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Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF
Open accessAbstract
CD8+ T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8+ T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8+ T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes—such as BATF—that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.
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Metadata
- Authors
- Quigley, M., Pereyra, F., Nilsson, B., Porichis, F., Fonseca, C., Eichbaum, Q., Julg, B., Jesneck, J. L., Brosnahan, K., Imam, S., Russell, K., Toth, I., Piechocka-Trocha, A., Dolfi, D., Angelosanto, J., Crawford, A., Shin, H., Kwon, D. S., Zupkosky, J., Francisco, L., Freeman, G. J., Wherry, E. J., Kaufmann, D. E., Walker, B. D., Ebert, B., & Haining, W. N.
- Venue
- Nature Medicine
- Published
- 2010-10
- Volume
- 16
- Issue
- 10
- Pages
- 1147-1151
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1997241837
- Cited by
- 517
- References
- 34
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- green
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