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

Kojima, H.; Wayne, C. R.; Somarribas Patterson, L. F.; Sanford, H.; Chen, T.-J.; Lin, Y.-H.; Schoenfeld, J. D.; McGary, L. H. F.; Chen, Y.-T.; Kropp, K. N.; Zhang, B.; Rahman, J.; Zhang, T. L.; Ropek, N.; Roberts, C.; Ai, Y.; Menon, K.; Hakimi, A. A.; Lyu, J.; Klebanoff, C. A.; Abdel-Wahab, O.; Vardhana, S. A.; Vinogradova, E. V.

doi:10.64898/2026.03.04.709614

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bioRxiv · 10.64898/2026.03.04.709614

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

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Abstract

T cells exposed to persistent antigen in the context of chronic viral infections or cancer lose self-renewal and cytotoxic capacity. 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 molecular landscape of human T cells during the development of chronic antigen-driven dysfunction. Persistent T cell receptor stimulation significantly remodeled the proteome, including changes in canonical T cell exhaustion-associated proteins and proteins related to mitochondrial function, redox homeostasis, nucleotide metabolism, and cell-cycle progression. Dysfunctional T cells displayed activation of stress response pathways that were recapitulated in vivo; targeting these pathways altered the cytotoxic capacity of T cells during persistent tumor exposure. Our comprehensive proteomic resource reveals unique post-transcriptional changes in dysfunctional T cells and lays the groundwork for novel cysteine-directed therapeutics to enhance cancer immunotherapy.

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Kojima, H., Wayne, C. R., Somarribas Patterson, L. F., Sanford, H., Chen, T.-J., Lin, Y.-H., Schoenfeld, J. D., McGary, L. H. F., Chen, Y.-T., Kropp, K. N., Zhang, B., Rahman, J., Zhang, T. L., Ropek, N., Roberts, C., Ai, Y., Menon, K., Hakimi, A. A., Lyu, J., Klebanoff, C. A., Abdel-Wahab, O., Vardhana, S. A., Vinogradova, E. V.. 2026-03-06. A post-translational regulatory map of chronic antigen-driven human T cell dysfunction.. https://doi.org/10.64898/2026.03.04.709614

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