Work

Butyrophilin 2A2 promotes T cell immunoregulation via CD45 phosphatase activation and protects against murine autoimmune glomerulonephritis and pregnancy loss

Year: 2026

Type: article

Abstract: B7 costimulatory family member Butyrophilin 2A2 (BTN2A2) is predominantly expressed by antigen presenting cells and regulates T cell immunity, but molecular mechanisms are unclear. Using immunoblots analyzing TCR-initiated signaling intermediaries, co-immunoprecipitation studies, confocal microscopy, structural modeling-guided mutational analyses, and microscale thermophoresis, we demonstrate that BTN2A2 directly interacts with CD45RO, resulting in CD45 retention within the immune synapse during TCR activation. Recombinant BTN2A2 increases murine CD4+Foxp3+ regulatory T cells (Treg) and reduces T helper 17 (Th17) cells in vitro through mechanisms dependent on CD45 phosphatase activity. BTN2A2 therapy alleviates disease severity in murine nephrotoxic glomerulonephritis and autoimmune miscarriage while increasing Treg/Th17 ratios. Analyses of BTN2A2-deficient animals show exacerbation of disease associated with reduced Treg/Th17 ratios. BTN2A2 functions analogously on human T cells suppressing Th17, Th1 and Th2 responses while inducing Tregs. Together, our studies identify BTN2A2 as a modulator of CD45RO signaling in T cells, providing insight into how BTN2A2 regulates T cell-dependent immune responses including those mediating autoimmunity and transplant rejection. Butyrophilin 2A2 is a member of the B7 costimulatory family that is expressed on antigen presenting cells and is linked to the regulation of T cells. Here the authors implicate butyrophilin 2A2 in enhancement of CD45 phosphatase activity within the immunological synapse during T cell activation, leading to expansion of regulatory T cells and reduction of proinflammatory Th17 CD4 T cells.

Source: Nature Communications

DOI: 10.1038/s41467-025-68077-6