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Robin Stephens, Alexander L Dent, Victor H Carpio, STAT3 in T cells Regulates Protective Capacity of Hybrid Type 1/Follicular helper T cells in Persistent Mouse Malaria Infection, The Journal of Immunology, Volume 202, Issue 1_Supplement, May 2019, Page 190.28, https://doi.org/10.4049/jimmunol.202.Supp.190.28
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Abstract
In infection with Plasmodium spp., IFN-γ+ T helper (Th)1 cells control peak parasitemia, while antibody and IL-21+ T follicular helper (Tfh) cells effect final clearance. However, we show that hybrid Th1/Tfh cells (IFN-γ+IL-21+CXCR5+), reported to be sub-optimal Th cells and to inhibit Germinal Centers (GC), dominate the immune response to P. chabaudi infection. Th1/Tfh expand but plateau at low levels while GC form, with GC-Tfh numbers stable throughout. To understand molecular mechanisms of differentiation of Th1/Tfh, mice deficient in several transcription factors targeted in T cells were infected. We found that T cell-intrinsic Bcl6 and Blimp-1 regulated CXCR5 and IL-10 expression in Th1/Tfh cells. Bcl6, Blimp-1 and STAT3 all dampen T-bet expression. However, neither of the Signal Transducer and Activator of Transcription (STAT) proteins known to regulate T-bet expression, STAT4 or STAT1, were required for IFN-γ production by Th1/Tfh. On the other hand, T cell deficiency of the Tfh-promoting transcription factor, STAT3, reduced antibody while non-hybrid Th1 cells increased and mice were fully protected from re-infection. Conversely, deficiency in T-bet, reduced Th1 differentiation, including dramatically reducing production of IFN-γ and specific antibody of the IgG2b isotype, and showed reduced control of re-infection. We have previously shown that few committed Th1 memory cells are generated in Plasmodium infection, importantly here the increase in Th1 features in STAT3-deficient T cells can improve control of reinfection. In summary, a flexible T cell population regulates each effector function with multiple transcription factors, providing plasticity to allow continuous responsiveness to prolonged infection.
