Bina Menon

Interleukin-17+CD8+ T Cells Are Enriched in the Joints of Patients With Psoriatic Arthritis and Correlate With Disease Activity and Joint Damage Progression

Psoriatic arthritis (PsA) is associated with HLA class I genes, in contrast to the association with HLA class II in rheumatoid arthritis (RA). Since IL‐17+ cells are considered important mediators of synovial inflammation, we sought to determine whether IL‐17–producing CD8+ T cells may be found in the joints of patients with PsA and whether these cells might contribute to the disease process.

CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL‐17 in a STAT3‐dependent manner

Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell‐based clinical therapy. However, human Treg cells are “plastic”, and are able to produce IL‐17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL‐17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL‐17 in vitro when activated in the presence of IL‐1β, but not IL‐6. “IL‐17 potential” is restricted to population III (CD4+CD25hiCD127loCD45RA−) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL‐17 induction. Importantly, we find that IL‐17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL‐17. Finally, we show that CD161+ population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL‐17‐producing Treg‐cell population at these sites. As IL‐17 production from this Treg‐cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary.

FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25-responder T cells, but not CD4+CD25+regulatory T cells

Conclusive resolution of an immune response is critical for the prevention of autoimmunity and chronic inflammation. We report that following co-culture with autologous CD4+CD25- responder T cells, human CD14+ monocytes and monocyte-derived macrophages become activated but also significantly more prone to apoptosis than monocytes/macrophages cultured alone. In contrast, in the presence of CD4+CD25+ regulatory T cells (Tregs), monocytes and macrophages survive whilst adopting an anti-inflammatory phenotype. The induction of monocyte death requires responder T cell activation and cell-contact between responder T cells and monocytes. We demonstrate a critical role for FAS/FAS-L ligation in responder T cell-induced monocyte killing since responder T cells, but not Tregs, upregulate FAS-ligand (FAS-L) mRNA, and induce FAS expression on monocytes. Furthermore, responder T cell-induced monocyte apoptosis is blocked by neutralising FAS/FAS-L interaction, and is not observed when monocytes from an autoimmune lymphoproliferative syndrome (ALPS) patient with complete FAS-deficiency are used as target cells. Finally, we show that responder T cell-induced killing of monocytes is impaired in patients with active rheumatoid arthritis (RA). Our data suggest that resolution of inflammation in the course of a healthy immune response is aided by the unperturbed killing of monocytes with inflammatory potential by responder T cells and the induction of longer-lived, Treg-induced, anti-inflammatory monocytes.

Phenotypic, Functional, and Gene Expression Profiling of Peripheral CD45RA+ and CD45RO+ CD4+CD25+CD127(low) Treg Cells in Patients With Chronic Rheumatoid Arthritis.

Conflicting evidence exists regarding the suppressive capacity of Treg cells in the peripheral blood (PB) of patients with rheumatoid arthritis (RA). The aim of this study was to determine whether Treg cells are intrinsically defective in RA.

Phenotypic, functional and gene expression profiling of peripheral CD45RA+ and CD45RO+ CD4+CD25+CD127low regulatory T cells in rheumatoid arthritis

Conflicting evidence exists regarding the suppressive capacity of Treg cells in the peripheral blood (PB) of patients with rheumatoid arthritis (RA). The aim of this study was to determine whether Treg cells are intrinsically defective in RA.

Interaction with activated monocytes enhances cytokine expression and suppressive activity of human CD4+CD45RO+CD25+CD127low regulatory T cells

Despite the high frequency of CD4+ T cells with a regulatory phenotype (CD25+CD127lowFoxP3+) in the joints of patients with rheumatoid arthritis (RA), inflammation persists. Regulatory T cells (Tregs) can be converted into pro-inflammatory IL-17-producing cells by inflammatory mediators, particularly IL-1β.