Ahmed, R. & Gray, D. Immunological memory and protective immunity: understanding their relation. Science 272, 54–60 (1996).
Sallusto, F., Lenig, D., Förster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).
Masopust, D., Vezys, V., Marzo, A. L. & Lefrançois, 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).
Mackay, C. R., Marston, W. L. & Dudler, L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J. Exp. Med. 171, 801–817 (1990).
Mackay, C. R. et al. Tissue-specific migration pathways by phenotypically distinct subpopulations of memory T cells. Eur. J. Immunol. 22, 887–895 (1992).
Gebhardt, T. 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).
This paper shows for the first time that TRM cells provide enhanced immunity against infection.
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).
Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010).
Klonowski, K. D. et al. Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity 20, 551–562 (2004).
Jiang, X. et al. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 483, 227–231 (2012).
Schenkel, J. M., Fraser, K. A., Vezys, V. & Masopust, D. Sensing and alarm function of resident memory CD8+ T cells. Nat. Immunol. 14, 509–513 (2013).
Iijima, N. & Iwasaki, A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science 346, 93–98 (2014).
Teijaro, J. R. et al. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187, 5510–5514 (2011).
Glennie, N. D. et al. Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection. J. Exp. Med. 212, 1405–1414 (2015).
Masopust, D. & Schenkel, J. M. The integration of T cell migration, differentiation and function. Nat. Rev. Immunol. 13, 309–320 (2013).
Steinert, E. M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).
Bergsbaken, T. & Bevan, M. J. Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8+ T cells responding to infection. Nat. Immunol. 16, 406–414 (2015).
Schenkel, J. M., Fraser, K. A. & Masopust, D. Cutting edge: resident memory CD8 T cells occupy frontline niches in secondary lymphoid organs. J. Immunol. 192, 2961–2964 (2014).
Anderson, K. G. et al. Cutting edge: intravascular staining redefines lung CD8 T cell responses. J. Immunol. 189, 2702–2706 (2012).
This paper shows the use of intravascular labelling for the identification of tissue-associated cells.
Mackay, L. K. et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).
This study defines the developmental pathway and core transcriptional signature of tissue-resident CD103+CD8+ memory T cells.
Skon, C. N. et al. Transcriptional downregulation of S1PR1 is required for the establishment of resident memory CD8+ T cells. Nat. Immunol. 14, 1285–1293 (2013).
This paper provides evidence that the expression of molecules associated with tissue egress needs to be downregulated for TRM cell generation.
Bromley, S. K., Thomas, S. Y. & Luster, A. D. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat. Immunol. 6, 895–901 (2005).
Debes, G. F. et al. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat. Immunol. 6, 889–894 (2005).
Tomura, M., Itoh, K. & Kanagawa, O. Naive CD4+ T lymphocytes circulate through lymphoid organs to interact with endogenous antigens and upregulate their function. J. Immunol. 184, 4646–4653 (2010).
Casey, K. A. et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J. Immunol. 188, 4866–4875 (2012).
Hofmann, M., Oschowitzer, A., Kurzhals, S. R., Kruger, C. C. & Pircher, H. Thymus-resident memory CD8+ T cells mediate local immunity. Eur. J. Immunol. 43, 2295–2304 (2013).
Hofmann, M. & Pircher, H. E-cadherin promotes accumulation of a unique memory CD8 T cell population in murine salivary glands. Proc. Natl Acad. Sci. USA 108, 16741–16746 (2011).
Wakim, L. M., Woodward-Davis, A. & Bevan, M. J. Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc. Natl Acad. Sci. USA 107, 17872–17879 (2010).
Anderson, K. G. et al. Intravascular staining for discrimination of vascular and tissue leukocytes. Nat. Protoc. 9, 209–222 (2014).
Tse, S. W., Cockburn, I. A., Zhang, H., Scott, A. L. & Zavala, F. Unique transcriptional profile of liver-resident memory CD8+ T cells induced by immunization with malaria sporozoites. Genes Immun. 14, 302–309 (2013).
Lynch, L. et al. Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of TReg cells and macrophages in adipose tissue. Nat. Immunol. 16, 85–95 (2015).
Peng, H. et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest. 123, 1444–1456 (2013).
Sojka, D. K. et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife 3, e01659 (2014).
Thomas, S. Y. et al. PLZF induces an intravascular surveillance program mediated by long-lived LFA–1-ICAM-1 interactions. J. Exp. Med. 208, 1179–1188 (2011).
Schenkel, J. M. & Masopust, D. Tissue-resident memory T cells. Immunity 41, 886–897 (2014).
Clark, R. A. et al. The vast majority of CLA+ T cells are resident in normal skin. J. Immunol. 176, 4431–4439 (2006).
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).
Cheuk, S. et al. Epidermal TH22 and TC17 cells form a localized disease memory in clinically healed psoriasis. J. Immunol. 192, 3111–3120 (2014).
Clark, R. A. et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci. Trans. Med. 4, 117ra7 (2012).
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).
Zhu, J. et al. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nat. Med. 15, 886–892 (2009).
Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).
Zhu, J. et al. Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection. Nature 497, 494–497 (2013).
Sathaliyawala, T. et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 38, 187–197 (2013).
Thome, J. J. et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159, 814–828 (2014).
References 45 and 46 provide a comprehensive evaluation of T cell distribution in human tissues.
Chang, J. T., Wherry, E. J. & Goldrath, A. W. Molecular regulation of effector and memory T cell differentiation. Nat. Immunol. 15, 1104–1115 (2014).
Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012).
Intlekofer, A. M. et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 6, 1236–1244 (2005).
Zhou, X. et al. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33, 229–240 (2010).
Wakim, L. M. et al. The molecular signature of tissue resident memory CD8 T cells isolated from the brain. J. Immunol. 189, 3462–3471 (2012).
Laidlaw, B. J. et al. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41, 633–645 (2014).
Gaide, O. et al. Common clonal origin of central and resident memory T cells following skin immunization. Nat. Med. 21, 647–653 (2015).
Sowell, R. T., Rogozinska, M., Nelson, C. E., Vezys, V. & Marzo, A. L. Cutting edge: generation of effector cells that localize to mucosal tissues and form resident memory CD8 T cells is controlled by mTOR. J. Immunol. 193, 2067–2071 (2014).
Slutter, B., Pewe, L. L., Kaech, S. M. & Harty, J. T. Lung airway-surveilling CXCR3hi memory CD8+ T cells are critical for protection against influenza A virus. Immunity 39, 939–948 (2013).
Mackay, L. K. et al. Cutting Edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention. J. Immunol. 194, 2059–2063 (2015).
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).
Ugur, M., Schulz, O., Menon, M. B., Krueger, A. & Pabst, O. Resident CD4+ T cells accumulate in lymphoid organs after prolonged antigen exposure. Nat. Commun. 5, 4821 (2014).
Sheridan, B. S. et al. Oral infection drives a distinct population of intestinal resident memory CD8+ T cells with enhanced protective function. Immunity 40, 747–757 (2014).
Zhang, N. & Bevan, M. J. Transforming growth factor-β signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity 39, 687–696 (2013).
Hu, Y., Lee, Y. T., Kaech, S. M., Garvy, B. & Cauley, L. S. SMAD4 promotes differentiation of effector and circulating memory CD8 T cells but is dispensable for tissue-resident memory CD8 T cells. J. Immunol. 194, 2407–2414 (2015).
Nakanishi, Y., Lu, B., Gerard, C. & Iwasaki, A. CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 462, 510–513 (2009).
Laidlaw, B. J., Craft, J. E. & Kaech, S. M. The multifacted role of CD4+ T cells in CD8+ T cell memory. Nat. Rev. Immunol. (in the press).
Mackay, L. K. et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc. Natl Acad. Sci. USA 109, 7037–7042 (2012).
Shin, H. & Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463–467 (2012).
Mackay, L. K. et al. Maintenance of T cell function in the face of chronic antigen stimulation and repeated reactivation for a latent virus infection. J. Immunol. 188, 2173–2178 (2012).
Zammit, D. J., Turner, D. L., Klonowski, K. D., Lefrançois, L. & Cauley, L. S. Residual antigen presentation after influenza virus infection affects CD8 T cell activation and migration. Immunity 24, 439–449 (2006).
Grundemann, C. et al. Cutting edge: identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1. J. Immunol. 176, 1311–1315 (2006).
Masopust, D., Vezys, V., Wherry, E. J., Barber, D. L. & Ahmed, R. Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J. Immunol. 176, 2079–2083 (2006).
This paper shows that the tissue microenvironment influences local T cell differentiation.
Lee, Y. T. et al. Environmental and antigen receptor-derived signals support sustained surveillance of the lungs by pathogen-specific cytotoxic T lymphocytes. J. Virol. 85, 4085–4094 (2011).
Zaid, A. et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl Acad. Sci. USA 111, 5307–5312 (2014).
Kadow, S. et al. Aryl hydrocarbon receptor is critical for homeostasis of invariant γδ T cells in the murine epidermis. J. Immunol. 187, 3104–3110 (2011).
Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).
Naik, S. et al. Commensal–dendritic cell interaction specifies a unique protective skin immune signature. Nature 520, 104–108 (2015).
Vezys, V. et al. Memory CD8 T cell compartment grows in size with immunological experience. Nature 457, 196–199 (2009).
Ariotti, S. et al. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc. Natl Acad. Sci. USA 109, 19739–19744 (2012).
Mueller, S. N., Zaid, A. & Carbone, F. R. Tissue-resident T cells: dynamic players in skin immunity. Front. Immunol. 5, 332 (2014).
Natsuaki, Y. et al. Perivascular leukocyte clusters are essential for efficient activation of effector T cells in the skin. Nat. Immunol. 15, 1064–1069 (2014).
Badovinac, V. P., Haring, J. S. & Harty, J. T. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8+ T cell response to infection. Immunity 26, 827–841 (2007).
Woodland, D. L. & Kohlmeier, J. E. Migration, maintenance and recall of memory T cells in peripheral tissues. Nat. Rev. Immunol. 9, 153–161 (2009).
Wherry, E. J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).
Yang, L., Yu, Y., Kalwani, M., Tseng, T.-W. J. & Baltimore, D. Homeostatic cytokines orchestrate the segregation of CD4 and CD8 memory T cell reservoirs in mice. Blood 118, 3039–3050 (2011).
Fraser, K. A., Schenkel, J. M., Jameson, S. C., Vezys, V. & Masopust, D. Preexisting high frequencies of memory CD8+ T cells favor rapid memory differentiation and preservation of proliferative potential upon boosting. Immunity 39, 171–183 (2013).
Hansen, S. G. et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat. Med. 15, 293–299 (2009).
Schmidt, N. W. et al. Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria. Proc. Natl Acad. Sci. USA 105, 14017–14022 (2008).
Schenkel, J. M. et al. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).
McMaster, S. R. et al. Memory T cells generated by prior exposure to influenza cross react with the novel H7N9 influenza virus and confer protective heterosubtypic immunity. PLoS ONE 10, e0115725 (2015).
Ariotti, S. et al. T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 346, 101–105 (2014).
References 86 and 88 show that TRM cells can function as innate sensors of infection, triggering an antiviral state in the tissue.
Stary, G. et al. Vaccines. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science 348, aaa8205 (2015).
Turner, D. L. & Farber, D. L. Mucosal resident memory CD4 T cells in protection and immunopathology. Front. Immunol. 5, 331 (2014).
Yawalkar, N., Hunger, R. E., Pichler, W. J., Braathen, L. R. & Brand, C. U. Human afferent lymph from normal skin contains an increased number of mainly memory/effector CD4+ T cells expressing activation, adhesion and co-stimulatory molecules. Eur. J. Immunol. 30, 491–497 (2000).
Turner, D. L. et al. Lung niches for the generation and maintenance of tissue-resident memory T cells. Mucosal Immunol. 7, 501–510 (2014).
Geissmann, F. et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol. 3, e113 (2005).
Burzyn, D., Benoist, C. & Mathis, D. Regulatory T cells in nonlymphoid tissues. Nat. Immunol. 14, 1007–1013 (2013).
Smigiel, K. S. et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J. Exp. Med. 211, 121–136 (2014).
Chennupati, V. et al. Intra- and intercompartmental movement of γδ T cells: intestinal intraepithelial and peripheral γδ T cells represent exclusive nonoverlapping populations with distinct migration characteristics. J. Immunol. 185, 5160–5168 (2010).
Fuchs, A. et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. Immunity 38, 769–781 (2013).
Joshi, N. S. et al. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281–295 (2007).
Pearce, E. L. et al. Control of effector CD8+ T cell function by the transcription factor eomesodermin. Science 302, 1041–1043 (2003).
Yang, C. Y. et al. The transcriptional regulators ID2 and ID3 control the formation of distinct memory CD8+ T cell subsets. Nat. Immunol. 12, 1221–1229 (2011).
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).
Purwar, R. et al. Resident memory T cells (TRM) are abundant in human lung: diversity, function, and antigen specificity. PLoS ONE 6, e16245 (2011).
Wakim, L. M., Gupta, N., Mintern, J. D. & Villadangos, J. A. Enhanced survival of lung tissue-resident memory CD8+ T cells during infection with influenza virus due to selective expression of IFITM3. Nat. Immunol. 14, 238–245 (2013).
Wu, T. et al. Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J. Leukoc. Biol. 95, 215–224 (2014).
Cuburu, N. et al. Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses. J. Clin. Invest. 122, 4606–4620 (2012).