TY - JOUR
T1 - T Helper Plasticity Is Orchestrated by STAT3, Bcl6, and Blimp-1 Balancing Pathology and Protection in Malaria
AU - Carpio, Victor H.
AU - Aussenac, Florentin
AU - Puebla-Clark, Lucinda
AU - Wilson, Kyle D.
AU - Villarino, Alejandro V.
AU - Dent, Alexander L.
AU - Stephens, Robin
N1 - Funding Information:
This work was supported by the NIH National Institute of Allergy and Infectious Diseases ( R01AI08995304 [R.S., V.H.C.], R01AI135061 [R.S., V.H.C., F.A.], R01AI132771 [A.L.D.], R01AI08995304S1 [R.S., V.H.C.], and F31AI126809 [V.H.C.]) and the James W. McLaughlin and Jeane B. Kempner Fellowships (V.H.C., K.D.W.). We appreciate the expertise of Mark Griffin in the UTMB Microbiology & Immunology Flow Cytometry Core, and Gabriela M. Kaus and Margarita Ramirez for expert animal colony maintenance. We appreciate the scientific contribution of all Stephens and Joint Immunology Lab meeting members (Y. Cong, J. Sun, H. Hu, J.J. Endsley, R. Rajsbaum, L. Soong). Thanks to Roza I. Nurieva, John O'Shea, and Noah S. Butler for ideas, reagents, and protocols.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/7/24
Y1 - 2020/7/24
N2 - Hybrid Th1/Tfh cells (IFN-γ+IL-21+CXCR5+) predominate in response to several persistent infections. In Plasmodium chabaudi infection, IFN-γ+ T cells control parasitemia, whereas antibody and IL-21+Bcl6+ T cells effect final clearance, suggesting an evolutionary driver for the hybrid population. We found that CD4-intrinsic Bcl6, Blimp-1, and STAT3 coordinately regulate expression of the Th1 master regulator T-bet, supporting plasticity of CD4 T cells. Bcl6 and Blimp-1 regulate CXCR5 levels, and T-bet, IL-27Rα, and STAT3 modulate cytokines in hybrid Th1/Tfh cells. Infected mice with STAT3 knockout (KO) T cells produced less antibody and more Th1-like IFN-γ+IL-21−CXCR5lo effector and memory cells and were protected from re-infection. Conversely, T-bet KO mice had reduced Th1-bias upon re-infection and prolonged secondary parasitemia. Therefore, each feature of the CD4 T cell population phenotype is uniquely regulated in this persistent infection, and the cytokine profile of memory T cells can be modified to enhance the effectiveness of the secondary response.
AB - Hybrid Th1/Tfh cells (IFN-γ+IL-21+CXCR5+) predominate in response to several persistent infections. In Plasmodium chabaudi infection, IFN-γ+ T cells control parasitemia, whereas antibody and IL-21+Bcl6+ T cells effect final clearance, suggesting an evolutionary driver for the hybrid population. We found that CD4-intrinsic Bcl6, Blimp-1, and STAT3 coordinately regulate expression of the Th1 master regulator T-bet, supporting plasticity of CD4 T cells. Bcl6 and Blimp-1 regulate CXCR5 levels, and T-bet, IL-27Rα, and STAT3 modulate cytokines in hybrid Th1/Tfh cells. Infected mice with STAT3 knockout (KO) T cells produced less antibody and more Th1-like IFN-γ+IL-21−CXCR5lo effector and memory cells and were protected from re-infection. Conversely, T-bet KO mice had reduced Th1-bias upon re-infection and prolonged secondary parasitemia. Therefore, each feature of the CD4 T cell population phenotype is uniquely regulated in this persistent infection, and the cytokine profile of memory T cells can be modified to enhance the effectiveness of the secondary response.
KW - Immunology
KW - Parasitology
UR - http://www.scopus.com/inward/record.url?scp=85087364233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087364233&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2020.101310
DO - 10.1016/j.isci.2020.101310
M3 - Article
AN - SCOPUS:85087364233
SN - 2589-0042
VL - 23
JO - iScience
JF - iScience
IS - 7
M1 - 101310
ER -