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 - 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
C2 - 32634740
AN - SCOPUS:85087364233
SN - 2589-0042
VL - 23
JO - iScience
JF - iScience
IS - 7
M1 - 101310
ER -