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TGF-β receptor maintains CD4 T helper cell identity during chronic viral infections
Gavin M. Lewis, … , Hendrik Streeck, Elina I. Zuniga
Gavin M. Lewis, … , Hendrik Streeck, Elina I. Zuniga
Published September 6, 2016
Citation Information: J Clin Invest. 2016;126(10):3799-3813. https://doi.org/10.1172/JCI87041.
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Research Article Immunology Article has an altmetric score of 10

TGF-β receptor maintains CD4 T helper cell identity during chronic viral infections

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Abstract

Suppression of CD8 and CD4 T cells is a hallmark in chronic viral infections, including hepatitis C and HIV. While multiple pathways are known to inhibit CD8 T cells, the host molecules that restrict CD4 T cell responses are less understood. Here, we used inducible and CD4 T cell–specific deletion of the gene encoding the TGF-β receptor during chronic lymphocytic choriomeningitis virus infection in mice, and determined that TGF-β signaling restricted proliferation and terminal differentiation of antiviral CD4 T cells. TGF-β signaling also inhibited a cytotoxic program that includes granzymes and perforin expression at both early and late stages of infection in vivo and repressed the transcription factor eomesodermin. Overexpression of eomesodermin was sufficient to recapitulate in great part the phenotype of TGF-β receptor–deficient CD4 T cells, while SMAD4 was necessary for CD4 T cell accumulation and differentiation. TGF-β signaling also restricted accumulation and differentiation of CD4 T cells and reduced the expression of cytotoxic molecules in mice and humans infected with other persistent viruses. These data uncovered an eomesodermin-driven CD4 T cell program that is continuously suppressed by TGF-β signaling. During chronic viral infection, this program limits CD4 T cell responses while maintaining CD4 T helper cell identity.

Authors

Gavin M. Lewis, Ellen J. Wehrens, Lara Labarta-Bajo, Hendrik Streeck, Elina I. Zuniga

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Figure 4

SMAD4 is required for accumulation and differentiation of CD4 and CD8 T cells during chronic LCMV infection.

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SMAD4 is required for accumulation and differentiation of CD4 and CD8 T ...
Reconstituted 1:1 mix of WT (CD45.1, black) and ERCre+ Smad4fl/fl (iSM4flox, red) bone marrow–chimeric mice were tamoxifen treated for 5 days and 1 week later infected with 2 × 106 PFU of LCMV Cl13. T cells were analyzed in blood by flow cytometry. (A) Percentage of PD1+ CD4 T cells after gating on CD4 T cells from each donor. (B) Expression of indicated markers in PD1+ CD4 T cells. (C) Percentage of PD1+ CD8 T cells after gating on CD8 T cells from each donor. (D) Expression of indicated markers in PD1+ CD8 T cells. WT (black) and iSM4flox (red). Representative of 3 independent experiments, with n = 4 or 5 mice/experiment. Paired t test, *P < 0.05, **P < 0.005, ***P < 0.0005.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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