Implication of the CD47 pathway in autoimmune diabetes.

CD47 and signal regulatory protein (SIRP) interactions have been proposed to take part in autoimmune disease susceptibility. Importantly, a recent genome-wide association study for type 1 diabetes susceptibility highlighted the association of the 20p13 region comprising the SIRP cluster, where some of the SIRP proteins encode functional ligands to CD47. Using a TCR transgenic mouse model at the brink of autoimmune disease, we demonstrate that CD47-deficiency is sufficient to break the immune tolerance and provoke the onset of autoimmune diabetes. Interestingly, CD47-deficient mice show a severe reduction in the number of mature CD4(-)CD8(-) T cells, and passive transfer of these CD4(-)CD8(-) T cells is sufficient to restore immune tolerance and prevent diabetes progression. Together, these findings constitute an in vivo demonstration that CD47 is involved in diabetes susceptibility and controls the homeostatic regulation of CD4(-)CD8(-) T cells.