NKT cell cytokine imbalance in murine diabetes mellitus

A minor subset of murine MHC class I-restricted T cells which express both the alpha beta form of the T cell receptor and a NK lineage marker, termed NKT cells, is capable of secreting significant amounts of Interleukin-4 and Interferon-gamma upon activation. As such NKT cells may play a role in dev elopment of Th1 and Th2 cells during T cell ontogeny or expansion of T cell s expressing a dominant cytokine pattern in the effector phase. We have stu died the role of NKT cells in a murine model of disease multidose streptozo tocin induced diabetes mellitus (MDSDM), Tn MDSDM thymic and splenic NKT ce lls are present at normal levels but have greatly reduced capacity to secre te Interleukin-4 upon stimulation with anti-TCR antibody compared to contro l mice; conversely, Interferon-gamma secretion is maintained. By analysis o f cytokine RNA production we found that treatment of several strains of mic e with streptozotocin changes the peripheral helper T cell phenotype elicit ed after immunization with Keyhole Limpet Hemocyanin from a mixed Th1- and Th2-type cytokine pattern (characterized by IFN-gamma and IL-4 and IL-5 exp ressions, respectively) to predominately Th1-type. Furthermore, susceptibil ity to MDSDM is significantly enhanced when NKT cells are selectively elimi nated in vivo by administration of depleting anti-CD122 antibody TM beta-1. In addition, antibody depletion of NKT cells from non-obese diabetic mice significantly accelerates onset of disease. Collectively these data support a model for development of murine diabetes mellitus in which NKT cell cyto kine expression influences the development of Th1-type diabetogenic T cells .