Variegated gene expression and Sox-13 mediated regulation of WC1, a hybrid PRR/Co-receptor exclusive to memory gd T cells

Abstract

Abstract γδ T cells have broader reactivity and respond more rapidly compared to αβ T cells which are restricted to peptide bound to MHC. Some γδ T cells bear lineage-specific glycoproteins known as WC1 that are coded by a multigenic family composed of 13 members. Structurally, WC1 molecules have 6–11 SRCR domains, followed by a conserved transmembrane and a variable cytoplasmic tail. γδ T cells expressing these molecules can be further divided into subsets that express either WC1-3 or WC1-4, a dichotomy analogous to CD4 and CD8 molecules and similarly set up in the thymus. While WC1-3+ and WC1-4+ γδ T cells share a restricted repertoire of the γδ TCR genes, expression of WC1-3 vs. WC1-4 determines whether the γδ T cell is activated by Leptospira; reactivity correlates with expression of WC1-3 and the ability of its SRCR domains to bind to Leptospira. ShRNA-mediated knockdown of WC1-3 significantly reduces the ability of WC1-3 expressing γδ T cells to respond to the bacteria, guiding us to a hypothesis that WC1 is essential for recognition of bacterial pathogens by γδ T cells and that the WC1 family members expressed by a particular cell will determine its ability to respond to an infection. Evaluation of WC1 gene expression among individual γδ T cells indicates that WC1-3 and WC1-4 are always expressed reciprocally, establishing functional subsets. These γδ T cell subsets appear to be set in the thymus, alluding to the transcription factor occupancy of WC1-3 vs WC1-4. Occupancy of candidate Sox13 binding sites differ between WC1-3 and WC1-4 loci, suggesting that Sox13 may play an important role in determining the ability of mature γδ T cells to respond to bacteria.