Sprouty-2 regulates HIV-specific T cell polyfunctionality

Yen Ling Chiu, Liang Shan, Hailiang Huang, Carl Haupt, Catherine Bessell, David H. Canaday, Hao Zhang, Ya Chi Ho, Jonathan D. Powell, Mathias Oelke, Joseph B. Margolick, Joel N. Blankson, Diane E. Griffin, Jonathan P. Schneck

Research output: Contribution to journalArticlepeer-review

Abstract

The ability of individual T cells to perform multiple effector functions is crucial for protective immunity against viruses and cancer. This polyfunctionality is frequently lost during chronic infections; however, the molecular mechanisms driving T cell polyfunctionality are poorly understood. We found that human T cells stimulated by a high concentration of antigen lacked polyfunctionality and expressed a transcription profile similar to that of exhausted T cells. One specific pathway implicated by the transcription profile in control of T cell polyfunctionality was the MAPK/ERK pathway. This pathway was altered in response to different antigen concentrations, and polyfunctionality correlated with upregulation of phosphorylated ERK. T cells that were stimulated with a high concentration of antigen upregulated sprouty-2 (SPRY2), a negative regulator of the MAPK/ERK pathway. The clinical relevance of SPRY2 was confirmed by examining SPRY2 expression in HIV-specific T cells, where high levels of SPRY2 were seen in HIV-specific T cells and inhibition of SPRY2 expression enhanced the HIV-specific polyfunctional response independently of the PD-1 pathway. Our findings indicate that increased SPRY2 expression during chronic viral infection reduces T cell polyfunctionality and identify SPRY2 as a potential target for immunotherapy.

Original languageEnglish (US)
Pages (from-to)198-208
Number of pages11
JournalJournal of Clinical Investigation
Volume124
Issue number1
DOIs
StatePublished - Jan 2 2014

ASJC Scopus subject areas

  • Medicine(all)

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