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 Powell, Mathias Oelke, Joseph Bernard Margolick, Joel N Blankson, Diane Griffin, Jonathan P Schneck

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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
Publication statusPublished - Jan 2 2014

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chiu, Y. L., Shan, L., Huang, H., Haupt, C., Bessell, C., Canaday, D. H., ... Schneck, J. P. (2014). Sprouty-2 regulates HIV-specific T cell polyfunctionality. Journal of Clinical Investigation, 124(1), 198-208. https://doi.org/10.1172/JCI70510