The skin of an adult human contains about 20 billion memory T cells. Epithelial barrier tissues are infiltrated by a combination of resident and recirculating T cells in mice, but the relative proportions and functional activities of resident versus recirculating T cells have not been evaluated in human skin. We discriminated resident from recirculating T cells in human-engrafted mice and lymphoma patients using alemtuzumab, a medication that depletes recirculating T cells from skin, and then analyzed these T cell populations in healthy human skin. All nonrecirculating resident memory T cells (T_RM) expressed CD69, but most were CD4⁺, CD103⁻, and located in the dermis, in contrast to studies in mice. Both CD4⁺ and CD8⁺ CD103⁺ T_RM were enriched in the epidermis, had potent effector functions, and had a limited proliferative capacity compared to CD103⁻ T_RM. T_RM of both types had more potent effector functions than recirculating T cells. We observed two distinct populations of recirculating T cells, CCR7⁺/L-selectin⁺ central memory T cells (T_CM) and CCR7⁺/L-selectin⁻ T cells, which we term migratory memory T cells (T_MM). Circulating skin-tropic T_MM were intermediate in cytokine production between T_CM and effector memory T cells. In patients with cutaneous T cell lymphoma, malignant T_CM and T_MM induced distinct inflammatory skin lesions, and T_MM were depleted more slowly from skin after alemtuzumab, suggesting that T_MM may recirculate more slowly. In summary, human skin is protected by four functionally distinct populations of T cells, two resident and two recirculating, with differing territories of migration and distinct functional activities.

In psoriasis, an IL-17–mediated inflammatory skin disease, skin lesions resolve with therapy, but often recur in the same locations when therapy is discontinued. We propose that residual T cell populations in resolved psoriatic lesions represent the pathogenic T cells of origin in this disease. Utilizing high-throughput screening (HTS) of the T cell receptor (TCR) and immunostaining, we found that clinically resolved psoriatic lesions contained oligoclonal populations of T cells that produced IL-17A in both resolved and active psoriatic lesions. Putative pathogenic clones preferentially utilized particular Vβ and Vα subfamilies. We identified 15 TCRβ and 4 TCRα antigen receptor sequences shared between psoriasis patients and not observed in healthy controls or other inflammatory skin conditions. To address the relative roles of αβ versus γδ T cells in psoriasis, we carried out TCR/δ HTS. These studies demonstrated that the majority of T cells in psoriasis and healthy skin are αβ T cells. γδ T cells made up 1% of T cells in active psoriasis, less than 1% in resolved psoriatic lesions, and less than 2% in healthy skin. All of the 70 most frequent putative pathogenic T cell clones were αβ T cells. In summary, IL-17–producing αβ T cell clones with psoriasis-specific antigen receptors exist in clinically resolved psoriatic skin lesions. These cells likely represent the disease-initiating pathogenic T cells in psoriasis, suggesting that lasting control of this disease will require suppression of these resident T cell populations.

Key Points: Idelalisib as upfront therapy for CLL caused an early hepatotoxicity in a subset of primarily younger patients with IGHV-mutated disease. Multiple lines of evidence suggest that this adverse effect is immune mediated, perhaps through inhibition of regulatory T cells.

Key Points: Homeostatic recovery after allogeneic HSCT favors the production, expansion, and survival of effector T cells over CD4Tregs. Unbalanced reconstitution of regulatory and effector T-cell subsets contributes to the development of chronic graft-versus-host disease.

CD4 ⁺ regulatory T cells (CD4Tregs) play a critical role in the maintenance of immune tolerance and prevention of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. IL-2 supports the proliferation and survival of CD4Tregs and previous studies have demonstrated that IL-2 induces selective expansion of CD4Tregs and improves clinical manifestations of chronic GVHD. However, mechanisms for selective activation of CD4Tregs and the effects of low-dose IL-2 on other immune cells are not well understood. Using mass cytometry, we demonstrate that low concentrations of IL-2 selectively induce STAT5 phosphorylation in Helios ⁺ CD4Tregs and CD56 ^bright CD16 ^– NK cells in vitro. Preferential activation and expansion of Helios ⁺ CD4Tregs and CD56 ^bright CD16 ^– NK cells was also demonstrated in patients with chronic GVHD receiving low-dose IL-2. With prolonged IL-2 treatment for 48 weeks, phenotypic changes were also observed in Helios ^– CD4Tregs. The effects of low-dose IL-2 therapy on conventional CD4 ⁺ T cells and CD8 ⁺ T cells were limited to increased expression of PD-1 on effector memory T cells. These studies reveal the selective effects of low-dose IL-2 therapy on Helios ⁺ CD4Tregs and CD56 ^bright NK cells that constitutively express high-affinity IL-2 receptors as well as the indirect effects of prolonged exposure to low concentrations of IL-2 in vivo.