TLR2 Supports γδ T cell IL-17A Response to ocular surface commensals by Metabolic Reprogramming

The ocular surface is a mucosal barrier tissue colonized by commensal microbes, which tune local immunity by eliciting IL-17 from conjunctival γδ T cells to prevent pathogenic infection. The commensal Corynebacterium mastitidis ( C. mast ) elicits protective IL-17 responses from conjunctival Vγ4 T cells through a combination of γδ TCR ligation and IL-1 signaling. Here, we identify Vγ6 T cells as a major C. mast -responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that Vγ6 cells require not only extrinsic (via dendritic cells) but also intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes responsible for metabolic shift to fatty acid oxidation to support Il17a transcription. We identify one key transcription factor, IκBζ, which is upregulated by TLR2 stimulation and is essential for this program. Our study highlights the importance of intrinsic TLR2 signaling in driving metabolic reprogramming and production of IL-17A in microbiome-specific mucosal γδ T cells.

Summary

The ocular commensal Corynebacterium mastitidis ( C. mast ) induces the IL-17 responses from γδ T cells by activating TLR2 signaling. γδ T cell-intrinsic TLR2 stimulation promotes fatty acid oxidation and increases IL-17A transcription, favoring IL-17A responses.

Highlights

(1) TLR2-deficient mice exhibit reduced γδ T cell responses to ocular commensal bacteria.

(2) γδ T cell-intrinsic TLR2 deficiency causes defects of fatty acid oxidation and IL-17A production in a γδ subset-specific manner.

(3) The transcription factor, IκBζ is upregulated by TLR2 stimulation and supports γδ IL-17A production through fatty acid oxidation.