Tissue-Resident Memory T Cells

Tissue-resident memory T (Trm) cells constitute a recently identified lymphocyte lineage that occupies tissues without recirculating. They provide a first response against infections reencountered at body surfaces, where they accelerate pathogen clearance. Because Trm cells are not present within peripheral blood, they have not yet been well characterized, but are transcriptionally, phenotypically, and functionally distinct from recirculating central and effector memory T cells. In this review, we will summarize current knowledge of Trm cell ontogeny, regulation, maintenance, and function and will highlight technical considerations for studying this population. Tissue-resident memory T (Trm) cells constitute a recently identified lymphocyte lineage that occupies tissues without recirculating. They provide a first response against infections reencountered at body surfaces, where they accelerate pathogen clearance. Because Trm cells are not present within peripheral blood, they have not yet been well characterized, but are transcriptionally, phenotypically, and functionally distinct from recirculating central and effector memory T cells. In this review, we will summarize current knowledge of Trm cell ontogeny, regulation, maintenance, and function and will highlight technical considerations for studying this population. Observations of phenotypic heterogeneity in the expression of homing receptors by human memory CD8+ and CD4+ T cells led to the conceptualization that memory T cells could be parsed into two subsets, which were labeled central memory (Tcm) and effector memory (Tem) cells (Sallusto et al., 1999Sallusto F. Lenig D. Förster R. Lipp M. Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.Nature. 1999; 401: 708-712Crossref PubMed Scopus (3421) Google Scholar). Importantly, this analysis was done in blood. Because Tcm and Tem cells not only expressed distinct homing receptors, but also unique effector properties, it was conceived that immunosurveillance patterns were intrinsically coupled with functional specialization. Much like naive T cells, Tcm cells patrol secondary lymphoid organs (SLOs), which include lymph nodes (LNs) and the white pulp (WP) of spleen (Figure 1) (von Andrian and Mackay, 2000von Andrian U.H. Mackay C.R. T-cell function and migration. Two sides of the same coin.N. Engl. J. Med. 2000; 343: 1020-1034Crossref PubMed Scopus (974) Google Scholar, Sallusto et al., 1999Sallusto F. Lenig D. Förster R. Lipp M. Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.Nature. 1999; 401: 708-712Crossref PubMed Scopus (3421) Google Scholar). Also like naive T cells, after Ag-recognition Tcm cells undergo rapid and robust proliferation, differentiate into effector cells, and then migrate from SLOs to other tissues in search of infections to eliminate (von Andrian and Mackay, 2000von Andrian U.H. Mackay C.R. T-cell function and migration. Two sides of the same coin.N. Engl. J. Med. 2000; 343: 1020-1034Crossref PubMed Scopus (974) Google Scholar). Like recently stimulated effector T cells, upon antigen recognition Tem cells remain poised for rapid execution of certain effector functions, such as cytolysis of infected host cells, rather than for proliferation. Tem cells also lack LN homing receptors (CD62L and CCR7), yet expressed distinct patterns of other homing receptors, and on that basis it was proposed that Tem cells recirculate between blood and nonlymphoid tissues (NLTs) or remain poised to mobilize to sites of inflammation (Butcher and Picker, 1996Butcher E.C. Picker L.J. Lymphocyte homing and homeostasis.Science. 1996; 272: 60-66Crossref PubMed Google Scholar, Mackay et al., 1990Mackay C.R. Marston W.L. Dudler L. Naive and memory T cells show distinct pathways of lymphocyte recirculation.J. Exp. Med. 1990; 171: 801-817Crossref PubMed Google Scholar, Sallusto et al., 1999Sallusto F. Lenig D. Förster R. Lipp M. Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.Nature. 1999; 401: 708-712Crossref PubMed Scopus (3421) Google Scholar). Consistent with this model, memory T cells were observed in many NLTs long after Ag clearance (Masopust et al., 2001bMasopust D. Vezys V. Marzo A.L. Lefrançois L. Preferential localization of effector memory cells in nonlymphoid tissue.Science. 2001; 291: 2413-2417Crossref PubMed Scopus (1218) Google Scholar, Reinhardt et al., 2001Reinhardt R.L. Khoruts A. Merica R. Zell T. Jenkins M.K. Visualizing the generation of memory CD4 T cells in the whole body.Nature. 2001; 410: 101-105Crossref PubMed Scopus (744) Google Scholar). These observations provided a justification for extrapolating observations from blood Tem cells to T cells isolated from NLTs, which was convenient because blood lymphocytes are far easier to sample. However, some observations were not consistent with the model that all NLT memory cells were recirculating Tem cells. For instance, for T cells to recirculate through NLTs they must enter from the blood and exit via afferent lymphatics. Elegant work demonstrated paradoxically that CCR7 expression by T cells might be required for egress from NLT (Bromley et al., 2005Bromley 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. 2005; 6: 895-901Crossref PubMed Scopus (263) Google Scholar, Debes et al., 2005Debes G.F. Arnold C.N. Young A.J. Krautwald S. Lipp M. 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This prompted speculation that memory T cells permanently resided within certain NLTs rather than recirculate through blood (Masopust et al., 2001bMasopust D. Vezys V. Marzo A.L. Lefrançois L. Preferential localization of effector memory cells in nonlymphoid tissue.Science. 2001; 291: 2413-2417Crossref PubMed Scopus (1218) Google Scholar). These discrepancies were partly clarified upon the clear demonstration that populations of memory T cells were settled within many NLTs (Figure 1) (Gebhardt et al., 2009Gebhardt T. Wakim L.M. Eidsmo L. Reading P.C. Heath W.R. Carbone F.R. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus.Nat. Immunol. 2009; 10: 524-530Crossref PubMed Scopus (327) Google Scholar, Jiang et al., 2012Jiang X. Clark R.A. Liu L. Wagers A.J. Fuhlbrigge R.C. Kupper T.S. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity.Nature. 2012; 483: 227-231Crossref PubMed Scopus (215) Google Scholar, Masopust et al., 2010Masopust D. Choo D. Vezys V. Wherry E.J. Duraiswamy J. Akondy R. Wang J. Casey K.A. Barber D.L. Kawamura K.S. et al.Dynamic T cell migration program provides resident memory within intestinal epithelium.J. Exp. Med. 2010; 207: 553-564Crossref PubMed Scopus (182) Google Scholar, Teijaro et al., 2011Teijaro J.R. Turner D. Pham Q. Wherry E.J. Lefrançois L. Farber D.L. Cutting edge: Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection.J. Immunol. 2011; 187: 5510-5514Crossref PubMed Scopus (135) Google Scholar, Wakim et al., 2010Wakim 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. 2010; 107: 17872-17879Crossref PubMed Scopus (154) Google Scholar). These tissue-resident memory T cells (abbreviated Trm cells to distinguish them from Tcm and Tem cells) derived from precursors that entered tissues during the effector phase of immune responses and remained positioned within this compartment. The identification of this memory T cell lineage precipitated many new questions. How are Trm cells regulated? When and how are they established? How are Trm cells maintained and for how long? How do they function and contribute to protective immunity? This review will summarize basic concepts in Trm cell biology, will draw attention to important technical considerations for their study, and will highlight remaining gaps within the field. It should be noted that the existing literature is more developed for CD8+ rather than CD4+ Trm cells, and the review will reflect this focus. T cell recirculation is a dynamic and active process that is regulated during all phases of immune responses (von Andrian and Mackay, 2000von Andrian U.H. Mackay C.R. T-cell function and migration. Two sides of the same coin.N. Engl. J. Med. 2000; 343: 1020-1034Crossref PubMed Scopus (974) Google Scholar, Masopust and Schenkel, 2013Masopust D. Schenkel J.M. The integration of T cell migration, differentiation and function.Nat. Rev. Immunol. 2013; 13: 309-320Crossref PubMed Scopus (107) Google Scholar, Mueller et al., 2013Mueller S.N. Gebhardt T. Carbone F.R. Heath W.R. Memory T cell subsets, migration patterns, and tissue residence.Annu. Rev. Immunol. 2013; 31: 137-161Crossref PubMed Scopus (171) Google Scholar). Naive T cells enter SLOs from blood using a combination of selectins, chemokines, and integrins, and then patrol for 12–24 hr before leaving to explore other SLOs in their continuous quest for cognate Ag (von Andrian and Mackay, 2000von Andrian U.H. Mackay C.R. 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When naive T cells are productively primed within SLOs, they give rise to effector cells that migrate throughout the host and leave behind a memory population that persists long after pathogen clearance (Dutton et al., 1998Dutton R.W. Bradley L.M. Swain S.L. T cell memory.Annu. Rev. Immunol. 1998; 16: 201-223Crossref PubMed Scopus (0) Google Scholar, Harty and Badovinac, 2008Harty J.T. Badovinac V.P. Shaping and reshaping CD8+ T-cell memory.Nat. Rev. Immunol. 2008; 8: 107-119Crossref PubMed Scopus (280) Google Scholar, Lefrançois, 2006Lefrançois L. Development, trafficking, and function of memory T-cell subsets.Immunol. Rev. 2006; 211: 93-103Crossref PubMed Scopus (0) Google Scholar, Sallusto et al., 2010Sallusto F. Lanzavecchia A. Araki K. Ahmed R. From vaccines to memory and back.Immunity. 2010; 33: 451-463Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, Williams and Bevan, 2007Williams M.A. Bevan M.J. Effector and memory CTL differentiation.Annu. Rev. 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Immunol. 2012; 188: 4866-4875Crossref PubMed Scopus (114) Google Scholar), the defining phenotype of a Tem cell. However, NLT-derived memory T cells also express many markers not shared by any circulating population of memory T cells within blood (Casey et al., 2012Casey K.A. Fraser K.A. Schenkel J.M. Moran A. Abt M.C. Beura L.K. Lucas P.J. Artis D. Wherry E.J. Hogquist K. et al.Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues.J. Immunol. 2012; 188: 4866-4875Crossref PubMed Scopus (114) Google Scholar, Gebhardt et al., 2009Gebhardt T. Wakim L.M. Eidsmo L. Reading P.C. Heath W.R. Carbone F.R. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus.Nat. Immunol. 2009; 10: 524-530Crossref PubMed Scopus (327) Google Scholar, Hawke et al., 1998Hawke 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. 1998; 187: 1575-1582Crossref PubMed Scopus (0) Google Scholar, Hofmann and Pircher, 2011Hofmann M. Pircher H. E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands.Proc. Natl. Acad. Sci. USA. 2011; 108: 16741-16746Crossref PubMed Scopus (52) Google Scholar, Jiang et al., 2012Jiang X. Clark R.A. Liu L. Wagers A.J. Fuhlbrigge R.C. Kupper T.S. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity.Nature. 2012; 483: 227-231Crossref PubMed Scopus (215) Google Scholar, Masopust et al., 2006Masopust 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. 2006; 176: 2079-2083Crossref PubMed Google Scholar, Ray et al., 2004Ray S.J. Franki S.N. Pierce R.H. Dimitrova S. Koteliansky V. 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USA. 2011; 108: 16741-16746Crossref PubMed Scopus (52) Google Scholar, Masopust et al., 2010Masopust D. Choo D. Vezys V. Wherry E.J. Duraiswamy J. Akondy R. Wang J. Casey K.A. Barber D.L. Kawamura K.S. et al.Dynamic T cell migration program provides resident memory within intestinal epithelium.J. Exp. Med. 2010; 207: 553-564Crossref PubMed Scopus (182) Google Scholar, Wakim et al., 2010Wakim 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. 2010; 107: 17872-17879Crossref PubMed Scopus (154) Google Scholar). Moreover, T cell populations within NLT grafts were not in equilibrium with host tissues when transplanted into isogenic recipients (Gebhardt et al., 2009Gebhardt T. Wakim L.M. Eidsmo L. Reading P.C. Heath W.R. Carbone F.R. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus.Nat. Immunol. 2009; 10: 524-530Crossref PubMed Scopus (327) Google Scholar, Masopust et al., 2010Masopust D. Choo D. Vezys V. Wherry E.J. Duraiswamy J. Akondy R. Wang J. Casey K.A. Barber D.L. Kawamura K.S. et al.Dynamic T cell migration program provides resident memory within intestinal epithelium.J. Exp. Med. 2010; 207: 553-564Crossref PubMed Scopus (182) Google Scholar). And when the vasculature of two mice was conjoined via parabiotic surgery, T cells did not equilibrate between the skin epidermis, female reproductive tract, or lung of each mouse (Iijima and Iwasaki, 2014Iijima N. Iwasaki A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells.Science. 2014; 346: 93-98Crossref PubMed Scopus (0) Google Scholar, Jiang et al., 2012Jiang X. Clark R.A. Liu L. Wagers A.J. Fuhlbrigge R.C. Kupper T.S. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity.Nature. 2012; 483: 227-231Crossref PubMed Scopus (215) Google Scholar, Schenkel et al., 2013Schenkel J.M. Fraser K.A. Vezys V. Masopust D. Sensing and alarm function of resident memory CD8+ T cells.Nat. Immunol. 2013; 14: 509-513Crossref PubMed Scopus (105) Google Scholar, Teijaro et al., 2011Teijaro J.R. Turner D. Pham Q. Wherry E.J. Lefrançois L. Farber D.L. Cutting edge: Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection.J. Immunol. 2011; 187: 5510-5514Crossref PubMed Scopus (135) Google Scholar). Taken together, these data indicate that NLTs contained populations of memory T cells that were not in circulation. Rather, they seeded NLTs during the effector phase of the response, and then became permanently established in situ (Hofmann and Pircher, 2011Hofmann M. Pircher H. E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands.Proc. Natl. Acad. Sci. USA. 2011; 108: 16741-16746Crossref PubMed Scopus (52) Google Scholar, Masopust et al., 2010Masopust D. Choo D. Vezys V. Wherry E.J. Duraiswamy J. Akondy R. Wang J. Casey K.A. Barber D.L. Kawamura K.S. et al.Dynamic T cell migration program provides resident memory within intestinal epithelium.J. Exp. Med. 2010; 207: 553-564Crossref PubMed Scopus (182) Google Scholar). These cells are now referred to as Trm. Examining the dynamics of phenotypic changes among antiviral CD8+ T cells within the small intestinal mucosa provides some insight into the ontogeny of Trm cells. After acute viral infections in mice and humans, effector T cells transiently upregulate α4β7 integrin, which facilitates migration into the small intestine (Campbell and Butcher, 2002Campbell 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. 2002; 195: 135-141Crossref PubMed Scopus (0) Google Scholar, Liu et al., 2006Liu L. Fuhlbrigge R.C. Karibian K. Tian T. Kupper T.S. Dynamic programming of CD8+ T cell trafficking after live viral immunization.Immunity. 2006; 25: 511-520Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, Masopust et al., 2010Masopust D. Choo D. Vezys V. Wherry E.J. Duraiswamy J. Akondy R. Wang J. Casey K.A. Barber D.L. Kawamura K.S. et al.Dynamic T cell migration program provides resident memory within intestinal epithelium.J. Exp. Med. 2010; 207: 553-564Crossref PubMed Scopus (182) Google Scholar). After acute viral infection in mice, α4β7 is rapidly downregulated after trafficking to gut, suggesting that recently arrived effector CD8+ T cells have lost capacity for re-entry after ingress (Masopust et al., 2010Masopust D. Choo D. Vezys V. Wherry E.J. Duraiswamy J. Akondy R. Wang J. Casey K.A. Barber D.L. Kawamura K.S. et al.Dynamic T cell migration program provides resident memory within intestinal epithelium.J. Exp. Med. 2010; 207: 553-564Crossref PubMed Scopus (182) Google Scholar). This loss of α4β7 is coupled with the in situ upregulation of αeβ7 integrin (αe is also referred to as CD103) and CD69, the maintenance of granzyme B, and the downregulation of Ly6C and CD122 expression (Masopust et al., 2006Masopust 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. 2006; 176: 2079-2083Crossref PubMed Google Scholar). The functional significance of CD69 and αeβ7 expression will be discussed later in the review. These data indicate that many Trm cell phenotypic signatures are acquired only after migration to destination tissues of residence. This observation supports the hypothesis that phenotype is inherently coupled with location and that NLT themselves might play an instructional role in shaping Trm cell differentiation. Indeed, when Trm cells are transferred from the intestinal mucosa to blood and then reactivated to induce proliferation and distribution throughout the host, daughter cells adopt the phenotypic signatures characteristic of their new environment (Masopust et al., 2006Masopust 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. 2006; 176: 2079-2083Crossref PubMed Google Scholar). In other words, effector progeny that trafficked back to the intestinal mucosa reacquired gut Trm cell-associated signatures, while daughter cells isolated from SLOs differentiated into recirculating Tcm (Masopust et al., 2006Masopust 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. 2006; 176: 2079-2083Crossref PubMed Google Sch