Aged regulatory T cells fail to control autoimmune lacrimal gland pathogenic CD4+ T cells

Abstract

CD25KO mice are a model of Sjögren disease. CD25KO mice have severe inflammation and infiltrating lymphocytes to the lacrimal glands (LG). Whether the pathogenicity of CD25KO CD4⁺ T cells can be controlled in vivo by Tregs is unknown. Eight-week-old B6 and CD25KO mice LGs were submitted for RNA bulk sequencing. A total of 3481 genes were differentially expressed in CD25KO LG compared to B6. Tear washing analysis identified CD25KO mice had elevated protein levels of TNF, IFN-γ, and CCL5 and decreased protein levels of IL-12p40 and VEGF-A. Co-adoptive transfer of CD25KO CD4⁺ T cells with either young or aged B6 Tregs was performed in RAG1KO mice. Recipients of CD25KO CD4⁺ T cells alone had higher LG inflammation than naive mice. However, in recipients of young B6 Tregs plus CD25KO CD4⁺ T cells, LGs had significantly reduced inflammation. Recipients of CD25KO CD4⁺ T cells with aged B6 Tregs had more inflamed LGs than young Tregs, suggesting aged Tregs have less suppressive capacity in vivo. Altogether, CD25KO mice have phenotypic and genetic changes resulting in increased inflammation and severe lymphocytic infiltration in the LGs. However, this autoimmunity can be controlled by the addition of young, but not aged, Tregs, suggesting that aging Tregs have dysfunctional suppression.