Stanley Cheuk

Composition of Innate Lymphoid Cell Subsets in the Human Skin: Enrichment of NCR+ ILC3 in Lesional Skin and Blood of Psoriasis Patients

Innate lymphoid cells (ILCs) are increasingly appreciated as important regulators of tissue homeostasis and inflammation. However, their role in human skin remains obscure. We found that healthy peripheral blood CD117(+) ILC3, lacking the natural cytotoxicity receptor (NCR) NKp44 (NCR(-) ILC3), CD117(-)NCR(-)CRTH2(-)CD161(+) ILC1, and CRTH2(+) ILC2, express the skin-homing receptor cutaneous lymphocyte antigen (CLA). NCR(+) ILC3 were scarce in peripheral blood. Consistently, we identified in normal skin ILC2 and NCR(-) ILC3, a small proportion of CD161(+) ILC1, and hardly any NCR(+) ILC3, whereas NCR(+) ILC3 were present in cultured dermal explants. The skin ILC2 and NCR(+) ILC3 subsets produced IL-13 and IL-22, respectively, upon cytokine stimulation. Remarkably, dermal NCR(-) ILC3 converted to NCR(+) ILC3 upon culture in IL-1β plus IL-23, cytokines known to be involved in psoriatic inflammation. In line with this observation, significantly increased proportions of NCR(+) ILC3 were present in lesional skin and peripheral blood of psoriasis patients as compared with skin and blood of healthy individuals, respectively, whereas the proportions of ILC2 and CD161(+) ILC1 remained unchanged. NCR(+) ILC3 from skin and blood of psoriasis patients produced IL-22, which is regarded as a key driver of epidermal thickening, suggesting that NCR(+) ILC3 may participate in psoriasis pathology.

Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed Psoriasis

Psoriasis is a common and chronic inflammatory skin disease in which T cells play a key role. Effective treatment heals the skin without scarring, but typically psoriasis recurs in previously affected areas. A pathogenic memory within the skin has been proposed, but the nature of such site-specific disease memory is unknown. Tissue-resident memory T (TRM) cells have been ascribed a role in immunity after resolved viral skin infections. Because of their localization in the epidermal compartment of the skin, TRM may contribute to tissue pathology during psoriasis. In this study, we investigated whether resolved psoriasis lesions contain TRM cells with the ability to maintain and potentially drive recurrent disease. Three common and effective therapies, narrowband-UVB treatment and long-term biologic treatment systemically inhibiting TNF-α or IL-12/23 signaling were studied. Epidermal T cells were highly activated in psoriasis and a high proportion of CD8 T cells expressed TRM markers. In resolved psoriasis, a population of cutaneous lymphocyte–associated Ag, CCR6, CD103, and IL-23R expressing epidermal CD8 T cells was highly enriched. Epidermal CD8 T cells expressing the TRM marker CD103 responded to ex vivo stimulation with IL-17A production and epidermal CD4 T cells responded with IL-22 production after as long as 6 y of TNF-α inhibition. Our data suggest that epidermal TRM cells are retained in resolved psoriasis and that these cells are capable of producing cytokines with a critical role in psoriasis pathogenesis. We provide a potential mechanism for a site-specific T cell–driven disease memory in psoriasis.

CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin

SUMMARY Tissue‐resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8+ Trm cells on a compartmental and functional basis. In human skin epithelia, CD8+CD49a+ Trm cells produced interferon‐&ggr;, whereas CD8+CD49a− Trm cells produced interleukin‐17 (IL‐17). In addition, CD8+CD49a+ Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL‐15, thereby promoting a strong cytotoxic response. In skin from patients with vitiligo, where melanocytes are eradicated locally, CD8+CD49a+ Trm cells that constitutively expressed perforin and granzyme B accumulated both in the epidermis and dermis. Conversely, CD8+CD49a– Trm cells from psoriasis lesions predominantly generated IL‐17 responses that promote local inflammation in this skin disease. Overall, CD49a expression delineates CD8+ Trm cell specialization in human epithelial barriers and correlates with the effector cell balance found in distinct inflammatory skin diseases. Graphical Abstract Figure. No Caption available. HighlightsCD49a expression marks CD8+ Trm cells poised for IFN‐&ggr; production in human skinIL‐15 drives potent cytotoxic capacity in CD49a+ Trm cellsIL‐17 is preferentially produced by CD49a− CD8+ Trm cells in the skinCD49a+ versus CD49‐ Trm cell functional dichotomy is preserved in vitiligo and psoriasis &NA; Tissue‐resident memory T (Trm) cells provide localized adaptive immunity in peripheral tissues. Cheuk et al. identify cytotoxic CD49a+CD8+ Trm cells and IL‐17‐producing CD49a−CD8+ Trm cells in healthy human skin. The functional dichotomy of pathogenic Trm cells based on CD49a expression is preserved in focal skin diseases vitiligo and psoriasis.

Dynamic Changes in Resident and Infiltrating Epidermal Dendritic Cells in Active and Resolved Psoriasis

Epidermal Langerhans cells (LCs) are spatially separated from dermal dendritic cells (DCs) in healthy human skin. In active psoriasis, maintained by local production of IL-23 and IL-17, inflammatory DCs infiltrate both skin compartments. Here we show that CCR2+ epidermal DCs (eDCs) were confined to lesional psoriasis and phenotypically distinct from dermal DCs. The eDCs exceeded the number of LCs and displayed high expression of genes involved in neutrophil recruitment and the activation of keratinocytes and T cells. Resident LCs responded to toll-like receptor 4 and toll-like receptor 7/8 activation with increased IL-23 production, whereas eDCs additionally produced IL-1β together with IL-23 and tumor necrosis factor. Psoriasis typically recur in fixed skin lesions. eDCs were absent from resolved psoriasis. Instead, LCs from anti-tumor necrosis factor-treated lesions retained high IL23A expression and responded to toll-like receptor stimulation by producing IL-23. Our results reveal phenotypic and functional properties of eDCs and resident LCs in different clinical phases of psoriasis, and the capacity of these cells to amplify the epidermal microenvironment through the secretion of IL-17 polarizing cytokines.

Resident T Cells in Resolved Psoriasis Steer Tissue Responses that Stratify Clinical Outcome

Psoriasis is driven by focal disruptions of the immune-homeostasis in human skin. Local relapse following cessation of therapy is common and unpredictable, which complicates clinical management of psoriasis. We have previously shown that pathogenic resident T cells accumulate in active and resolved psoriasis, but whether these cells drive psoriasiform tissue reactions is less clear. Here, we activated T cells within skin explants using the pan-T cell activating antibody OKT-3. To explore if T cells induced different tissue response patterns in healthy and psoriasis afflicted skin, transcriptomic analyses were performed with RNA-sequencing and Nanostring. Core tissue responses dominated by IFN-induced pathways were triggered regardless of the inflammatory status of the skin. In contrast, pathways induced by IL-17A, including Defensin beta 2 and keratinocyte differentiation markers, were activated in psoriasis samples. An integrated analysis of IL-17A and IFN-related responses revealed that IL-17 dominated tissue response correlated with early relapse following UVB treatment. Stratification of tissue responses to T cell activation in resolved lesions could potentially offer individualized prediction of disease relapse during long-term immunomodulatory treatment.

Increased numbers of CD103-CD8+ TRM cells in the cervical mucosa of HIV-infected women

Hormonal contraceptive use affects HIV susceptibility : mechanisms revealed by image analysis