Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4+ T cells

Abstract

Key Points• GARP efficiently represses proliferation of naïve and resting CD4 1 T cells and is involved in the induction of adaptive regulatory T cells.• In vivo, GARP prevents T cell-mediated destructive inflammation in a preclinical humanized mouse model of GVHD.Glycoprotein A repetitions predominant (GARP) is expressed on the surface of activated human regulatory T cells (Treg) and regulates the bioavailability of transforming growth factor-b (TGF-b). GARP has been assumed to require membrane anchoring. To investigate the function of GARP in more detail, we generated a soluble GARP protein (sGARP) and analyzed its impact on differentiation and activation of human CD4 1 T cells.We demonstrate that sGARP efficiently represses proliferation and differentiation of naïve

B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex

“…Active TGF-β1 was significantly reduced in both GARP WT and OE mice after pristane treatment, although GARP OE mice had a significant increase in total TGF-β1 pre-PIL (Supplemental Figure 4F). Strikingly, GARP OE mice had an increase in soluble GARP in the serum after pristane treatment (Supplemental Figure 4G), which has been implicated in promoting tolerance (13,34). Thus, the roles of GARP-LTGF-β1 in immune tolerance and systemic autoimmunity are illustrated by both loss-of-function and gain-of-function studies.…”

“…Recent work on GARP in the context of TGF-β has attempted to address the role of GARP in promoting a tolerogenic environment (6,(34)(35)(36). However, no study has addressed the physiologic role of GARP in tolerance in vivo.…”

Impairment of Circulating CD4+CD25+GARP+Regulatory T Cells in Patients with Acute Coronary Syndrome

“…Moreover, GARP, which is considered a safeguard of the regulatory phenotype, is part of a positive feedback loop that involves FOXP3 and can adjust Treg and Th17 cell differentiation under distinct inflammatory conditions [32]. Therefore, GARP is more than a maker of activated Tregs; as a double-edged sword, this molecule likely function to adjust the imbalance of Treg and Th17 cells during atherosclerosis.…”

“…These findings may provide new targets for atherosclerosis therapy, such as the use of soluble GARP as an anti-inflammatory immunosuppressive drug [32], as well as methods aimed at correcting the imbalanced immune response to stabilize plaques.…”

Association of Pneumococcal Carriage and Expression of Foxp3+ Regulatory T Cells and Th17 Cells in the Adenoids of Children

“…The differentiation of Foxp3+ T reg and Th17 cells from naive CD4+ T cells is controlled by the local cytokine milieu and is critically dependent on TGF-β and IL-6. In the absence of IL-6, TGF-β mediates the generation of immunosuppressive T reg cells [21,22] . The reciprocal balance between Foxp3+ T reg and Th17 cells is critical for immune homeostasis, and, if not properly regulated, Th17 cells can drive pathogenic inflammation [23] .…”