Type 1 diabetes mellitus (T1D) results from the autoimmune attack of pancreatic β-cells, resulting in a loss of functional β-cell mass. The CD6 molecule is a membrane glycoprotein predominantly expressed on T cells and is implicated in lymphocyte adhesion, activation, and proinflammatory commitment. The CD6 ligand CD166/ALCAM is upregulated in mature dendritic cells and the inflamed tissue, facilitating infiltrating lymphocytes into the target organs. Furthermore, CD166 is implicated as essential in pancreatic development, and it has been found in the membrane of islet endocrine cells.

CD318/CDCP1 was recently identified as a second CD6 ligand, contributing to the autoimmune response in experimental models. We have discovered in healthy human donors that CD318 is expressed by a subset of myeloid Dendritic Cells and activated monocytes. Moreover, CD318 expression can be induced on peripheral monocytes by proinflammatory cytokines. CD318+ cells significantly reduced the proliferation of polyclonal T cells and antigen-specific CD4+ T cells. Our unpublished data also uncover CD318 expression in human pancreatic islets from non-diabetic donors, and its expression is increased by proinflammatory cytokines.

These findings suggest a novel role for CD318 as a co-inhibitory ligand for T cell activation and effector function. Therefore, we propose CD6 as a novel immune checkpoint with dual function based on the ligand expression: CD6 binding to CD166 triggers T cell inflammatory response in the pancreas while CD318 acts as a co-inhibitory ligand down-regulating T cell responses and preventing the perpetuation of local autoimmunity. This project aims to characterize the expression of CD6 and its ligands CD318 and CD166 in human pancreatic islets from T1D donors. This study may describe a novel natural mechanism for human islet protection from autoimmunity and may aid developing novel therapeutic strategies to cure T1D by targeting CD6.