CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging

Chronic systemic inflammation is one of the hallmarks of the aging immune system. Here we show that activated T cells from older adults contribute to inflammaging by releasing mitochondrial DNA (mtDNA) into their environment due to an increased expression of the cytokine-inducible SH2-containing protein (CISH). CISH targets ATP6V1A, an essential component of the proton pump V-ATPase, for proteasomal degradation, thereby impairing lysosomal function. Impaired lysosomal activity caused intracellular accumulation of multivesicular bodies and amphisomes and the export of their cargos, including mtDNA. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal release. In antigen-specific responses in vivo, CISH-deficient CD4+ T cells released less mtDNA and induced fewer inflammatory cytokines. Attenuating CISH expression may present a promising strategy to reduce inflammation in an immune response of older individuals. Chronic inflammation is a sign of immune system aging. Here the authors show that T cells from older adults contribute to inflammation due to CISH-mediated enhanced proteasomal degradation of a component of the proton pump V-ATPase, resulting in reduced lysosome function and the release of mtDNA and other amphisomal content.