Spontaneous Corneal Inflammation in gd T cell absence

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DESCRIPTION (provided by applicant): The role of gamma-delta T cells in immune responses is still being worked out. Although the cells clearly play an immunoregulatory role, up until now, mice incapable of producing gamma-delta T cells due to genetic inactivation of gamma-delta T cell receptor component (TCR-delta knockout mice) appeared to be largely normal, though defects were apparent when infectious or autoimmune disease was deliberately induced. We recently discovered what we believe to be the first reported spontaneous disease in TCR-delta knockout mice - an inflammation of the cornea that in these mice develops at a high frequency. The keratitis is only apparent when the defective TCR-delta gene is on the C567BL/10 (B10) background. Its incidence increases with age, and it is more common in females than in males. The disease develops slowly, but even in early stages, one can see inflammatory infiltrates in the corneal stroma along with neovascularization. We hypothesize that B10-TCR ( knockout mice develop corneal inflammation because their lack of gamma-delta T cells renders them defective in a mechanism of self-tolerance, which on the B10 background leads to an increased in incidence of spontaneous keratitis. We propose to carry out a pilot/feasibility study to further investigate the origin and features of this disease, and determine whether it is likely to be a useful model for the study of the immunological role of gamma-delta T cells. Our specific aims are: 1. To further define and describe the spontaneous keratitis in B210-TCR delta knockout mice. This will include further recording of the incidence and progression of the disease, as well as an initial investigation into the B 10-derived genes that apparently contribute to the disease. 2. To investigate the mechanisms that lead to the development of spontaneous keratitis in B10-TCR-delta knockout mice. We plan first to examine whether the disease can be improved or prevented by reconstituting affected mice with gamma-delta T cells, or with particular gamma-delta T cell subsets. In addition, we will carryout experiments designed to examine whether the disease is autoimmune, results from bacterial infection, or stems from damage caused by a chemical released from dirty cage litter.