in mice. J. Immunol. 152, 4976–4983.
Moskophidis, D., F. Lechner, H. Pircher and R. M. Zinkernagel (1993b). Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362, 758–761.
Ou, R., S. Zhou, L. Huang and D. Moskophidis (2001). Critical role for α/β and λ interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells. J. Virol. 75, 8407–8423.
Pantaleo, G. et al. (1997). Evidence for rapid disappearance of initially expanded HIVspecific CD8+ T cell clones during primary HIV infection. Proc. Natl Acad. Sci. U.S.A. 94, 9848–9853.
Planz, O., S. Ehl, E. Furrer, E. Horvath, M. A. Brundler, H. Hengartner and R. M. Zinkernagel (1997). A critical role for neutralizing-antibody-producing B cells, CD4+ T cells, and interferons in persistent and acute infections of mice with lymphocytic choriomeningitis virus: implications for adoptive immunotherapy of virus carriers. Proc. Natl Acad. Sci. U.S.A. 94, 6874–6879.
Segel, L. A. (2001a). Controlling the immune system: diffuse feedback via a diffuse informational network. Novartis. Found. Symp. 239, 31–40.
Segel, L. A. (2001b). Diffuse Feedback from a Diffuse Informational Network: In the Immune System and Other Distributed Autonomous Systems, in Design Principles for the Immune System and Other Distributed Autonomous Systems, L. A. Segel and I. R. Cohen (Eds), Oxford, U.K.: Oxford University Press, pp. 203–226.
Thomsen, A. R., J. Johansen, O. Marker and J. P. Christensen (1996). Exhaustion of CTL memory and recrudescence of viremia in lymphocytic choriomeningitis virus-infected MHC class II-deficient mice and B cell-deficient mice. J. Immunol. 157, 3074–3080.
Thomsen, A. R. and M. Volkert (1983). Studies on the role of mononuclear phagocytes in resistance to acute lymphocytic choriomeningitis virus infection. Scand. J. Immunol. 18, 271–277.
Tishon, A., P. Borrow, C. Evans and M. B. Oldstone (1993). Virus-induced immunosuppression. 1. Age at infection relates to a selective or generalized defect. Virology 195, 397–405.
Van den Broek, M. F., U. Muller, S. Huang, M. Aguet and R. M. Zinkernagel (1995). Antiviral defense in mice lacking both α/β and λ interferon receptors. J. Virol. 69, 4792–4796.
Van Stipdonk, M. J., E. E. Lemmens and S. P. Schoenberger (2001). Naive CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation. Nat. Immunol. 2, 423–429.
Varadhachary, A. S., S. N. Perdow, C. Hu, M. Ramanarayanan and P. Salgame (1997). Differential ability of T cell subsets to undergo activation-induced cell death. Proc. Natl Acad. Sci. U.S.A. 94, 5778–5783.
Welsh, R. M. and J. M. McNally (1999). Immune deficiency, immune silencing, and clonal exhaustion of T cell responses during viral infections. Curr. Opin. Microbiol. 2, 382–387.
Wodarz, D., P. Klenerman and M. A. Nowak (1998). Dynamics of cytotoxic T-lymphocyte exhaustion. Proc. R. Soc. Lond. B. Biol. Sci. 265, 191–203.
Zajac, A. J., K. Murali-Krishna, J. N. Blattman and R. Ahmed (1998). Therapeutic vaccination against chronic viral infection: the importance of cooperation between CD4+ and CD8+ T cells. Curr. Opin. Immunol. 10, 444–449.
Zheng, L., G. Fisher, R. E. Miller, J. Peschon, D. H. Lynch and M. J. Lenardo (1995). Induction of apoptosis in mature T cells by tumour necrosis factor. Nature 377, 348–351.
Zimmermann, C., M. Rawiel, C. Blaser, M. Kaufmann and H. Pircher (1996). Homeostatic regulation of CD8+ T cells after antigen challenge in the absence of Fas (CD95). Eur. J. Immunol. 26, 2903–2910.
Zimmermann, C., P. Seiler, P. Lane and R. M. Zinkernagel (1997). Antiviral immune responses in CTLA4 transgenic mice. J. Virol. 71, 1802–1807.
Zinkernagel, R. M. (1996). Immunology taught by viruses. Science 271, 173–178.
Zinkernagel, R. M., M. F. Bachmann, T. M. Kundig, S. Oehen, H. Pirchet and H. Hengartner (1996). On immunological memory. Annu. Rev. Immunol. 14, 333–367.
Zinkernagel, R. M., D. Moskophidis, T. Kundig, S. Oehen, H. Pircher and H. Hengartner (1993). Effector T-cell induction and T-cell memory versus peripheral deletion of T cells. Immunol. Rev. 133, 199–223.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Keşmir, C., De Boer, R.J. Clonal exhaustion as a result of immune deviation. Bull. Math. Biol. 65, 359–374 (2003). https://doi.org/10.1016/S0092-8240(03)00009-0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1016/S0092-8240(03)00009-0