Samuel Huber

T regulatory type 1 (Tr1) cells, which are defined by their regulatory function, lack of Foxp3, and high expression of IL-10, CD49b, and LAG-3, are known to be able to suppress Th1 and Th17 in the intestine. Th1 and Th17 cells are also the main drivers of crescentic glomerulonephritis (GN), the most severe form of renal autoimmune disease. However, whether Tr1 cells emerge in renal inflammation and, moreover, whether they exhibit regulatory function during GN have not been thoroughly investigated yet. To address these questions, we used a mouse model of experimental crescentic GN and double Foxp3mRFP IL-10eGFP reporter mice. We found that Foxp3neg IL-10–producing CD4+ T cells infiltrate the kidneys during GN progression. Using single-cell RNA sequencing, we could show that these cells express the core transcriptional factors characteristic of Tr1 cells. In line with this, Tr1 cells showed a strong suppressive activity ex vivo and were protective in experimental crescentic GN in vivo. Finally, we could also identify Tr1 cells in the kidneys of patients with antineutrophil cytoplasmic autoantibody–associated GN and define their transcriptional profile. Tr1 cells are currently used in several immune-mediated inflammatory diseases, such as T-cell therapy. Thus, our study provides proof of concept for Tr1 cell–based therapies in experimental GN.

During an immune response, T cells migrate from blood vessel walls into inflamed tissues by migrating across the endothelium and through extracellular matrix (ECM). Integrins facilitate T cell binding to endothelial cells and ECM proteins. Here, we report that Ca 2+ microdomains observed in the absence of T cell receptor (TCR)/CD3 stimulation are initial signaling events triggered by adhesion to ECM proteins that increase the sensitivity of primary murine T cells to activation. Adhesion to the ECM proteins collagen IV and laminin-1 increased the number of Ca 2+ microdomains in a manner dependent on the kinase FAK, phospholipase C (PLC), and all three inositol 1,4,5-trisphosphate receptor (IP 3 R) subtypes and promoted the nuclear translocation of the transcription factor NFAT-1. Mathematical modeling predicted that the formation of adhesion-dependent Ca 2+ microdomains required the concerted activity of two to six IP 3 Rs and ORAI1 channels to achieve the increase in the Ca 2+ concentration in the ER–plasma membrane junction that was observed experimentally and that required SOCE. Further, adhesion-dependent Ca 2+ microdomains were important for the magnitude of the TCR-induced activation of T cells on collagen IV as assessed by the global Ca 2+ response and NFAT-1 nuclear translocation. Thus, adhesion to collagen IV and laminin-1 sensitizes T cells through a mechanism involving the formation of Ca 2+ microdomains, and blocking this low-level sensitization decreases T cell activation upon TCR engagement.