Decoding the principles of gamma-delta T cell selection and functional maturation through IL17RA, a novel superantigen-like gamma-delta TCR ligand.

About This Grant

PROJECT SUMMARY/ABSTRACT Three types of antigen receptors – BCR, αβTCR, and γδTCR – define the three types of lymphocytes that constitute the adaptive immune system of jawed vertebrates. Understanding the rules of antigen recognition by these receptors is the key to understanding the biological functions of these cell types. While the antigen receptor specificities and therefore the functions of B cells and αβT cells are well-understood, the principles of antigen recognition by γδT cells remain unclear and the nature of these antigens is largely elusive. Multiple lines of evidence indicate that the TCR repertoire, functional properties, and tissue localization of γδT cells can be shaped by interactions with endogenous γδTCR ligands. However, the nature of such endogenous γδTCR ligands remains largely unknown. Recent findings showed that superantigen-like interactions of butyrophilin family members with germline-encoded sequences of Vγ chains regulate several epithelial γδT cell subsets. However, it remains unclear whether similar interactions could control γδT cells in other tissues. To assess how prevalent the recognition of endogenous ligands by γδTCRs is and to what extent it can be explained by known γδTCR ligands, we established a pipeline for screening of γδTCR reactivities. Assessment of the reactivities of a panel of murine γδTCRs indicated that a large fraction of these TCRs recognize a diverse set of unknown self-molecules. To start revealing the molecular nature of these ligands, we performed a cDNA library screen that identified IL17 receptor A (IL17RA), a proinflammatory cytokine receptor chain not previously implicated in γδTCR signaling, as an unexpected γδTCR ligand candidate. Further analysis demonstrated that IL17RA is responsible for the accumulation and induction of an effector program in up to 20% of γδT cells found in secondary lymphoid organs. Repertoire analysis and mutagenesis experiments demonstrated that germline- encoded sequences in Vδ7 chain were the principal determinants of IL17RA reactivity, indicating that IL17RA is acting in superantigen-like fashion. In this project, we will utilize this novel ligand to explore the molecular and cellular mechanisms that regulate development and homeostasis of γδ lineage cells. In Aim 1 of this project, we will use mutagenesis and structural approaches to define the molecular basis of this unique interaction between a class of TCRs utilized by up to 20% of peripheral γδT cells and a cytokine receptor. In Aim 2 we will utilize this novel ligand to uncover the fundamental mechanisms governing the selection, functional maturation and maintenance of γδ lineage cells. Taken together, these experiments will allow us to uncover the molecular mechanisms and functional implications of the superantigen-like interaction between IL17RA and Vδ7 γδTCRs, thereby clarifying the fundamental principles of γδT cell lineage regulation by their endogenous TCR ligands. They will also reveal for the first time how the endogenous superantigen-like γδTCR ligands shape the γδT cell compartment of non-epithelial tissues.