IL-17A and IL-2-Expanded Regulatory T Cells Cooperate to Inhibit Th1-Mediated Rejection of MHC II Disparate Skin Grafts

Abstract

Several evidences suggest that regulatory T cells (Treg) promote Th17 differentiation. Based on this hypothesis, we tested the effect of IL-17A neutralization in a model of skin transplantation in which long-term graft survival depends on a strong in vivo Treg expansion induced by transient exogenous IL-2 administration. As expected, IL-2 supplementation prevented rejection of MHC class II disparate skin allografts but, surprisingly, not in IL-17A-deficient recipients. We attested that IL-17A was not required for IL-2-mediated Treg expansion, intragraft recruitment or suppressive capacities. Instead, IL-17A prevented allograft rejection by inhibiting Th1 alloreactivity independently of Tregs. Indeed, T-bet expression of naive alloreactive CD4+ T cells and the subsequent Th1 immune response was significantly enhanced in IL-17A deficient mice. Our results illustrate for the first time a protective role of IL-17A in CD4+-mediated allograft rejection process.

Differential effects of palmitoleic acid on human lymphocyte proliferation and function

“…We found that both PA and OA promoted a reduction in the percentage of these cells in both concentrations when compared to control cells. Treg lymphocytes reduce the clonal expansion of Th1 and Th17A cells and, consequently, decreasing the inflammatory response [30, 31]. However, in the present study, PA inhibited proliferative capacity of lymphocytes and the production of inflammatory cytokines (Th1 and Th17 response), as well as the percentage of Treg cells.…”

Effector CD4+ T cells recognize intravascular antigen presented by patrolling monocytes

“…For production of ovalbumin peptide (pOVA)-conjugated 8D1, we used 8D1 mAb 15 , 33 (grown from hybridoma), chemical linker N -succinimidyl-6-maleimido-caproate (EMCS, Sigma Aldrich), and a custom OVA 323–339 peptide containing an amino terminal cysteine residue and C-terminal biotin tag (Mimotopes, Notting Hill, VIC, Australia). As control for these experiments, isotype control mouse IgG1 (clone MOPC-21, Bio X Cell) 58 was used. For activation and polarization of OT-II T cells, cells were cultured in RPMI 1640 supplemented with 10% heat-inactivated fetal calf serum (both from Life Technologies), 2-mercaptoethanol, recombinant mouse (rm)IL-12 (eBioscience), rat anti-IL-4 (clone 11B11, ATCC) and rmIL-2 (R&D Systems).…”

Interleukin-2: Biology, Design and Application

“…IL-2/JES6-1 complexes are also stimulatory for ILC2 that express trimeric IL-2Rs, which contributes to IL-5 production and eosinophilia [30,57]. IL-2/JES6-1 complexes have shown promising results in the prevention of pancreatic [56] and skin [58] allograft rejection as well as in the treatment of several autoimmune and inflammatory diseases in mice, including type 1 diabetes in nonobese diabetic mice [59], experimental autoimmune encephalomyelitis (a model of multiple sclerosis) [56], experimental myasthenia [60], collagen-induced arthritis [61], dextran sodium sulfate-induced acute colitis [13], and T cell-mediated allergic airway disease [62]. Interestingly, administration of IL-2/JES6-1 complexes also improved the pathology of some metabolic, cardiovascular, and degenerative disorders, such as murine obesity-induced inflammation and insulin resistance ('type 2 diabetes') [63], atherosclerosis in high-fat diet-fed apolipoprotein E-deficient animals [64], and the mdx mouse model of Duchenne muscular dystrophy [65], that feature inflammatory infiltrates and are thus amenable to suppression by CD25 + Foxp3 + Treg cells.…”