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Targeting TFH cells in human diseases and vaccination: rationale and practice

Abstract

The identification of CD4+ T cells localizing to B cell follicles has revolutionized the knowledge of how humoral immunity is generated. Follicular helper T (TFH) cells support germinal center (GC) formation and regulate clonal selection and differentiation of memory and antibody-secreting B cells, thus controlling antibody affinity maturation and memory. TFH cells are essential in sustaining protective antibody responses necessary for pathogen clearance in infection and vaccine-mediated protection. Conversely, aberrant and excessive TFH cell responses mediate and sustain pathogenic antibodies to autoantigens, alloantigens, and allergens, facilitate lymphomagenesis, and even harbor viral reservoirs. TFH cell generation and function are determined by T cell antigen receptor (TCR), costimulation, and cytokine signals, together with specific metabolic and survival mechanisms. Such regulation is crucial to understanding disease pathogenesis and informing the development of emerging therapies for disease or novel approaches to boost vaccine efficacy.

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Fig. 1: Elements of TFH function.
Fig. 2: Protective functions of TFH cells in infection, vaccination, and cancer.
Fig. 3: Pathogenic roles of TFH cells in human diseases.
Fig. 4: Targeting TFH cells’ critical regulatory pathways in disease therapy and vaccination.

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Acknowledgements

We thank members of the Yu group for constructive discussion and P.F. Canete for editing. D.Y. is supported by the Bellberry-Viertel Senior Medical Research Fellowship and Australian National Health and Medical Research Council grants (GNT2009554, GNT1147709, GNT1147769). L.S.K.W. is supported by a Wellcome Investigator Award (220772/Z/20/Z), the Medical Research Council (MR/N001435/1) and Diabetes UK (15/0005253). M.A.L is supported by funding from the Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0407, BBS/E/B/000C0427) and is an EMBO Young Investigator and Lister Prize Fellow. This research was carried out at the Translational Research Institute, Woolloongabba, QLD 4102, Australia. The Translational Research Institute is supported by a grant from the Australian Government.

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Yu, D., Walker, L.S.K., Liu, Z. et al. Targeting TFH cells in human diseases and vaccination: rationale and practice. Nat Immunol 23, 1157–1168 (2022). https://doi.org/10.1038/s41590-022-01253-8

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