Each feature of Th plasticity is regulated individually, balancing pathology and protection in malaria

• Published in: The Journal of immunology (1950) Vol. 204; no. 1_Supplement; pp. 75 - 75.8
• Main Authors: Stephens, Robin, Aussenac, Florentin, Clark, Lucinda Puebla, Wilson, Kyle D., Dent, Alexander L., Carpio, Victor H.
• Format: Journal Article
• Language: English
• Published: 01.05.2020
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.204.Supp.75.8

Abstract Hybrid Th1/Tfh cells (IFN-γ+IL-21+CXCR5+) predominate in response to persistent infections. However, it is not clear if the function of these cells is plastic and might be modulated. In infection with Plasmodium spp, an IFN-γ+ T helper-1 (Th1) response controls initial parasitemia, while antibody and IL-21+CXCR5+ T follicular helper (Tfh) function effect final clearance. Supporting plasticity, we found that CD4-intrinsic Bcl6, Blimp-1 and STAT3 all regulate T-bet expression, which controls IFN-γ expression. While Bcl6 and Blimp-1 regulate the level of CXCR5, only T-bet, IL-27Rα and STAT3 strongly affected the cytokine bias of the Th1/Tfh phenotype. Infected mice with STAT3-deficient T cells produced less antibody, and more Th1-like IFN-γ+IL-21−CXCR5lo T cells, significantly increasing protection from re-infection. Conversely, reduced Th1 bias in re-infected T-bet KO was reflected in prolonged secondary parasitemia. Signs of pathology were somewhat prolonged in Th1-biased animals supporting an evolutionary tradeoff between control of parasite and tissue damage. In summary, each feature of hybrid Th1/Tfh population in Plasmodium infection is uniquely regulated and the cytokine bias of memory T cells can be modified to enhance the effectiveness of the response.