T Helper Plasticity Is Orchestrated by STAT3, Bcl6, and Blimp-1 Balancing Pathology and Protection in Malaria

Abstract

Summary 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 − CXCR5 lo 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.

Cytokine-skewed Tfh cells: functional consequences for B cell help

“…In addition, STAT3, which transduces signals from the IL-6 receptor, also regulates the commitment of CD4 + T cells to either a Tfh1 or Th1 phenotype in a Plasmodium sp. mouse infection model by regulating T-bet expression to avoid potential immunopathology [46].…”

“…Ligation of the IL-12 receptor activates STAT4 and STAT3 in mouse [44] and human [45] CD4 + T cells, leading to the expression of a Th1 and Tfh transcriptional profile in this hybrid population, driven by T-bet and Bcl-6, respectively [44]. IL-27 signaling also drives a Tfh1 phenotype [46] whereas IL-2 signaling suppresses this differentiation [44].…”

Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy

“…T FH 2 cells, but not T FH 1 and T FH 17 cells, have been identified to promote IgE secretion from B cells 21 . It is now coming to the surface that the antigen type impacts the differentiation of T FH cells 22,53,63,64 . For example, T FH 1 cells are generated during human immunodeficiency virus and Ehrlichia muris infection, 63 whereas T FH 2 and T FH 13 cells are induced during allergen sensitization 22 .…”

“…For example, T FH 1 cells are generated during human immunodeficiency virus and Ehrlichia muris infection, 63 whereas T FH 2 and T FH 13 cells are induced during allergen sensitization 22 . The discovery of dual transcription factor‐expressing or cytokine‐producing T FH cells indicates the plasticity and functional complexity of T FH cells 22,53,63,64 . These dual transcription factor‐expressing or cytokine‐producing T FH cells play a specific role in dictating selective features of GC reaction.…”

Identification and Immune Assessment of T Cell Epitopes in Five Plasmodium falciparum Blood Stage Antigens to Facilitate Vaccine Candidate Selection and Optimization

“…The role of T cell immune responses against blood stage malaria infection has been elucidated through studies in mouse models and in clinical trials. Helper CD4 T cell responses are important for B cell stimulation and B cell-mediated clearance of parasites during models of chronic infection (8)(9)(10). Moreover, these cells can play a direct role in enabling the killing of activated phagocytes that have phagocytosed infected erythrocytes (11).…”