Monin, L. | Search bioRxiv

bioRxiv2026

Atypical T cell receptor signalling permits distinct gut gd T cell responses to healthy versus dysregulated tissues

Intraepithelial lymphocytes (IEL) are conserved across vertebrates and commonly enriched in {gamma}{delta} T cells. Several such {gamma}{delta} IELs depend upon homeostatic interactions of their T cell receptors (TCRs) with butyrophilin-like (BTNL) proteins expressed by healthy enterocytes and colonocytes. What limits such interactions from inducing full-blown T cell activation which would disrupt barrier integrity is unknown. Here, using primary IEL, we describe an atypical TCR signalling pathway (Signal 1) downstream of BTNL engagement, that fails to activate either global protein synthesis or cell proliferation. This attenuation could be overcome by provision of a co-stimulator (Signal 2) or inflammatory cytokines (Signal 3). It could also be relieved cell-intrinsically by blocking a lipid phosphatase. These findings can, at least in part, explain how extrinsic and intrinsic regulators permit IEL to be constitutively active in healthy tissues and additionally make full-blown responses to adaptive TCR ligands during tissue perturbation.

immunology↗

bioRxiv2020

A loss-of-function mutation in IL-17F enhances susceptibility of mice to oropharyngeal candidiasis

Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungus C. albicans. IL-17 receptor signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this experiment of nature by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR/Cas9.The resulting Il17fS65L/S65L mice showed increased susceptibility to OPC, but only in homozygous, not heterozygous, mutant mice. The mutation was linked to impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi.

immunology↗