UC San Diego

Maintenance of the regulatory T (Treg) cell pool is essential for peripheral tolerance and prevention of autoimmunity. Integrins, heterodimeric transmembrane proteins consisting of and subunits that mediate cell-cell and cell-extracellular matrix interactions, play an important role in facilitating Treg cell contact-mediated suppression. Here we show that integrin activation plays an essential, previously unappreciated role in maintaining the identity and function of the Treg cell pool. Talin, a cytoskeletal protein essential in mediating integrin activation, has been previously shown to be involved in the regulation of T cell proliferation and function. T cell-specific deletion of talin in Tln1fl/flCd4Cre mice resulted in spontaneous lymphocyte activation, primarily due to numerical and functional deficiencies of Treg cells in the periphery. Peripheral talin-deficient Treg cells were unable to maintain high expression of IL-2Rα, resulting in impaired IL-2 signaling and ultimately leading to increased apoptosis through downregulation of pro-survival proteins Bcl-2 and Mcl-1. Treg cell-specific loss of talin, or expression of talin(L325R), a mutant that selectively abrogates integrin activation, resulted in dysregulation of Treg cell identity and lethal systemic autoimmunity. This dysfunction could be attributed, in part, to a failure of Treg cells to maintain high expression of important Treg cell suppressive molecules and global dysregulation of the Treg cell transcriptome. Activation of 41 or L2 integrins led to increased expression of IL-2R and boosted the size of the Treg cell population, respectively, suggesting that modulating integrin activation on Treg cells may be a useful therapeutic strategy for autoimmune and inflammatory disorders. Taken together, these results reveal a critical role for integrin-mediated signals in controlling peripheral tolerance by virtue of maintaining Treg cell identity and function.