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- Title
Sprouty-2 regulates HIV-specific T cell polyfunctionality.
- Authors
Yen-Ling Chill; Liang Shan; Hailiang Huang; Carl Haupt; Catherine Bessell; Canaday, David H.; Hao Zhang; Ya-Chi Ho; Powell, Jonathan D.; Oelke, Mathias; Margolick, Joseph B.; Blankson, Joel N.; Griffin, Diane E.; Schneck, Jonathan P.
- 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.
- Subjects
HUMAN T cells; LYMPHOCYTES; T cells; HIV-positive persons; CLINICAL immunology; VIRUS diseases; ANTIGENS
- Publication
Journal of Clinical Investigation, 2014, Vol 124, Issue 1, p198
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI70510