Deborah. A. Witherden

Background: Allergic contact dermatitis (ACD) is an inflammatory disease with a complex pathophysiology in which epidermal-resident memory CD8(+) T (T-RM) cells play a key role. The mechanisms involved in the activation of CD8(+) T-RM cells during allergic flare-up responses are not understood. Methods: The expression of CD100 and its ligand Plexin B2 on CD8(+) T-RM cells and keratinocytes before and after allergen exposure was determined by flow cytometry and RT-qPCR. The role of CD100 in the inflammatory response during the challenge phase of ACD was determined in a model of ACD in CD100 knockout and wild-type mice. Results: We show that CD8(+) TRM cells express CD100 during homeostatic conditions and up-regulate it following re-exposure of allergen-experienced skin to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene (DNFB). Furthermore, Plexin B2 is up-regulated on keratinocytes following exposure to some contact allergens. We show that loss of CD100 results in a reduced inflammatory response to DNFB with impaired production of IFN gamma, IL-17A, CXCL1, CXCL2, CXCL5, and IL-1 ss and decreased recruitment of neutrophils to the epidermis. Conclusion: Our study demonstrates that CD100 is expressed on CD8(+) TRM cells and is required for full activation of CD8(+) TRM cells and the flare-up response of ACD.

Background: The junctional adhesion molecule‐like protein (JAML) plays important roles in wound healing and activation of epidermal γδ T cells in mice. Whether JAML plays a role in contact hypersensitivity (CHS), the animal model of allergic contact dermatitis (ACD), is not known.Methods: To examine the role of JAML in CHS, we used various mouse models of CHS in JAML knockout (KO) and wild‐type (WT) mice. Furthermore, the expression of the JAML ligand coxsackievirus and adenovirus receptor (CXADR) on keratinocytes was accessed in vitro and in vivo.Results: JAML KO mice had a diminished inflammatory response during both the sensitization and elicitation phase of CHS and had reduced numbers of CD8⁺ and CD4⁺ T cells in the epidermis. Furthermore, interferon γ (IFNγ), interleukin 1β (IL‐1β) and CXCL10 production were significantly reduced in JAML KO mice during the elicitation phase. We found that CD8⁺ T cells express JAML and that JAML is essential for rapid flare‐up responses to contact allergens. Finally, we show that keratinocytes up‐regulate the JAML ligand CXADR following exposure to contact allergens.Conclusion: Our study is the first to show a central role of JAML in CHS and reveals a potential new target for the treatment of ACD in humans.

Antitumor immunity relies on the ability of T cells to recognize and kill tumor targets. γδ T cells are a specialized subset of T cells that predominantly localizes to non-lymphoid tissue such as the skin, gut, and lung where they are actively involved in tumor immunosurveillance. γδ T cells respond to self-stress ligands that are increased on many tumor cells, and these interactions provide costimulatory signals that promote their activation and cytotoxicity. This review will cover costimulatory molecules that are known to be critical for the function of γδ T cells with a specific focus on mouse dendritic epidermal T cells (DETC). DETC are a prototypic tissue-resident γδ T cell population with known roles in antitumor immunity and are therefore useful for identifying mechanisms that may control activation of other γδ T cell subsets within non-lymphoid tissues. This review concludes with a brief discussion on how γδ T cell costimulatory molecules can be targeted for improved cancer immunotherapy.

T cells are critical mediators of antitumor immunity and a major target for cancer immunotherapy. Antibody blockade of inhibitory receptors such as PD-1 can partially restore the activity of tumor-infiltrating lymphocytes (TILs). However, the activation signals required to promote TIL responses are less well characterized. Here we show that the antitumor activity of CD8 and γδ TIL is supported by interactions between junctional adhesion molecule–like protein (JAML) on T cells and its ligand coxsackie and adenovirus receptor (CXADR) within tumor tissue. Loss of JAML through knockout in mice resulted in accelerated tumor growth that was associated with an impaired γδ TIL response and increased CD8 TIL dysfunction. In mouse tumor models, therapeutic treatment with an agonistic anti-JAML antibody inhibited tumor growth, improved γδ TIL activation, decreased markers of CD8 TIL dysfunction, and significantly improved response to anti–PD-1 checkpoint blockade. Thus, JAML represents a novel therapeutic target to enhance both CD8 and γδ TIL immunity.

Tissue‐resident γδ T cells form the first line of defense at barrier surfaces where they survey host tissue for signs of stress or damage. Following recognition of injury, γδ T cells play a crucial role in the wound‐healing response through the production of growth factors and cytokines that promote proliferation in surrounding epithelial cells. To initiate this response, γδ T cells require interactions with a variety of epithelial‐expressed costimulatory molecules in addition to primary signaling through their TCR. In the epidermis these signals include the coxsackie and adenovirus receptor (CAR), histocompatibility antigen 60c (H60c), and plexin B2, which interact with γδ T cell‐expressed junctional adhesion molecule‐like protein (JAML), NKG2D, and CD100, respectively. Here we identify heat shock protein family A member 8 (Hspa8) and ICAM‐1 as two additional keratinocyte‐expressed costimulatory molecules for epidermal resident γδ T cells (termed DETC). These molecules were rapidly up‐regulated in the epidermis following wounding in both mouse and human tissue. Both Hspa8 and ICAM‐1 had a costimulatory effect on DETC, inducing proliferation, CD25 up‐regulation, and IL‐2 production. We also provide evidence that DETC can be activated through the potential ICAM‐1 and Hspa8 receptors LFA‐1 and CD316. Finally, knockdown of Hspa8 in keratinocytes reduced their ability to activate DETC in culture and ICAM‐1^−/− mice exhibited impaired rates of healing in skin‐organ culture suggesting a role for these proteins in the DETC‐mediated damage response. Together with previous work on CAR, H60c, and plexin B2, these results add to a picture of a complex keratinocyte wound signature that is required for efficient DETC activation.

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.

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.

Chronic wounds represent a growing clinical problem for which limited treatment strategies exist. Defects in immune cell-mediated healing play an important role in chronic wound development, presenting an attractive clinical target in the treatment of chronic wounds. However, efforts to improve healing through the application of growth factors and cytokines have been limited by the rapid degradation and diffusion of these molecules in the wound environment. In this study we sought to overcome the challenge of rapid diffusion through the development of a hydrogel delivery system in which protein cargo can be released into the wound environment at a constant and tunable rate. This system was used to deliver the intercellular adhesion molecule-1 (ICAM-1) in order to target endogenous cells upstream of growth factor and cytokine production and circumvent the issue of their rapid degradation. We demonstrated that our delivery system was able to release cargo at different and highly controllable rates and thereby improved cargo retention in the wound environment. Additionally, treatment with ICAM-1 in the delivery system improved healing in both ICAM-1-deficient mice and an aged mouse model of delayed healing, highlighting a potential clinical benefit for this protein in the treatment of chronic wounds.

Wendy Havran, Professor and Associate Dean of Graduate Studies at Scripps Research, passed away on January 20th, 2020 following a heart attack

While forming a minor population in the blood and lymphoid compartments, γδ T cells are significantly enriched within barrier tissues. In addition to providing protection against infection, these tissue-resident γδ T cells play critical roles in tissue homeostasis and repair. γδ T cells in the epidermis and intestinal epithelium produce growth factors and cytokines that are important for the normal turnover and maintenance of surrounding epithelial cells and are additionally required for the efficient recognition of, and response to, tissue damage. A role for tissue-resident γδ T cells is emerging outside of the traditional barrier tissues as well, with recent research indicating that adipose tissue-resident γδ T cells are required for the normal maintenance and function of the adipose tissue compartment. Here we review the functions of tissue-resident γδ T cells in the epidermis, intestinal epithelium, and adipose tissue, and compare the mechanisms of their activation between these sites.