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

Abstract

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.

A twist in the tail: Of T cell subsets and disease

“…It is known that EOMES expressing CD4 + CTLs can evolve in type 2 milieus as seen in human nasal polyps (Ma et al, 2021), so there is no formal basis to link CD4 + CTLs to a type 1 milieu. The serial studies from Joachim et al (2023) clearly demonstrate that Th1 cells are not even a required intermediate for CD4 + CTL generation. The broader inference, therefore, is that diseases driven by CD4 + CTLs represent a distinct category that does not fit the type 1, type 2, or type 3 paradigms for immune responses and disease.…”

“…Using a single-cell transcriptomic approach, Joachim et al (2023) serially examined immune cells in the spleens of LAT Y136F mice at different times after birth, and they also used high-dimensional flow cytometry in the spleen and in the lungs to examine T and B cell subsets that infiltrate tissues and are likely drivers of tissue inflammation. TCR levels on T cells in these mice are low and re-triggering of T cells depends heavily on the ligation of CD28.…”

Redox Regulation of LAT Enhances T Cell-Mediated Inflammation

“…LAT expression, function, and localization have previously been shown to be regulated by post-translational modifications to residues on its cytoplasmic tail. A LAT knock-in strain with a tyrosine-to-phenylalanine mutation (LAT Y136F ) peculiarly exhibits a partial block in T cell maturation combined with a lethal autoimmune and lymphoproliferative disorder [16], mimicking human IgG4related disease [17]. Ubiquitylation of lysines K52 and K204 promotes the degradation of internalized LAT and prevents efficient recycling of LAT to the plasma membrane [18,19].…”