Abstract
Emerging evidence indicates that CD8+ and CD4+ T-cell immunity is differentially regulated. Here we have delineated differences and commonalities among antiviral T-cell responses by enumeration and functional profiling of eight specific CD8+ and CD4+ T-cell populations during primary, memory and recall responses. A high degree of coordinate regulation among all specific T-cell populations stood out against an approximately 20-fold lower peak expansion and prolonged contraction phase of specific CD4+ T-cell populations. Surprisingly, although CD8+ T-cell memory was stably maintained for life, levels of specific CD4+ memory T cells gradually declined. However, this decay, which seemed to result from less efficient rescue from apoptosis, did not affect functionality of surviving virus-specific CD4+ T cells. Our results indicate that CD4+ T-cell memory might become limiting under physiological conditions and that conditions precipitating CD4+ T-cell loss might compromise protective immunity even in the presence of unimpaired CD8+ T-cell responses.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ahmed, R. & Gray, D. Immunological memory and protective immunity: Understanding their relation. Science 272, 54–60 (1996).
Zinkernagel, R.M. & Doherty, P.C. MHC-restricted cytotoxic T cells: Studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv. Immunol. 27, 51–177 (1979).
Oldstone, M.B. Immunotherapy for virus infection. Curr. Top. Microbiol. Immunol. 134, 211–229 (1987).
Homann, D. Immunocytotherapy. Curr. Top. Microbiol. Immunol. (in the press).
Guidotti, L.G. & Chisari, F.V. Cytokine-induced viral purging—role in viral pathogenesis. Curr. Opin. Microbiol. 2, 388–391 (1999).
Kalams, S.A. & Walker, B.D. The critical need for CD4+ help in maintaining effective cytotoxic T lymphocyte responses. J. Exp. Med. 188, 2199–2204 (1998).
Whitmire, J.K. & Ahmed, R. Costimulation in antiviral immunity: differential requirements for CD4+ and CD8+ T-cell responses. Curr. Opin. Immunol. 12, 448–455 (2000).
Berger, D.P., Homann, D. & Oldstone, M.B. Defining parameters for successful immunocytotherapy of persistent viral infection. Virology 266, 257–263 (2000).
Beverley, P.C. & Maini, M.K. Differences in the regulation of CD4+ and CD8+ T-cell clones during immune responses. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 355, 401–406 (2000).
Maini, M.K., Casorati, G., Dellabona, P., Wack, A. & Beverley, P.C. T-cell clonality in immune responses. Immunol. Today 20, 262–266 (1999).
Murali-Krishna, K. et al. Counting antigen-specific CD8+ T cells: A reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998).
Doherty, P.C. & Christensen, J.P. Accessing complexity: The dynamics of virus-specific T-cell responses. Annu. Rev. Immunol. 18, 561–592 (2000).
Welsh, R.M. Assessing CD8 T-cell number and dysfunction in the presence of antigen. J. Exp. Med. 193, F19–22 (2001).
Topham, D.J. et al. Quantitative analysis of the influenza virus-specific CD4+ T-cell memory in the absence of B cells and Ig. J. Immunol. 157, 2947–2952 (1996).
Topham, D.J. & Doherty, P.C. Longitudinal analysis of the acute Sendai virus-specific CD4+ T-cell response and memory. J. Immunol. 161, 4530–4535 (1998).
Christensen, J.P. & Doherty, P.C. Quantitative analysis of the acute and long-term CD4(+) T-cell response to a persistent gammaherpesvirus. J. Virol. 73, 4279–4283 (1999).
Varga, S.M. & Welsh, R.M. Stability of virus-specific CD4+ T-cell frequencies from acute infection into long term memory. J. Immunol. 161, 367–374 (1998).
Whitmire, J.K., Asano, M.S., Murali-Krishna, K., Suresh, M. & Ahmed, R. Long-term CD4+ Th1 and Th2 memory following acute lymphocytic choriomeningitis virus infection. J. Virol. 72, 8281–8288 (1998).
Kamperschroer, C. & Quinn, D.G. Quantification of epitope-specific MHC class-II-restricted T cells following lymphocytic choriomeningitis virus infection. Cell. Immunol. 193, 134–146 (1999).
Varga, S.M. & Welsh, R.M. High frequency of virus-specific interleukin-2-producing CD4(+) T cells and Th1 dominance during lymphocytic choriomeningitis virus infection. J. Virol. 74, 4429–4432 (2000).
Pitcher, C.J. et al. HIV-1–specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nature Med. 5, 518–525 (1999).
Rentenaar, R.J. et al. Development of virus-specific CD4(+) T cells during primary cytomegalovirus infection. J. Clin. Invest. 105, 541–548 (2000).
Hudrisier, D., Oldstone, M.B. & Gairin, J.E. The signal sequence of lymphocytic choriomeningitis virus contains an immunodominant cytotoxic T-cell epitope that is restricted by both H-2D(b) and H-2K(b) molecules. Virology. 234, 62–73 (1997).
Stratmann, T. et al. The I-Ag7 MHC class II molecule linked to murine diabetes is a promiscuous peptide binder. J. Immunol. 165, 3214–3225 (2000).
Ferlin, W., Glaichenhaus, N. & Mougneau E. Present difficulties and future promise of MHC multimers in autoimmune exploration. Curr. Opin. Immunol. 12, 670–675 (2000).
Hou, S., Hyland, L., Ryan, K.W., Portner, A. & Doherty, P.C. Virus-specific CD8+ T-cell memory determined by clonal burst size. Nature 369, 652–654 (1994).
Hobbs, M.V. et al. Patterns of cytokine gene expression by CD4+ T cells from young and old mice. J. Immunol. 150, 3602–3614 (1993).
Chao, D.T. & Korsmeyer, S.J. BCL-2 family: Regulators of cell death. Annu. Rev. Immunol. 16, 395–419 (1998).
Lenardo, M. et al. Mature T lymphocyte apoptosis—immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221–253 (1999).
Belz, G.T., Altman, J.D. & Doherty, P.C. Characteristics of virus-specific CD8+ T cells in the liver during the control and resolution phases of influenza pneumonia. Proc. Natl. Acad. Sci. USA 95, 13812–13817 (1998).
Mehal, W.Z., Juedes, A.E. & Crispe, I.N. Selective retention of activated CD8+ T cells by the normal liver. J. Immunol. 163, 3202–3210 (1999).
Homann, D. et al. Evidence for an underlying CD4+ helper and CD8+ T-cell defect in B-cell–deficient mice: Failure to clear persistent virus infection after adoptive immunotherapy with virus-specific memory cells from μMT/μMT mice. J. Virol. 72, 9208–9216 (1998).
van Essen, D., Dullforce, P. & Gray, D. Role of B cells in maintaining helper T-cell memory. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 355, 351–355 (2000).
Murali-Krishna, K. et al. Persistence of memory CD8+ T cells in MHC class I-deficient mice. Science 286, 1377–1381 (1999).
Garcia, S., DiSanto, J. & Stockinger, B. Following the development of a CD4+ T-cell response in vivo: From activation to memory formation. Immunity 11, 163–171 (1999).
Swain, S.L., Hu, H. & Huston, G. Class II-independent generation of CD4+ memory T cells from effectors. Science 286, 1381–1383 (1999).
Goldrath, A.W. & Bevan, M.J. Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 (1999).
Ciurea, A. et al. Persistence of lymphocytic choriomeningitis virus at very low levels in immune mice. Proc. Natl. Acad. Sci. USA 96, 11964–11969 (1999).
Ogg, G.S. et al. Quantitation of HIV-1–specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279, 2103–2106 (1998).
Marrack, P. et al. Homeostasis of αβ TCR+ T cells. Nature Immunol. 1, 107–111 (2000).
Grayson, J.M., Zajac, A.J., Altman, J.D. & Ahmed, R. Increased expression of Bcl-2 in antigen-specific memory CD8+ T cells. J. Immunol. 164, 3950–3954 (2000).
Slifka, M.K. & Whitton, J.L. Activated and memory CD8+ T cells can be distinguished by their cytokine profiles and phenotypic markers. J. Immunol. 164, 208–216 (2000).
Opferman, J.T., Ober, B.T. & Ashton-Rickardt, P.G. Linear differentiation of cytotoxic effectors into memory T lymphocytes. Science 283, 1745–1748 (1999).
Fearon, D.T. & Locksley, R.M. The instructive role of innate immunity in the acquired immune response. Science 272, 50–53 (1996).
McCune, J.M. The dynamics of CD4+ T-cell depletion in HIV disease. Nature 410, 974–979 (2001).
Acknowledgements
We thank V. Apostolopolous and V. Mallet-Designé for help with MHC class II tetramer preparation and staining; A. Saluk and J. Trotter for assistance with 5- and 6-color flow cytometry; and M. von Herrath, M. Manchester, J. Sprent and I. Abramson for insightful discussions. This work is supported by NIH grants AG-04342 and AI-09484 (to M.B.A.O.) as well as NIH training grant AG-00080 and Juvenile Diabetes Foundation International fellowship 3-1999-629 (to D.H.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Homann, D., Teyton, L. & Oldstone, M. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat Med 7, 913–919 (2001). https://doi.org/10.1038/90950
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/90950
This article is cited by
-
c-Myc uses Cul4b to preserve genome integrity and promote antiviral CD8+ T cell immunity
Nature Communications (2023)
-
CD4+ T cell memory
Nature Immunology (2023)
-
Lower risk of primary Sjogren’s syndrome in patients with dengue virus infection: a nationwide cohort study in Taiwan
Clinical Rheumatology (2021)
-
Immune reconstitution and clinical recovery following anti-CD28 antibody (TGN1412)-induced cytokine storm
Cancer Immunology, Immunotherapy (2021)
-
The Role of Antigen-Competitive Dynamics in Regulating the Immune Response
Bulletin of Mathematical Biology (2021)