947;δ T cells play roles in immune regulation and tumor resistance, although how they carry out these functions remains poorly understood. The overall objective of this project is to further understand γδ T cell function by identifying and characterizing ligands for γδ T cell receptors (TCRs). Using soluble γδ TCR multimers (smTCRs), and in particular a newly developed self-pentamerizing mouse smTCR, we can detect putative ligands. Based on preliminary work, we hypothesize that γδ TCR ligands are most commonly cellsurface host-encoded protein molecules, whose expression is induced during inflammation.
Our aims are:
Specific Aim 1 - To identify the ligands for two common mouse γδ TCRs, the invariant Vγ6Vδ1+ TCR and a typical Vγ1Vδ6.3+ TCR. We hypothesize that the ligands for these two TCRs are cell surface protein molecules encoded by a single gene, expressed by certain cells and induced during inflammation. These ligands will be identified using expression cloning, based on soluble multimeric γδ TCRs (smTCRs) as reagents to detect their own ligands, or via a proteomics approach. Candidates will be verified by functional tests.
Specific Aim 2 - To generate smTCRs representing two recently discovered subsets of γδ T cells with defined functions, and to identify their ligands. We have recently discovered two new functionally distinct subsets of γδ T cells - one expressing a Vγ4Vδ4 TCR with highly restricted junctional regions that responds during collagen-induced arthritis, and the other a Vγ1Vδ5 TCR that promotes airway hyperreactivity. Our hypothesis is that these two γδ TCR types recognize a particular host protein ligand whose expression is induced or enhanced in the course of the relevant disease. Two new self-pentamerizing smTCRs representing the TCRs expressed by these two subsets will be generated to further investigate the ligand each recognizes.
Specific Aim 3 - To investigate the possibility that mice and humans express certain conserved γδ TCR ligands, which are recognized by conserved Vδ chains. We hypothesize that several closely related mouse and human Vδ genes may also be functionally equivalent. We plan to test whether mouse γδ smTCRs can detect potential ligands on relevant human cells or cell lines, and will generate mouse/human recombinant γδ TCRs to test whether a mouse Vδ can be replaced by its human Vδ equivalent. Taken together, these studies will provide insight into the mechanism of γδ TCR-ligand interactions and their conservation between mice and humans. This information will be useful in future studies of γδ T cell immunobiology, and could ultimately provide a basis for treatment strategies in diseases such as autoimmunities, infectious diseases, and cancer.
Gamma/delta T lymphocytes are known to be important in regulating immune responses and in tumor immunity, but little is understood about how they bring about their functions. This project will investigate and identify molecules that activate gamma/delta T cells - ligands for the gamma/delta T cell receptors. This information is crucial to further progress in this field, and may identify important molecules that could be targeted for preventing inflammatory damage or promoting tumor rejection.
| Roark, Christina L; Huang, Yafei; Jin, Niyun et al. (2013) A canonical V?4V?4+ ?? T cell population with distinct stimulation requirements which promotes the Th17 response. Immunol Res 55:217-30 |
