Defective LAT signalosome pathology in mice mimics human IgG4-related disease at single-cell level

Mice with a loss-of-function mutation in the LAT adaptor (Lat(Y136F)) develop an autoimmune and type 2 inflammatory disorder called defective LAT signalosome pathology (DLSP). We analyzed via single-cell omics the trajectory leading to Lat(Y136F) DLSP and the underlying CD4+ T cell diversification. T follicular helper cells, CD4+ cytotoxic T cells, activated B cells, and plasma cells were found in Lat(Y136F) spleen and lung. Such cell constellation entailed all the cell types causative of human IgG4-related disease (IgG4-RD), an autoimmune and inflammatory condition with Lat(Y136F) DLSP-like histopathological manifestations. Most previously described T cell-mediated autoimmune manifestations require persistent TCR input. In contrast, following their first engagement by self-antigens, the autoreactive TCR expressed by Lat(Y136F)CD4+ T cells hand over their central role in T cell activation to CD28 costimulatory molecules. As a result, all subsequent Lat(Y136F)DLSP manifestations, including the production of autoantibodies, solely rely on CD28 engagement. Our findings elucidate the etiology of the Lat(Y136F) DLSP and qualify it as a model of IgG4-RD.