A post-translational regulatory map of chronic antigen-driven human T cell dysfunction

Several transcriptional, epigenetic, and metabolic drivers of this process have been identified. However, the post-transcriptional regulatory mechanisms influencing the proteome of dysfunctional T cells are not well understood.

Here we present a time-resolved cysteine reactivity landscape of human T cells during the development of chronic antigen-driven dysfunction. Persistent T cell receptor stimulation of human T cells following activation significantly remodeled the T cell proteome compared with cytokine-mediated expansion, including changes in canonical T cell exhaustion-associated proteins as well as proteins related to mitochondrial function, redox homeostasis, nucleotide metabolism, and cell cycle progression.