Sprouty-2 regulates HIV-specific T cell polyfunctionality
Yen-Ling Chiu, … , Diane E. Griffin, Jonathan P. Schneck
Yen-Ling Chiu, … , Diane E. Griffin, Jonathan P. Schneck
Published December 2, 2013
Citation Information: J Clin Invest. 2014;124(1):198-208. https://doi.org/10.1172/JCI70510.
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Research Article Virology

Sprouty-2 regulates HIV-specific T cell polyfunctionality

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.

Authors

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

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Figure 1

Influenza virus M1-pulsed moDCs induce concentration-dependent proliferation of M1-specific CD8+ T cells with variable levels of polyfunctionality.

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Influenza virus M1-pulsed moDCs induce concentration-dependent prolifera...
(A–C) Percentage of M1-specific T cells and M1-specific T cell expansion. Autologous moDCs pulsed with variable amounts of the HLA-A*0201 restricted immunodominant M1 peptide (10 μM∼10 fM) were used to stimulate HLA-A*A201+ CD8+ T cells ex vivo weekly for 2 weeks. Cultures were analyzed on D14. (D–H) Functional assessment of M1-specific T cells: polyfunctionality assessment of M1-specific T cells reveals significant impairment of T cells induced with a high antigen concentration (10 μM peptide-pulsed moDCs). (D) Top row: intracellular cytokine staining for IL-2 versus CD107. Numbers in red represent the percentage of IL-2–producing (right upper quadrant) versus IL-2–negative cells (right lower quadrant) in the CD107a-positive cell population. Bottom row: intracellular cytokine staining for TNF-α versus MIP-1β. Numbers in red represent the percentage of TNF-α–producing (right upper quadrant) versus TNF-α–negative cells (right lower quadrant) in the MIP-1β–positive cell population. (E) Percentage of individual effector function expression out of total antigen specific response. (F) Polyfunctionality pie charts. Each slice of pie represents the percentage of cells expressing between 1 and 5 effector functions. To compare different pie charts, permutation test with 10,000 repetitions was used. (G) The percentage of 5+ function cells in each T cell culture. (H) Amount of IL-2 produced by 5+ function cells. IL-2 production was quantified by measuring MFI and plotted for 5+ function cells. *P < 0.05. The data are representative of at least 3 assessments with 5 different donors.