In order to protect the body from viruses and cancer, T cells must perform multiple functions, a feature that is often lost during chronic infection. Jonathan Schneck and colleagues examined the molecular mechanisms that maintain T cell polyfunctionality. They found that MAPK/ERK signaling was upregulated in polyfunctional T cells and that activation of this pathway was altered in response to different levels of antigen. Importantly, high levels of antigen increased levels of sprouty-2 (SPRY2), a negative regulator of MAPK/ERK signaling. High levels of SPRY2 were observed in HIV-specific T cells and inhibition of SPRY2 expression increased polyfunctional responses to HIV. These findings suggest that SPRY2 could be targeted to increase T cell polyfunctionality in the context of chronic viral infections.
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 (
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