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Article Dans Une Revue Journal of Experimental Medicine Année : 2023

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

Résumé

Mice with a loss-of-function mutation in the LAT adaptor (LatY136F) develop an autoimmune and type 2 inflammatory disorder called defective LAT signalosome pathology (DLSP). We analyzed via single-cell omics the trajectory leading to LatY136F 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 LatY136F 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 LatY136F 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 LatY136F CD4+ T cells hand over their central role in T cell activation to CD28 costimulatory molecules. As a result, all subsequent LatY136F DLSP manifestations, including the production of autoantibodies, solely rely on CD28 engagement. Our findings elucidate the etiology of the LatY136F DLSP and qualify it as a model of IgG4-RD.
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Dates et versions

hal-04239647 , version 1 (12-10-2023)

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Anais Joachim, Rudy Aussel, Léna Gélard, Fanghui Zhang, Daiki Mori, et al.. Defective LAT signalosome pathology in mice mimics human IgG4-related disease at single-cell level. Journal of Experimental Medicine, 2023, 220 (11), ⟨10.1084/jem.20231028⟩. ⟨hal-04239647⟩

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