NKT Cell Cytokine Imbalance in Murine Diabetes Mellitus

Abstract

A minor subset of murine MHC class I-restricted T cells which express both the a/3 form of the T cell receptor and a NK lineage marker, termed NKT cells, is capable of secreting significant amounts of InterIeukin-4 and Interferon-γ upon activation. As such NKT cells may play a role in development of Thl and Th2 cells during T cell ontogeny or expansion of T cells expressing a dominant cytokine pattern in the effector phase. We have studied the role of NKT cells in a murine model of disease multidose streptozotocin induced diabetes mellitus (MDSDM). In MDSDM thymic and splenic NKT cells are present at normal levels but have greatly reduced capacity to secrete Interleukin-γ upon stimulation with anti-TCR antibody compared to control mice; conversely, Interferon-γ - secretion is maintained. By analysis of cytokine RNA production we found that treatment of several strains of mice with streptozotocin changes the peripheral helper T cell phenotype elicited after immunization with Keyhole Limpet Hemocyanin from a mixed Thl- and Th2-type cytokine pattern (characterized by IFN-γ and 1L-4 and IL-5 expressions, respectively) to predominately Thl-type. Furthermore, susceptibility to MDSDM is significantly enhanced when NKT cells are selectively eliminated in vivo by administration of depleting anti-CDl 22 antibody TMβ-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 cytokine expression influences the development of Thl-type diabetogenic T cells.

Key Words:

• lntcrleukin-4
• NKT cells. Diabetes
• Streptozotocin
• Non-obese diabetic mouse