Dysregulated Foxp3⁺ Treg functions result in uncontrolled immune activation and autoimmunity. Therefore, identifying cellular factors modulating Treg functions is an area of great importance. Here, using Treg-specific Il27ra^−/− mice, we report that IL-27 signaling in Foxp3⁺ Tregs is essential for Tregs to control autoimmune inflammation in the central nervous system (CNS). Following experimental autoimmune encephalomyelitis (EAE) induction, Treg-specific Il27ra^−/− mice develop more severe EAE. Consistent with the severe disease, the numbers of IFNγ- and IL-17–producing CD4 T cells infiltrating the CNS tissues are greater in these mice. Treg accumulation in the inflamed CNS tissues is not affected by the lack of IL-27 signaling in Tregs, suggesting a functional defect of Il27ra^−/− Tregs. IL-10 production by conventional CD4 T cells and their CNS accumulation are rather elevated in Treg-specific Il27ra^−/− mice. Analysis with Treg fate-mapping reporter mice further demonstrates that IL-27 signaling in Tregs may control stability of Foxp3 expression. Finally, systemic administration of recombinant IL-27 in Treg-specific Il27ra^−/− mice fails to ameliorate the disease even in the presence of IL-27–responsive conventional CD4 T cells. These findings uncover a previously unknown role of IL-27 in regulating Treg function to control autoimmune inflammation.

IgG and albumin are the most abundant proteins in the circulation and have the longest half‐lives. These properties are due to a unique receptor, the neonatal Fc receptor (FcRn). Although FcRn is named for its function of transferring IgG across the placenta from maternal to fetal circulation, FcRn functions throughout life to maintain IgG and albumin concentrations. FcRn protects IgG and albumin from intracellular degradation and recycles them back into the circulation. Clinical trials have confirmed that pathogenic antibodies can be depleted by blocking this homeostatic function of FcRn. Moreover, understanding the molecular interactions between IgG and FcRn has resulted in the design of therapeutic monoclonal antibodies with more efficacious pharmacokinetics. As a result of genetic engineering these monoclonals can be delivered at lower doses and at longer intervals. More recent findings have demonstrated that FcRn enhances phagocytosis by neutrophils, immune complex clearance by podocytes and antigen presentation by dendritic cells, macrophages, and B cells. This minireview highlights the relevance of FcRn to transplantation.

Th 17 cells have been implicated in the pathogenesis of colitis; however, a cellular mechanism by which colitogenic Th17 immunity arises in vivo remains unclear. In this study, we report that a subset of IL-17⁺ γδ T cells plays a crucial role in enhancing in vivo Th17 differentiation and T cell-mediated colitis. TCRβ^−/− mice were highly susceptible to T cell-mediated colitis, whereas TCRβδ^−/− mice were resistant to the disease. Importantly, cotransfer of IL-17⁺ but not of IL-17⁻ γδ T cells with CD4 T cells was sufficient to enhance Th17 differentiation and induce full-blown colitis in TCRβδ^−/− recipients. Collectively, our results provide a novel function of IL-17⁺ γδ T cell subsets in supporting in vivo Th17 differentiation and possibly in fostering the development of intestinal inflammation.

Acute and chronic rejection impact distinct compartments of cardiac allografts. Intramyocardial mononuclear cell infiltrates define acute rejection, whereas chronic rejection affects large arteries. Hearts transplanted from male to female C57BL/6 mice undergo acute rejection with interstitial infiltrates at 2 weeks that resolve by 6 weeks when large arteries develop arteriopathy. These processes are dependent on T cells because no infiltrates developed in T cell–deficient mice and transfer of CD4 T cells restored T cell as well as macrophage infiltrates and ultimately neointima formation. Markers of inflammatory macrophages were up‐regulated in the interstitium acutely and decreased as markers of wound healing macrophages increased chronically. Programmed cell death protein, a negative costimulator, and its ligand PDL1 were up‐regulated in the interstitium during resolution of acute rejection. Blocking PDL1:PD1 interactions in the acute phase increased interstitial T cell infiltrates. Toll‐like receptor (TLR) 4 and its endogenous ligand hyaluronan were increased in arteries with neointimal expansion. Injection of hyaluronan fragments increased intragraft production of chemokines. Our data indicate that negative costimulatory pathways are critical for the resolution of acute interstitial infiltrates. In the arterial compartment recognition of endogenous ligands including hyaluronan by the innate TLRs may support the progression of arteriopathy.

The presence of CD28⁻ memory CD8 T cells in the peripheral blood of renal transplant patients is a risk factor for graft rejection and resistance to CTLA‐4Ig induction therapy. In vitro analyses have indicated poor alloantigen‐induced CD28⁻ memory CD8 T cell proliferation, raising questions about mechanisms mediating their clonal expansion in kidney grafts to mediate injury. Candidate proliferative cytokines were tested for synergy with alloantigen in stimulating CD28⁻ memory CD8 T cell proliferation. Addition of IL‐15, but not IL‐2 or IL‐7, to co‐cultures of CD28⁻ or CD28⁺ memory CD8 T cells and allogeneic B cells rescued proliferation of the CD28⁻ and enhanced CD28⁺ memory T cell proliferation. Proliferating CD28⁻ memory CD8 T cells produced high amounts of interferon gamma and tumor necrosis factor alpha and expressed higher levels of the cytolytic marker CD107a than CD28⁺ memory CD8 T cells. CTLA‐4Ig inhibited alloantigen‐induced proliferation of CD28⁺ memory CD8 T cell proliferation but had no effect on alloantigen plus IL‐15‐induced proliferation of either CD28⁻ or CD28⁺ memory CD8 T cells. These results indicate the ability of IL‐15, a cytokine produced by renal epithelial during inflammation, to provoke CD28⁻ memory CD8 T cell proliferation and to confer memory CD8 T cell resistance to CTLA‐4Ig‐mediated costimulation blockade.