Biology subjects

Zindl, C. L.

Publications and source records attributed to Zindl, C. L..

3 recordsLinked to original sources

bioRxiv2026

IL-23 Licenses Pathogenic Th17 Transdifferentiation via STAT4-dependent Upregulation of IL-12Rβ2

Th17 cells exhibit substantial developmental plasticity, transdifferentiating into pathogenic, interferon-{gamma} (IFN-{gamma})-producing Th1-like effectors during chronic autoimmune inflammation. While both IL-23 and IL-12 are implicated in this process, how these structurally related cytokines coordinate to drive transdifferentiation remains unresolved. Here, we show that IL-23 acts as a developmental licensor rather than a terminal trigger, priming Th17 cells for transdifferentiation upon subsequent IL-12 encounter. IL-23 signals through STAT4 to upregulate the IL-12-specific receptor subunit IL-12R{beta}2, lowering the signalling threshold for IL-12. This licensing can be conferred at both early and late stages of Th17 development and produces a temporal logic in which IL-23-mediated STAT4 signaling functionally arms Th17 cells to terminally transdifferentiate in response to IL-12. Using Stat4 conditional knockouts and a structure-based IL-23 mutein that selectively abolishes IL-23-driven STAT4 signaling while preserving STAT3-dependent lineage maintenance, we genetically establish the IL-23-STAT4-IL-12R{beta}2 axis as a discrete licensing module. Furthermore, using the adoptive Th17 transfer colitis model, we show that host-derived IL-23 and IL-12 are required for Th17-driven colitis, and the inflamed colonic environment reconstitutes transdifferentiation capacity in classically "non-pathogenic" Th17 cells. These findings reframe the pathogenic dichotomy of Th17 cells as one of cumulative cytokine exposure rather than fixed cellular fate, and reveal a stepwise architecture of Th17 plasticity in which IL-23 licensing and IL-12 triggering operate as functionally distinct events. Significance StatementTh17 cells protect mucosal barriers but can convert into pathogenic, IFN-{gamma}-producing effectors that drive inflammatory bowel disease (IBD). Although IL-23 is essential for this conversion, the underlying molecular mechanism remains elusive. We show that IL-23 does not directly trigger transdifferentiation but instead licenses Th17 cells for this conversion, during both early and late stages of their development. By signaling through STAT4, IL-23 upregulates the IL-12-specific receptor subunit IL-12R{beta}2 on Th17 cells, rendering them responsive to subsequent IL-12 exposure. Our findings reframe the classical "pathogenic" versus "non-pathogenic" Th17 distinction and provide a mechanistic basis for the clinical efficacy of IL-23-targeted therapies in IBD.

immunology↗

bioRxiv2026

Barrier Immune Memory is Promoted by Intestinal Epithelial Cell Presentation of Injected Bacterial Antigens

The contributions of antigen compartmentalization to recognition differences between CD4 and CD8 T cells have long been appreciated, but little is known of how subcellular localization of different antigens expressed by a single pathogen impacts T cell immunity. By tracking a clonal CD4 T cell response to its cognate epitope shuttled between different virulence proteins of the enteropathogenic bacterium, Citrobacter rodentium (Cr), we find a remarkable bias in the magnitude and quality of the response contingent on whether antigen remains bacterially associated or is introduced into intestinal epithelial cells colonized by the bacterium. Only proteins injected into the cytosol of colonocytes via the type 3 secretion system (T3SS) of Cr were found to recruit robust antigen-specific T cell responses to the infected mucosa and give rise to CD4 resident memory T (Trm) cells that populate the mucosal epithelium--and this required direct presentation of these antigens by infected epithelial cells. Single-cell transcriptomic analyses revealed that sustained, bidirectional epithelial-T cell communication was required both to elicit epithelial barrier-protective T cell help and to promote transcriptional networks that program a tissue-residency rather than central memory fate. These results establish a central role for antigen presentation by non-professional APCs in controlling memory fate decisions by CD4 T cells, with important implications for development of successful mucosal vaccines.

immunology↗

bioRxiv2021

A Non-redundant Role for T cell-derived IL-22 in Antibacterial Defense of Colonic Crypts

IL-22 is a key cytokine in immune defense against pathogens at barrier sites. In response to enteric attaching and effacing bacteria, IL-22 produced by type 3 innate lymphoid cells (ILC3s) is thought to be important early for induction of antimicrobial peptides (AMPs) that protect intestinal epithelial cells (IECs) in advance of T cell-derived IL-22 that arises later. Yet, the basis for a requirement for both innate and adaptive IL-22-producing immune cells in protecting the intestinal mucosa is unknown. Here, using novel mice that both report IL-22 expression and can be targeted for its lineage-specific deletion, we show that mice with deficiency of IL-22 targeted to innate immune cells, including ILC3s, have impaired STAT3 activation of surface colonic IECs colonized by bacteria early in infection. In contrast, mice with IL-22 deficiency limited to T cells have complete loss of STAT3 activation in IECs lining colonic crypts and fail to protect the crypts from bacterial invasion late despite ongoing production of IL-22 from ILC3s. T cell-derived IL-22 is required for upregulation of many host-protective genes by crypt IECs, including those encoding AMPs, neutrophil-recruiting chemokines, and mucins and mucin-related molecules, while also restricting pro-inflammatory genes downstream of IFN{gamma} and TNF signals. Thus, T cell-derived IL-22 is indispensable for antibacterial defense and damage control of intestinal crypts.

immunology↗