The role of CD8:B-lymphocyte interactions in type 1 diabetes pathogenesis

Under particular circumstances human leukocyte antigen (HLA) class I molecules may present peptides derived from extracellular proteins to CD8⁺ T cells (a process termed cross-presentation) to induce or maintain cytotoxic T cell responses (CTL). This interaction is likely to be important in autoimmune disorders, such as Type 1 Diabetes (T1D), in which autoreactive CD8⁺ T cells interact with self-peptide-HLA-I complexes to mediate cell damage. Professional antigen-presenting cells (APCs) are known to be important cross-presenters; but little is known of the key cells mediating this process in T1D. Since recent evidence has highlighted the B lymphocyte involvement in insulitic lesions in T1D, we set out to test the hypothesis that these cells are able to cross-present to CD8⁺ T cells and thus maintain cytotoxic T cell responses that could be relevant to destruction of β-cells. Using an antigen delivery system (ADS) to target antigen uptake via the B cell receptor (BCR), we assessed B lymphocyte cross-presentation of a test polypeptide, and utilised CD8⁺ antigen-specific T cell clones as read-outs. We showed the presence of ADS complexes on the B lymphocyte surface, and confirmed no direct binding of test polypeptide to HLA class I molecules. Co-culture of polypeptide-ADS-pulsed B lymphocytes with specific CD8⁺ T cell clones induced marked T cell degranulation as shown by surface appearance of CD107a expression. As a comparison of cross-presentation potency, we generated immature monocyte-derived dendritic cells (MoDCs). When matured in the presence of the same test polypeptide, similar levels of degranulation were observed, indicating that B lymphocytes and MoDCs have comparable cross-presentation potency. Thus, these data suggest that B lymphocytes are capable of cross-presenting antigen and inducing cytotoxic responses. This feature may be relevant to their role in the cellular and molecular interactions that underlie tissue pathology in T1D.