TGF-β receptor maintains CD4 T helper cell identity during chronic viral infections.
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.
Gavin M
GM
Lewis
Ellen J
EJ
Wehrens
Lara
L
Labarta-Bajo
Hendrik
H
Streeck
Elina I
EI
Zuniga
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002908:Chronic Disease; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism; D020825:T-Box Domain Proteins
D000914:Antibodies, Viral; C491198:Eomes protein, mouse; D007074:Immunoglobulin G; D018125:Receptors, Transforming Growth Factor beta; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D020825:T-Box Domain Proteins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II