Epithelial surfaces line the body and provide a crucial interface between the body and the external environment. Tissue-resident epithelial γδ T cells represent a major T cell population in the ...epithelial tissues and are ideally positioned to carry out barrier surveillance and aid in tissue homeostasis and repair. In this Review, we focus on the intraepithelial γδ T cell compartment of the two largest epithelial tissues in the body - namely, the epidermis and the intestine - and provide a comprehensive overview of the crucial contributions of intraepithelial γδ T cells to tissue integrity and repair, host homeostasis and protection in the context of the symbiotic relationship with the microbiome and during pathogen clearance. Finally, we describe epithelium-specific butyrophilin-like molecules and briefly review their emerging role in selectively shaping and regulating epidermal and intestinal γδ T cell repertoires.
Summary
In response to infection, naive CD4+ T‐cells proliferate and differentiate into several possible effector subsets, including conventional T helper effector cells (TH1, TH2, TH17), T ...regulatory cells (Treg) and T follicular helper cells (TFH). Once infection is cleared, a small population of long‐lived memory cells remains that mediate immune defenses against reinfection. Memory T lymphocytes have classically been categorized into central memory cell (TCM) and effector memory cell (TEM) subsets, both of which circulate between blood, secondary lymphoid organs and in some cases non‐lymphoid tissues. A third subset of memory cells, referred to as tissue‐resident memory cells (TRM), resides in tissues without recirculation, serving as ‘first line’ of defense at barrier sites, such as skin, lung and intestinal mucosa, and augmenting innate immunity in the earliest phases of reinfection and recruiting circulating CD4+ and CD8+ T‐cells. The presence of multiple CD4+ T helper subsets has complicated studies of CD4+ memory T‐cell differentiation, and the mediators required to support their function. In this review, we summarize recent investigations into the origins of CD4+ memory T‐cell populations and discuss studies addressing CD4+ TRM differentiation in barrier tissues.
During an immune response to pathogen, CD4+ T‐cells differentiate into short‐lived effector cells that mediate pathogen clearance and ‘memory’ T‐cells that provide long‐lasting protection from reinfection. The presence of multiple CD4+ T helper subsets has complicated studies of CD4+ memory T‐cell differentiation, and the mediators required to support their function in secondary lymphoid organs and non‐lymphoid tissues. In this review, we summarize recent investigations into the origins of CD4+ memory T‐cell populations and discuss studies addressing CD4+ TRM differentiation in barrier tissues.
Innate and adaptive immune systems continuously interchange information and orchestrate their immune responses to protect the host. γδT cells play crucial roles, as they incorporate both innate and ...adaptive immune characteristics. Dendritic epidermal T cells (DETC) are specialized γδT cells, which are uniquely positioned to rapidly respond to skin wounds and infections. Their elongated dendrite morphology allows them to be in continuous contact with multiple neighboring keratinocytes and Langerhans cells. Cellular interactions are fundamental to the formation, activation and maintenance of immune cell functions during steady state and pathology. Recent technological advances, especially in the field of cellular imaging, have contributed greatly to the characterization of complex cellular interactions in a spatiotemporally resolved manner. In this review, we will highlight the often-underappreciated function of DETC and other γδT cells during steady state and an ongoing immune response. More specifically, we discuss how DETC-precursors are shaped in the fetal thymus during embryogenesis as well as how direct cell-cell interactions of DETC with neighboring epidermal cells shape skin homeostasis and effector functions. Furthermore, we will discuss seminal work and recent discoveries made in the γδT cell field, which have highlighted the importance of γδT cells in the skin, both in humans and mice.
Tissue-resident memory CD8+ T cells (Trm) provide host protection through continuous surveillance of non-lymphoid tissues. Using single-cell RNA-sequencing (scRNA-seq) and genetic reporter mice, we ...identified discrete lineages of intestinal antigen-specific CD8+ T cells, including a Blimp1hiId3lo tissue-resident effector cell population most prominent in the early phase of acute viral and bacterial infections and a molecularly distinct Blimp1loId3hi tissue-resident memory population that subsequently accumulated at later infection time points. These Trm populations exhibited distinct cytokine production, secondary memory potential, and transcriptional programs including differential roles for transcriptional regulators Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal Trm. Extending our analysis to malignant tissue, we also identified discrete populations of effector-like and memory-like CD8+ T cell populations with tissue-resident gene-expression signatures that shared features of terminally exhausted and progenitor-exhausted T cells, respectively. Our findings provide insight into the development and functional heterogeneity of Trm cells, which has implications for enhancing vaccination and immunotherapy approaches.
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•Blimp1 and Id3 expression identify distinct tissue-resident T cell subsets•Id3hi siIEL CD8+ T cells exhibit heightened multifunctionality and memory potential•Id2 and Id3 are required for homeostasis of tissue-resident memory cells•Id3hi cells in tumors have features of tissue-residency and progenitor exhausted cells
Tissue-resident memory CD8+ T cells (Trm) provide long-lasting immunity in non-lymphoid tissues. Milner et al. use single-cell RNA sequencing to reveal Trm cell heterogeneity in response to infection and identify effector-like Id3loBlimp1hi and memory-like Id3hiBlimp1lo tissue-resident populations with differential effector function, memory potential, and transcriptional programming. Analogous populations of CD8+ T cells with tissue-residency features were also identified in tumors.
Adoptive T cell therapies (ACTs) hold great promise in cancer treatment, but low overall response rates in patients with solid tumors underscore remaining challenges in realizing the potential of ...this cellular immunotherapy approach. Promoting CD8+ T cell adaptation to tissue residency represents an underutilized but promising strategy to improve tumor-infiltrating lymphocyte (TIL) function. Here, we report that deletion of the HIF negative regulator von Hippel-Lindau (VHL) in CD8+ T cells induced HIF-1α/HIF-2α-dependent differentiation of tissue-resident memory-like (Trm-like) TILs in mouse models of malignancy. VHL-deficient TILs accumulated in tumors and exhibited a core Trm signature despite an exhaustion-associated phenotype, which led to retained polyfunctionality and response to αPD-1 immunotherapy, resulting in tumor eradication and protective tissue-resident memory. VHL deficiency similarly facilitated enhanced accumulation of chimeric antigen receptor (CAR) T cells with a Trm-like phenotype in tumors. Thus, HIF activity in CD8+ TILs promotes accumulation and antitumor activity, providing a new strategy to enhance the efficacy of ACTs.
γδ T cells respond rapidly to keratinocyte damage, providing essential contributions to the skin wound healing process. The molecular interactions regulating their response are unknown. Here, we ...identify a role for interaction of plexin B2 with the CD100 receptor in epithelial repair. In vitro blocking of plexin B2 or CD100 inhibited γδ T cell activation. Furthermore, CD100 deficiency in vivo resulted in delayed repair of cutaneous wounds due to a disrupted γδ T cell response to keratinocyte damage. Ligation of CD100 in γδ T cells induced cellular rounding via signals through ERK kinase and cofilin. Defects in this rounding process were evident in the absence of CD100-mediated signals, thereby providing a mechanistic explanation for the defective wound healing in CD100-deficient animals. The discovery of immune functions for plexin B2 and CD100 provides insight into the complex cell-cell interactions between epithelial resident γδ T cells and the neighboring cells they support.
► Plexin B2 is a functional ligand for CD100 in mouse skin ► Plexin B2-CD100 interaction is required for epidermal γδ T cell activation ► CD100 ligation induces cellular rounding ► Plexin B2-CD100 interaction delivers signals through ERK and cofilin
The epidermis, the outer layer of the skin, forms a physical and antimicrobial shield to protect the body from environmental threats. Skin injury severely compromises the epidermal barrier and ...requires immediate repair. Dendritic epidermal T cells (DETC) reside in the murine epidermis where they sense skin injury and serve as regulators and orchestrators of immune responses. Here, we determined that TCR stimulation and skin injury induces IL-17A production by a subset of DETC. This subset of IL-17A-producing DETC was distinct from IFN-γ producers, despite similar surface marker profiles. Functionally, blocking IL-17A or genetic deletion of IL-17A resulted in delayed wound closure in animals. Skin organ cultures from Tcrd-/-, which lack DETC, and Il17a-/- mice both exhibited wound-healing defects. Wound healing was fully restored by the addition of WT DETC, but only partially restored by IL-17A-deficient DETC, demonstrating the importance of IL-17A to wound healing. Following skin injury, DETC-derived IL-17A induced expression of multiple host-defense molecules in epidermal keratinocytes to promote healing. Together, these data provide a mechanistic link between IL-17A production by DETC, host-defense, and wound-healing responses in the skin. These findings establish a critical and unique role of IL-17A-producing DETC in epidermal barrier function and wound healing.
Coxsackie and adenovirus receptor (CAR) is the primary cellular receptor for group B coxsackieviruses and most adenovirus serotypes and plays a crucial role in adenoviral gene therapy. Recent ...discovery of the interaction between junctional adhesion molecule-like protein (JAML) and CAR uncovered important functional roles in immunity, inflammation, and tissue homeostasis. Crystal structures of JAML ectodomain (2.2 angstroms) and its complex with CAR (2.8 angstroms) reveal an unusual immunoglobulin-domain assembly for JAML and a charged interface that confers high specificity. Biochemical and mutagenesis studies illustrate how CAR-mediated clustering of JAML recruits phosphoinositide 3-kinase (P13K) to a JAML intracellular sequence motif as delineated for the αβ T cell costimulatory receptor CD28. Thus, CAR and JAML are cell signaling receptors of the immune system with implications for asthma, cancer, and chronic nonhealing wounds.
•Epithelial-resident γδ T cells respond to stress-induced self-antigens.•Epithelial-resident γδ T cells promote repair of tissue injury.•Molecules that regulate tissue-resident γδ T cell and γβ T ...cell functions differ.
Immunology has traditionally focused on the lymphocytes circulating among primary lymphoid organs while the large reservoir of tissue-resident T cells have received relatively less attention. In epithelia, these populations are comprised of significant, and sometimes exclusive, subsets of γδ T cells that are highly specialized in promoting tissue homeostasis. As the epithelial layers of the skin and gut are permanently exposed to the environment, they are continually subject to injury and therefore require highly efficient repair processes to maintain barrier functions. Here, we review the role of γδ T cells in promoting wound healing, a critical and complex process occurring in the skin and other barrier sites.
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