Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

Tonnerre, P.; Wolski, D.; Subudhi, S.; Al-Jabban, J.; Hoogeveen, R. C.; Damasio, M.; Drescher, H. K.; Bartsch, L. M.; Tully, D. C.; Sen, D. R.; Bean, D. J.; Brown, J.; Torres-Cornejo, A.; Robidoux, M.; Kvistad, D.; Alatrakchi, N.; Cui, A.; Lieb, D.; Cheney, J. A.; Gustafson, J.; Lewis-Ximenez, L. L.; Massenet-Regad, L.; Eisenhaure, T.; Aneja, J.; Haining, W. N.; Chung, R. T.; Hacohen, N.; Allen, T. M.; Kim, A. Y.; Lauer, G. M.

doi:10.1101/2021.04.03.437705

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bioRxiv · 10.1101/2021.04.03.437705

Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory

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Abstract

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Analysis of antigen-specific CD8+ T cells before and after antigen removal in human hepatitis C virus (HCV) infection confirmed pervasive phenotypic, functional, and transcriptional differences between exhausted and memory CD8+ T cells. After viral cure, we observed broad phenotypic and transcriptional changes in clonally stable exhausted T-cell populations suggesting differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for shorter periods of time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved acute HCV infection. Thus, duration of T cell stimulation impacts the ability to recover from exhaustion, as antigen removal after long-term T cell exhaustion is insufficient for the development of key T cell memory characteristics.

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Tonnerre, P., Wolski, D., Subudhi, S., Al-Jabban, J., Hoogeveen, R. C., Damasio, M., Drescher, H. K., Bartsch, L. M., Tully, D. C., Sen, D. R., Bean, D. J., Brown, J., Torres-Cornejo, A., Robidoux, M., Kvistad, D., Alatrakchi, N., Cui, A., Lieb, D., Cheney, J. A., Gustafson, J., Lewis-Ximenez, L. L., Massenet-Regad, L., Eisenhaure, T., Aneja, J., Haining, W. N., Chung, R. T., Hacohen, N., Allen, T. M., Kim, A. Y., Lauer, G. M.. 2021-04-04. Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. https://doi.org/10.1101/2021.04.03.437705

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