Gamma/delta T cells play specialized but still poorly understood roles in the immune system.
Our aim i s to understand their biological function and the developmental processes that produce them. The specialized roles are carried out by gamma/delta T cell subsets that express distinct Vgamma and Vdelta genes and localize to distinct barrier sites or to lymphoid tissue. T cell receptor genes are assembled by the process of V(D)J recombination, a highly developmentally regulated process. In the case of gamma/deltaT cells, a strikingly coordinated process of programmed gene rearrangement and cellular selection acts between the early fetal and adult stages within the thymus, to generate the distinct subsets of gamma/deltaT cells observed in the mature animal. One of our interests is in defining the developmental processes that supervise the production of different gamma/delta T cell subsets. Our previous studies have defined key aspects of these developmental processes, but some key molecular events remain to be defined at a molecular level. More fundamentally, although important progress has been made, the physiologic role of gamma/delta T cells in disease is still poorly understood. Our preliminary data shows that mice with a deficiency in subsets of gamma/delta T cells are highly susceptible to eye disease characterized by inflammation of the conjunctival and corneal epithelium and a type 2 immune response indicative of allergic inflammation. Our first specific aim is to determine the etiology of the disease, the components of the immune response that are dysregulated and leave to immune inflammation, and the role of gamma/delta T cells in regulating the normal immune response. Our second specific aim addresses the molecular mechanism of a genetic switch that represses rearrangement of Vgamma3 and 4 in adult thymocytes. We propose to define the roles of Vgamma promoters in repressing rearrangement of these Vgamma genes in the adult period, and the role of nuclear factors in regulating the promoters.
The third aim i s based on our data demonstrating that the genomic location of Vgamma genes determines the pattern of rearrangement in fetal thymocytes. We propose to test whether competition between Vgamma promoters and/or RSS, or alternatively the distance from Jgamma1, are major determinants of location-dependent rearrangement. By developing an understanding of how gamma/delta T cells are produced, and defining the disregulated immune pathology that arise when specific sets are not produced, we propose to identify the normal role of that gamma/delta T cells in preventing disease. An understanding of the role of gamma/delta T cells and the rules that govern their production will undoubtedly aid in efforts marshal the immune system for therapeutic application
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