Advisor(s)
Andre Ballesteros-Tato
Committee Member(s)
Casey Weaver
Jianmei Leavenworth
Robert Welner
Troy Randall
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Joint Health Sciences
Date of Award
9-11-2025
Abstract
T follicular helper (Tfh) cells are a specialized subset of CD4+ T cells that sup-port germinal center (GC) B cells and promote antibody (Ab)-mediated immunity. There is growing recognition of the heterogeneity and functional diversity of Tfh cells, supported by accumulating evidence that highlights their context-specific roles across a range of disease settings. While their contribution to B cell responses is well-established, our data demonstrate that Tfh cells have a broader and more dynamic function. In this study, we uncover a novel function of Tfh cells in maintaining immune homeostasis by supporting T regulatory cell (Treg) responses under normal physiological conditions. Interleukin-2 (IL-2) is a non-redundant cytokine essential for the development, maintenance, and function of Tregs. However, the relative contribution of IL-2-producing CD4⁺ T cell subsets across different spatial niches within gut-associated lymphoid tissues (GALT) remains poorly understood. We show that, under steady-state conditions, Tfh cells in the mesenteric lymph nodes (mLNs) and Peyer’s patches (PPs) serve as a prominent source of IL-2. Within the mLNs, IL-2-producing Tfh cells are primarily localized to the interfollicular (IF) region and the T: B border. In addition to the T cell area, our data show that Tregs are also present in the IF region and at the T: B border, where they frequently co-localize with Tfh cells. This spatially restricted IL-2 production appears to be essential for maintaining Treg identity and function within the gastrointestinal (G.I) tract. Strikingly, selective deletion of IL-2 from Tfh cells results in a breakdown of immune tolerance, characterized by Treg dysfunction, uncontrolled immune activation, and fatal multi-organ inflammation. Comprehensive functional assays and transcriptional profiling revealed that IL-2 derived from Tfh cells is essential for sustaining the competitive fit-ness of Tregs in the context of constant exposure to the G.I antigens. Taken together, our findings reveal an unappreciated role for Tfh cells as a key source of paracrine IL-2 re-quired for sustaining Treg-mediated immune regulation in the gut. This study highlights an essential axis of Tfh-Treg crosstalk that extends the functional scope of Tfh cells be-yond B cell help.
ProQuest ID
Recommended Citation
Dave, Shivangi, "A Noncanonical Role Of T Follicular Helper Cells In Promoting Peripheral Tolerance By Supporting T Regulatory Cells" (2025). All ETDs from UAB. 7357.
https://digitalcommons.library.uab.edu/etd-collection/7357
