CD69 Is Indispensable for Development of Functional Local Immune Memory in Murine Contact Hypersensitivity.

Local immune memory develops at the site of antigen exposure and facilitates a rapid and strong local adaptive defense upon re-exposure. Resident memory T (TRM) cells play a role in local immune memory, and their cell-surface molecules CD69 and CD103 promote their tissue residency. However, the contribution of these molecules to skin immune memory remains unclear. In this study, by inducing contact hypersensitivity (CHS) in CD69KO (CD69-deficient) and CD103-deficient mice, where different degrees of TRM cell contribution are observed by repeated challenges on the right ear and a single challenge on the left ear, we found that the deficiency of CD69 but not CD103 leads to impaired CHS upon repeated antigen challenges, even although TRM cells-like CD8 T cells developed at the challenged site of CD69KO. CHS responses in both ears were diminished in CD69KO by FTY720 or CD8 neutralization, suggesting that CHS in CD69KO is ascribed to circulating CD8 T cells and that the developed TRM cell-like CD8 T cells do not behave as TRM cells. The infiltration of macrophages was reduced in the rechallenged site of CD69KO, along with the downregulation of Cxcl1 and Cxcl2. Thus, CD69 is considered essential for an effective recall response, involving the development of functional TRM cells and the recruitment of macrophages.

Melanocyte-specific CD49a+ CD8+ T cells in vitiligo lesion potentiate to maintain activity during systemic steroid therapy.

Vitiligo is a common depigmenting skin disease that is often difficult to treat. Even if repigmentation is achieved by treatment, recurrence in the same lesion is often found within a year after stopping treatment. As a background of these issues, a subset of CD8+ T cells that recognize melanocyte-specific antigens or CD49a+ tissue-resident memory T cells that reside in the vitiligo lesion are thought to be involved. We investigated the MHC class I-restricted tyrosinase pentamer-positive CD8+ skin T cells in a progressive generalized vitiligo patient with HLA-A*02:01 who showed resistance to intravenous methylprednisolone pulse therapy. We found that HLA-A*02:01-restricted tyrosinase pentamer-positive CD8+ T cells remained in the lesions after the treatment and expressed IFN-γ and granzyme B. Interestingly, the expression of these cytokines in the pentamer-negative CD8+ T cells was decreased after intravenous methylprednisolone pulse therapy. These findings suggest that, in vitiligo patients, melanocyte-specific CD49a+ CD8+ T cells are in a potent activation state that is uncontrolled despite systemic immunosuppressive treatment, which may contribute to treatment resistance and local recurrence.

Ganglioside GD3 May Suppress the Functional Activities of Benign Skin T Cells in Cutaneous T-Cell Lymphoma.

In cutaneous T-cell lymphoma (CTCL), which arises from skin-tropic memory T cells, malignant T cells and benign T cells are confined in the same skin lesions. It is thus difficult to evaluate the phenotypic characteristics and functional activities of benign T cells in CTCL. Disialoganglioside with three glycosyl groups (GD3) is increasingly expressed on the surface of solid malignant tumor cells and takes part in tumor progression and suppression of tumor immunity. However, the role of GD3 in CTCL is not well-understood. In this study, the malignant and benign T cells in CTCL skin lesions were distinguished by flow cytometry and their phenotypic characteristics were compared with those of T cells from control skin specimens. In CTCL skin lesions, the benign T cells included limited resident memory T cells (TRM), which are sessile in skin and known to exert strong antitumor function. The benign T cells showed diminished Th17 property, and the expression of GD3 was high in the malignant T cells. The expression of GD3 in the malignant T cells inversely correlated with IL-17A production from the benign CD4 T cells. GD3 from the malignant T cells was implied to be involved in suppressing the Th17 activity of the benign T cells independent of the regulation of TRM differentiation in CTCL. Revealing the role of GD3 in inhibiting the production of IL-17A in CTCL would aid the understanding of the suppressive mechanism of the antitumor activity by malignant tumor cells.