A potent role for memory CD8+ T cells in heterologous immunity was shown with a respiratory mucosal model of viral infection. Memory CD8+ T cells generated after lymphocytic choriomeningitis virus (LCMV) infection were functionally activated in vivo to produce interferon-γ (IFN-γ) during acute infection with vaccinia virus (VV). Some of these antigen-specific memory cells selectively expanded in number, which resulted in modulation of the original LCMV-specific T cell repertoire. In addition, there was an organ-selective compartmental redistribution of these LCMV-specific T cells during VV infection. The presence of these LCMV-specific memory T cells correlated with enhanced VV clearance, decreased mortality and marked changes in lung immunopathology. Thus, the participation of pre-existing memory T cells specific to unrelated agents can alter the dynamics of mucosal immunity and disease course in response to a pathogen.
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Murali-Krishna, K. et al. Counting antigen-specific CD8+ T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998).
Flynn, K. J. et al. Virus-specific CD8+ T cells in primary and secondary influenza pneumonia. Immunity 8, 683–691 (1998).
Selin, L. K., Vergilis, K., Welsh, R. M. & Nahill, S. R. Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections. J. Exp. Med. 183, 2489–2499 (1996).
Hogan, R. J. et al. Activated antigen-specific CD8+ T Cells persist in the lungs following recovery from respiratory virus infections. J. Immunol. 166, 1813–1822 (2001).
Masopust, D., Vezys, V., Marzo, A. L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).
Razvi, E. S., Welsh, R. M. & McFarland, H. I. In vivo state of antiviral CTL precursors. Characterization of a cycling cell population containing CTL precursors in immune mice. J. Immunol. 154, 620–632 (1995).
Tabi, Z., Lynch, F., Ceredig, R., Allan, J. E. & Doherty, P. C. Virus-specific memory T cells are Pgp-1+ and can be selectively activated with phorbol ester and calcium ionophore. Cell Immunol. 113, 268–277 (1988).
Tough, D. F., Sun, S., Zhang, X. & Sprent, J. Stimulation of naïve and memory T cells by cytokines. Immunol. Rev. 170, 39–47 (1999).
Bradley, L. M., Croft, M. & Swain, S. L. T-cell memory: new perspectives. Immunol. Today 14, 197–199 (1993).
Selin, L. K. & Welsh, R. M. Cytolytically active memory CTL present in lymphocytic choriomeningitis virus-immune mice after clearance of virus infection. J. Immunol. 158, 5366–5373 (1997).
Yang, H. Y., Dundon, P. L., Nahill, S. R. & Welsh, R. M. Virus-induced polyclonal cytotoxic T lymphocyte stimulation. J. Immunol. 142, 1710–1718 (1989).
Selin, L. K., Nahill, S. R. & Welsh, R. M. Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses. J. Exp. Med. 179, 1933–1943 (1994).
Kuwano, K., Reyes, V. E., Humphreys, R. E. & Ennis, F. A. Recognition of disparate HA and NS1 peptides by an H-2Kd-restricted, influenza specific CTL clone. Mol. Immunol. 28, 1–7 (1991).
Shimojo, N., Maloy, W. L., Anderson, R. W., Biddison, W. E. & Coligan, J. E. Specificity of peptide binding by the HLA-A2.1 molecule. J. Immunol. 143, 2939–2947 (1989).
Loftus, D. J., Chen, Y., Covell, D. G., Engelhard, V. H. & Appella, E. Differential contact of disparate class I/peptide complexes as the basis for epitope cross-recognition by a single T cell receptor. J. Immunol. 158, 3651–3658 (1997).
Mason, D. A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol. Today 19, 395–404 (1998).
Selin, L. K., Varga, S. M., Wong, I. C. & Welsh, R. M. Protective heterologous antiviral immunity and enhanced immunopathogenesis mediated by memory T cell populations. J. Exp. Med. 188, 1705–1715 (1998).
Pabst, R. Is BALT a major component of the human lung immune system? Immunol. Today 13, 119–122 (1992).
Elson, C. O. In defense of mucosal surfaces. Regulation and manipulation of the mucosal immune system. Adv. Exp. Med. Biol. 412, 373–385 (1997).
Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996).
Callan, M. F. et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus In vivo. J. Exp. Med. 187, 1395–1402 (1998).
Selin, L. K. et al. Attrition of T cell memory: selective loss of LCMV epitope-specific memory CD8+ T cells following infections with heterologous viruses. Immunity 11, 733–742 (1999).
Greten, T. F. et al. Direct visualization of antigen-specific T cells: HTLV-1 Tax11-19- specific CD8+ T cells are activated in peripheral blood and accumulate in cerebrospinal fluid from HAM/TSP patients. Proc. Natl Acad. Sci. USA 95, 7568–7573 (1998).
Welsh, R. M. in Encyclopedia of Virology (eds Granoff, A. & Webster, R. G.) 915–925 (Academic Press, New York, 1999).
Welsh, R. M. in Effects of Microbes on the Immune System (eds Cunningham, M. W. & Fujinami, R. S.) 289–312 (Lippincott William & Wilkins, Philadephia, 2000).
Marrie, T. J. & Saron, M. F. Seroprevalence of lymphocytic choriomeningitis virus in Nova Scotia. Am. J. Trop. Med. Hyg. 58, 47–49 (1998).
Whitton, J. L., Southern, P. J. & Oldstone, M. B. Analyses of the cytotoxic T lymphocyte responses to glycoprotein and nucleoprotein components of lymphocytic choriomeningitis virus. Virology 162, 321–327 (1988).
van der Most, R. G. et al. Identification of Db- and Kb-restricted subdominant cytotoxic T-cell responses in lymphocytic choriomeningitis virus-infected mice. Virology 240, 158–167 (1998).
Blattman, J. N., Sourdive, D. J., Murali-Krishna, K., Ahmed, R. & Altman, J. D. Evolution of the T cell repertoire during primary, memory, and recall responses to viral infection. J. Immunol. 165, 6081–6090 (2000).
Fenner, F., Henderson, D. A., Arital, I., Ladnyi, I. D. & Jezek, Z. Smallpox and its Eradication (World Health Organization, Geneva, 1988).
Tufariello, J., Cho, S. & Horwitz, M. S. The adenovirus E3 14.7-kilodalton protein which inhibits cytolysis by tumor necrosis factor increases the virulence of vaccinia virus in a murine pneumonia model. J. Virol. 68, 453–462 (1994).
Selin, L. K., Lin, M. Y., Varga, S. M. & Welsh, R. M. in Cytotoxic Cells: Basic mechanisms and medical applications (eds Sitkovsky, M. V. & Henkart, P. A.) 327–361 (Lippincott Williams & Wilkins, Philadelphia, 2000).
Butz, E. A. & Bevan, M. J. Massive expansion of antigen-specific CD8+ T cells during an acute virus infection. Immunity 8, 167–175 (1998).
Selin, L. K., Santolucito, P. A., Pinto, A. K., Szomolanyi-Tsuda, E. & Welsh, R. M. Innate Immunity to Viruses: Control of Vaccinia Virus Infection by γ/δ T Cells. J. Immunol. 166, 6784–6794 (2001).
Tay, C. H. et al. The role of LY49 NK cell subsets in the regulation of murine cytomegalovirus infections. J. Immunol. 162, 718–726 (1999).
Muller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994).
Mahalingam, S., Foster, P. S., Lobigs, M., Farber, J. M. & Karupiah, G. Interferon-inducible chemokines and immunity to poxvirus infections. Immunol. Rev. 177, 127–133 (2000).
Skinner, P. J., Daniels, M. A., Schmidt, C. S., Jameson, S. C. & Haase, A. T. Cutting edge: In situ tetramer staining of antigen-specific T cells in tissues. J. Immunol. 165, 613–617 (2000).
Haanen, J. B. et al. In situ detection of virus- and tumor-specific T-cell immunity. Nature Med. 6, 1056–1060 (2000).
Gairin, J. E., Mazarguil, H., Hudrisier, D. & Oldstone, M. B. Optimal lymphocytic choriomeningitis virus sequences restricted by H- 2Db major histocompatibility complex class I molecules and presented to cytotoxic T lymphocytes. J. Virol. 69, 2297–2305 (1995).
Schlesinger, C., Meyer, C. A., Veeraraghavan, S. & Koss, M. N. Constrictive (obliterative) bronchiolitis: diagnosis, etiology, and a critical review of the literature. Ann. Diag. Pathol. 2, 321–334 (1998).
Ehl, S., Hombach, J., Aichele, P., Hengartner, H. & Zinkernagel, R. M. Bystander activation of cytotoxic T cells: studies on the mechanism and evaluation of in vivo significance in a transgenic mouse model. J. Exp. Med. 185, 1241–1251 (1997).
Zarozinski, C. C. & Welsh, R. M. Minimal bystander activation of CD8+ T cells during the virus-induced polyclonal T cell response. J. Exp. Med. 185, 1629–1639 (1997).
Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).
Champagne, P. et al. Skewed maturation of memory HIV-specific CD8+ T lymphocytes. Nature 410, 106–111 (2001).
Rickinson, A. B. & Kieff, E. in Virology (eds Fields, B. N. et al.) 2397–2446 (Lippincott-Raven Publishers, Philadephia, 1996).
Weinstein, L. & Meade, R. H. Respiratory manifestations of chickenpox. Arch. Intern. Med. 98, 91–99 (1956).
Simonsen, L. et al. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J. Infect. Dis. 178, 53–60 (1998).
Amara, R. R. et al. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292, 69–74 (2001).
Seth, A. et al. Recombinant modified vaccinia virus Ankara-simian immunodeficiency virus gag pol elicits cytotoxic T lymphocytes in rhesus monkeys detected by a major histocompatibility complex class I/peptide tetramer. Proc. Natl Acad. Sci. USA 95, 10112–10116 (1998).
Shirakawa, T., Enomoto, T., Shimazu, S. & Hopkin, J. M. The inverse association between tuberculin responses and atopic disorder. Science 275, 77–79 (1997).
Erb, K. J., Holloway, J. W., Sobeck, A., Moll, H. & Le Gros, G. Infection of mice with Mycobacterium bovis-Bacillus Calmette-Guerin (BCG) suppresses allergen-induced airway eosinophilia. J. Exp. Med. 187, 561–569 (1998).
Martinez, F. D. et al. Asthma and wheezing in the first six years of life. N. Engl. J. Med. 332, 133–138 (1995).
Walzl, G., Tafuro, S., Moss, P., Openshaw, P. J. & Hussell, T. Influenza virus lung infection protects from respiratory syncytial virus-induced immunopathology. J. Exp. Med. 192, 1317–1326 (2000).
Mathew, A. et al. Dominant recognition by human CD8+ cytotoxic T lymphocytes of dengue virus nonstructural proteins NS3 and NS1.2a. J. Clin. Invest. 98, 1684–1691 (1996).
Khalil, N. & Greenberg, A. H. Natural killer cell regulation of murine embryonic pulmonary fibroblast survival in vivo. Cell Immunol. 120, 439–449 (1989).
Mylin, L. M. et al. Quantitation of CD8(+) T-lymphocyte responses to multiple epitopes from simian virus 40 (SV40) large T antigen in C57BL/6 mice immunized with SV40, SV40 T-antigen-transformed cells, or vaccinia virus recombinants expressing full-length T antigen or epitope minigenes. J. Virol. 74, 6922–6934 (2000).
We thank S. S. Tevethia for assistance with the MHC tetramer protocols; D. M. Pardoll, J. P. Schneck and K. A. Kraemer for providing reagents, protocols and help in making IgG1 MHC dimers; and Y. Liu for technical assistance. Supported by National Institutes of Health research grants AR-35506 (to R. M. W.), AI-46578 (to L. K. S.) and Center Grant DK32520 (to I. J.). The contents of this publication are solely the responsibility of the authors and do not represent the official view of the National Institute of Health.
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Chen, H., Fraire, A., Joris, I. et al. Memory CD8+ T cells in heterologous antiviral immunity and immunopathology in the lung. Nat Immunol 2, 1067–1076 (2001). https://doi.org/10.1038/ni727
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