WC1 proteins are uniquely expressed on γδ T cells and belong to the scavenger receptor cysteine-rich (SRCR) superfamily. While present in variable, and sometimes high, numbers in the genomes of mammals and birds, in cattle there are 13 distinct genes (WC1-1 to WC1-13). All bovine WC1 proteins can serve as coreceptors for the TCR in a tyrosine phosphorylation dependent manner, and some are required for the γδ T cell response to Leptospira. We hypothesized that individual WC1 receptors encode Ag specificity via coligation of bacteria with the γδ TCR. SRCR domain binding was directly correlated with γδ T cell response, as WC1-3 SRCR domains from Leptospira-responsive cells, but not WC1-4 SRCR domains from Leptospira-nonresponsive cells, bound to multiple serovars of two Leptospira species, L. borgpetersenii, and L. interrogans. Three to five of eleven WC1-3 SRCR domains, but none of the eleven WC1-4 SRCR domains, interacted with Leptospira spp. and Borrelia burgdorferi, but not with Escherichia coli or Staphylococcus aureus. Mutational analysis indicated that the active site for bacterial binding in one of the SRCR domains is composed of amino acids in three discontinuous regions. Recombinant WC1 SRCR domains with the ability to bind leptospires inhibited Leptospira growth. Our data suggest that WC1 gene arrays play a multifaceted role in the γδ T cell response to bacteria, including acting as hybrid pattern recognition receptors and TCR coreceptors, and they may function as antimicrobials.
Leptin interferes with ACTH/cAMP signaling, possibly through a cAMP-degrading mechanism involving activation of JAK2, phosphatidylinositol 3-kinase, and PDE3, to down-regulate P450scc expression and consequent adrenal steroidogenesis.
WC1 coreceptors are scavenger receptor cysteine-rich (SRCR) family members, related to T19 in sheep, SCART in mice, and CD163c-α in humans, and form a 13-member subfamily in cattle exclusively expressed on γδ T cells. Subpopulations of γδ T cells are defined by anti-WC1 mAbs and respond to different pathogen species accordingly. In this study, variegated WC1 gene expression within subpopulations and differences in signaling and cell activation due to endodomain sequences are described. The endodomains designated types I to III differ by a 15- or 18-aa insert in type II and an additional 80 aa containing an additional eight tyrosines for type III. Anti-WC1 mAbs enhanced cell proliferation of γδ T cells when cross-linked with the TCR regardless of the endodomain sequences. Chimeric molecules of human CD4 ectodomain with WC1 endodomains transfected into Jurkat cells showed that the tyrosine phosphorylation of the type II was the same as that of the previously reported archetypal sequence (type I) with only Y24EEL phosphorylated, whereas for type III only Y199DDV and Y56TGD were phosphorylated despite conservation of the Y24EEL/Y24QEI and Y199DDV/I tyrosine motifs among the three types. Time to maximal phosphorylation was more rapid with type III endodomains and sustained longer. Differences in tyrosine phosphorylation were associated with differences in function in that cross-linking of type III chimeras with TCR resulted in significantly greater IL-2 production. Identification of differences in the signal transduction through the endodomains of WC1 contributes to understanding the functional role of the WC1 coreceptors in the γδ T cell responses.
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