ABSTRACT CD6 is a critical regulator of T cells that is present on all T cells including γδ T cells. In our recently published work, we discovered that CUB-Domain-Containing Protein 1 (CDCP1) is a new and important ligand of CD6. This new discovery demonstrated a surprising role of CDCP1 in immune regulation. CDCP1 was originally discovered as an overexpressed transmembrane protein on certain solid tumor cells intrinsically regulating tumor-cell anoikis resistance. However, the distribution of CDCP1 in the eye and its potential role in ocular immunity and tissue homeostasis were unknown. In our latest (unpublished) work, we used primary human and mouse corneal epithelial cells, as well as CDCP1- and CD6-knockout (KO) mice, to demonstrate for the first time that CDCP1 is highly and selectively expressed on normal corneal epithelial cells among all ocular cells, and that CDCP1 is critical for controlling P. aeruginosa corneal infection, whose underlying mechanisms integrally involve CD6-expressing γδ T cells. In this proposed project, we will use unique reagents and models that we have developed, including CDCP1-KO mice, CD6-KO mice, γδ T cell-deficient mice, CDCP1-KO human corneal epithelial cells and recombinant CDCP1 proteins, to elucidate both intrinsic and extrinsic mechanisms by which CDCP1 controls bacterial infection of the cornea. We will also test novel CDCP1-targeted approaches as new therapeutic strategies for managing P. aeruginosa keratitis. The proposed work is expected to establish a previously unknown role of CDCP1 in the pathogenesis of P. aeruginosa keratitis, facilitate the development of new and effective therapies for this painful and blinding disease, and open a new avenue for research on CDCP1 in corneal immunohomeostasis.