Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity

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Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity

Authors

Dalit, L.; Tan, C. W.; Sheikh, A. A.; Munnings, R.; Alvarado, C.; Hussain, T.; Zaini, A.; Cooper, L.; Kirn, A.; Hailes, L.; Nguyen, A.; Mackay, L.; Harris, N.; Zaph, C.; La Gruta, N. L.; Nutt, S. L.; Good-Jacobson, K.; Davis, M. J.; Bryant, V. L.; Groom, J. R.

Abstract

Adaptive immune responses protect against multiple classes of pathogens, including viral, bacterial, fungal, and helminth infections. In all these settings, CD4+ T follicular helper (Tfh) cells tailor high-affinity class-switched B cells responses. How Tfh lineage sovereignty is established while allowing for this context-specific functional heterogeneity is unclear. Here, we identify Tfh transcriptional networks in response to diverse infections. While Bcl-6 is the transcriptional linchpin of the core Tfh signature, this is overlayed with pathogen-specific transcriptional modules that shape Tfh function. Cytokine-transcriptional Tfh programing in mouse and human lymphoid tissue demonstrated that type I interferon and TGFb; signaling direct individual Tfh subpopulations to instruct B cell output. Here, we provide a transcriptional map and cell surface resource to interrogate Tfh diversity in humans and mice. This resource can be leveraged to further understand the origins of immune flexibility, perform immune monitoring in infection and antibody-mediated diseases and to develop context-specific vaccines.

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