Abstract
Effective immunity is dependent on long-surviving memory T cells. Various memory subsets make distinct contributions to immune protection, especially in peripheral infection. It has been suggested that T cells in nonlymphoid tissues are important during local infection, although their relationship with populations in the circulation remains poorly defined. Here we describe a unique memory T cell subset present after acute infection with herpes simplex virus that remained resident in the skin and in latently infected sensory ganglia. These T cells were in disequilibrium with the circulating lymphocyte pool and controlled new infection with this virus. Thus, these cells represent an example of tissue-resident memory T cells that can provide protective immunity at points of pathogen entry.
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References
Welsh, R.M., Selin, L.K. & Szomolanyi-Tsuda, E. Immunological memory to viral infections. Annu. Rev. Immunol. 22, 711–743 (2004).
Bachmann, M.F., Kundig, T.M., Hengartner, H. & Zinkernagel, R.M. Protection against immunopathological consequences of a viral infection by activated but not resting cytotoxic T cells: T cell memory without “memory T cells”? Proc. Natl. Acad. Sci. USA 94, 640–645 (1997).
Bachmann, M.F., Wolint, P., Schwarz, K. & Oxenius, A. Recall proliferation potential of memory CD8+ T cells and antiviral protection. J. Immunol. 175, 4677–4685 (2005).
Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).
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).
Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).
Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).
Reinhardt, R.L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M.K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001).
Kaech, S.M., Wherry, E.J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nat. Rev. Immunol. 2, 251–262 (2002).
Clark, R.A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006).
Hikono, H. et al. T-cell memory and recall responses to respiratory virus infections. Immunol. Rev. 211, 119–132 (2006).
Harris, N.L., Watt, V., Ronchese, F. & Le Gros, G. Differential T cell function and fate in lymph node and nonlymphoid tissues. J. Exp. Med. 195, 317–326 (2002).
Klonowski, K.D. et al. Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity 20, 551–562 (2004).
Masopust, D. et al. Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. J. Immunol. 172, 4875–4882 (2004).
Hawke, S., Stevenson, P.G., Freeman, S. & Bangham, C.R. Long-term persistence of activated cytotoxic T lymphocytes after viral infection of the central nervous system. J. Exp. Med. 187, 1575–1582 (1998).
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).
Simmons, A. & Nash, A.A. Zosteriform spread of herpes simplex virus as a model of recrudescence and its use to investigate the role of immune cells in prevention of recurrent disease. J. Virol. 52, 816–821 (1984).
van Lint, A. et al. Herpes simplex virus-specific CD8+ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation. J. Immunol. 172, 392–397 (2004).
Stanberry, L.R. Pathogenesis of herpes simplex virus infection and animal models for its study. Curr. Top. Microbiol. Immunol. 179, 15–30 (1992).
Simmons, A. & Tscharke, D.C. Anti-CD8 impairs clearance of herpes simplex virus from the nervous system: implications for the fate of virally infected neurons. J. Exp. Med. 175, 1337–1344 (1992).
Khanna, K.M., Bonneau, R.H., Kinchington, P.R. & Hendricks, R.L. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia. Immunity 18, 593–603 (2003).
Wakim, L.M., Waithman, J., van Rooijen, N., Heath, W.R. & Carbone, F.R. Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science 319, 198–202 (2008).
Liu, T., Khanna, K.M., Chen, X., Fink, D.J. & Hendricks, R.L. CD8+ T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons. J. Exp. Med. 191, 1459–1466 (2000).
Mueller, S.N., Heath, W., McLain, J.D., Carbone, F.R. & Jones, C.M. Characterization of two TCR transgenic mouse lines specific for herpes simplex virus. Immunol. Cell Biol. 80, 156–163 (2002).
Stock, A.T., Jones, C.M., Heath, W.R. & Carbone, F.R. CTL response compensation for the loss of an immunodominant class I-restricted HSV-1 determinant. Immunol. Cell Biol. 84, 543–550 (2006).
Cepek, K.L. et al. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the αEβ7 integrin. Nature 372, 190–193 (1994).
Pauls, K. et al. Role of integrin αE(CD103)β7 for tissue-specific epidermal localization of CD8+ T lymphocytes. J. Invest. Dermatol. 117, 569–575 (2001).
Hemler, M.E. VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu. Rev. Immunol. 8, 365–400 (1990).
Ray, S.J. et al. The collagen binding α1β1 integrin VLA-1 regulates CD8 T cell-mediated immune protection against heterologous influenza infection. Immunity 20, 167–179 (2004).
Ely, K.H., Cookenham, T., Roberts, A.D. & Woodland, D.L. Memory T cell populations in the lung airways are maintained by continual recruitment. J. Immunol. 176, 537–543 (2006).
Hogan, R.J. et al. Long-term maintenance of virus-specific effector memory CD8+ T cells in the lung airways depends on proliferation. J. Immunol. 169, 4976–4981 (2002).
Zammit, D.J., Turner, D.L., Klonowski, K.D., Lefrancois, L. & Cauley, L.S. Residual antigen presentation after influenza virus infection affects CD8 T cell activation and migration. Immunity 24, 439–449 (2006).
Nash, A.A. et al. Different roles for L3T4+ and Lyt2+ T cell subsets in the control of an acute herpes simplex virus infection of the skin and nervous system. J. Gen. Virol. 68, 825–833 (1987).
Jennings, S.R., Bonneau, R.H., Smith, P.M., Wolcott, R.M. & Chervenak, R. CD4-positive T lymphocytes are required for the generation of the primary but not the secondary CD8-positive cytolytic T lymphocyte response to herpes simplex virus in C57BL/6 mice. Cell. Immunol. 133, 234–252 (1991).
Smith, C.M. et al. Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat. Immunol. 5, 1143–1148 (2004).
Mintern, J.D., Davey, G.M., Belz, G.T., Carbone, F.R. & Heath, W.R. Cutting edge: precursor frequency affects the helper dependence of cytotoxic T cells. J. Immunol. 168, 977–980 (2002).
Knickelbein, J.E. et al. Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322, 268–271 (2008).
Liu, T., Khanna, K.M., Carriere, B.N. & Hendricks, R.L. Gamma interferon can prevent herpes simplex virus type 1 reactivation from latency in sensory neurons. J. Virol. 75, 11178–11184 (2001).
van Lint, A.L. et al. Latent infection with herpes simplex virus is associated with ongoing CD8+ T-cell stimulation by parenchymal cells within sensory ganglia. J. Virol. 79, 14843–14851 (2005).
Mintern, J.D., Guillonneau, C., Carbone, F.R., Doherty, P.C. & Turner, S.J. Cutting edge: tissue-resident memory CTL down-regulate cytolytic molecule expression following virus clearance. J. Immunol. 179, 7220–7224 (2007).
Campbell, D.J. & Butcher, E.C. Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lymphoid tissues. J. Exp. Med. 195, 135–141 (2002).
Mora, J.R. & von Andrian, U.H. T-cell homing specificity and plasticity: new concepts and future challenges. Trends Immunol. 27, 235–243 (2006).
Zhu, J. et al. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J. Exp. Med. 204, 595–603 (2007).
Mizukawa, Y. et al. Direct evidence for interferon-γ production by effector-memory-type intraepidermal T cells residing at an effector site of immunopathology in fixed drug eruption. Am. J. Pathol. 161, 1337–1347 (2002).
Shiohara, T. & Moriya, N. Epidermal T cells: their functional role and disease relevance for dermatologists. J. Invest. Dermatol. 109, 271–275 (1997).
Boyman, O. et al. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-α. J. Exp. Med. 199, 731–736 (2004).
Stock, A.T. et al. Optimization of TCR transgenic T cells for in vivo tracking of immune responses. Immunol. Cell Biol. 85, 394–396 (2007).
Acknowledgements
We thank S. Tevethia (Pennsylvania State University) for WSN/NA/gB; P. Doherty (The University of Melbourne) for WSN/NA/OVA; J. Yewdell (U.S. National Institutes of Health) for vaccinia-NP.; D. Masopust for discussions; and H. Kosaka for suggesting that fixed drug eruptions are caused by resident T cells. Supported by the Australian National Health and Medical Research Council, the Howard Hughes Medical Institute and the German Research Foundation (GE1666/1-1 to T.G.).
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Gebhardt, T., Wakim, L., Eidsmo, L. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 10, 524–530 (2009). https://doi.org/10.1038/ni.1718
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DOI: https://doi.org/10.1038/ni.1718
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