Memory regulatory T cells reside in human skin

Abstract

Regulatory T cells (Tregs), which are characterized by expression of the transcription factor Foxp3, are a dynamic and heterogeneous population of cells that control immune responses and prevent autoimmunity. We recently identified a subset of Tregs in murine skin with properties typical of memory cells and defined this population as memory Tregs (mTregs). Due to the importance of these cells in regulating tissue inflammation in mice, we analyzed this cell population in humans and found that almost all Tregs in normal skin had an activated memory phenotype. Compared with mTregs in peripheral blood, cutaneous mTregs had unique cell surface marker expression and cytokine production. In normal human skin, mTregs preferentially localized to hair follicles and were more abundant in skin with high hair density. Sequence comparison of TCRs from conventional memory T helper cells and mTregs isolated from skin revealed little homology between the two cell populations, suggesting that they recognize different antigens. Under steady-state conditions, mTregs were nonmigratory and relatively unresponsive; however, in inflamed skin from psoriasis patients, mTregs expanded, were highly proliferative, and produced low levels of IL-17. Taken together, these results identify a subset of Tregs that stably resides in human skin and suggest that these cells are qualitatively defective in inflammatory skin disease.

Tumor immune profiling predicts response to anti–PD-1 therapy in human melanoma

“…Multiparameter flow cytometry was performed on pretreatment and treatment samples obtained from metastatic tumors as previously described (20). Freshly isolated samples were minced and digested overnight with buffer consisting of collagenase type 4 (4188; Worthington Biochemical Corp.), DNAse (SDN25-1G; Sigma-Aldrich), 10% FBS, 1% HEPES, and 1% penicillin-streptavidin in RPMI medium.…”

“…Single-cell suspensions were double filtered, centrifuged, and counted. For intracellular cytokine analysis, digested tumor cell suspensions were stimulated with PMA and ionomycin for 4 hours as previously described (20). Flow cytometric standardization and gating strategy.…”

Fine-Needle Aspiration Biopsy of the Lymph Node: A Novel Tool for the Monitoring of Immune Responses after Skin Antigen Delivery

“…In addition to the testing of the delayed hypersensitivity response in the LN, shown in this study, this approach has a potential for monitoring of the response to less potent Ags and alternative aspects of memory such as recall regulatory T cell responses (30). Further studies using different antigenic challenges, cytokine readouts, and time points as well as simultaneous skin sampling will be required to confirm the exact nature and time course of the cellular signaling between skin and draining LNs.…”

Mechanisms of human autoimmunity

“…This may be accompanied by a relative decline in Treg number, or increased numbers of dysfunctional Tregs (39)(40)(41). Paradoxically, the inflamed skin of patients with psoriasis has increased numbers of Tregs; however, these cells appear to function abnormally, in that they are capable of producing increased amounts of IL-17 (42,43). It is not clear whether production of seemingly pathogenic cytokines from Tregs in inflamed tissues significantly contributes to disease pathology.…”

“…Both populations of Tregs likely acquire their potent suppressive function only after encountering their target antigen, which in most cases is likely to be a self-antigen. Some of these activated Tregs may survive in tissues as long-lived populations that are capable of controlling autoimmune reactions in that tissue, termed "effector Tregs" or "effector memory Tregs" (43,46,51,52). In mouse models, there is convincing evidence that the induction of systemic or tissue-specific autoimmune inflammation is followed by the activation of Tregs and control of the inflammation, resulting in a cycle of disease and resolution.…”