Mark R Rigby, Alison Trexler, Danxia Duan, Leslie Kean and Christian P Larsen
Using co stimulatory blockade to prevent activation and activity of beta cell specific effector T cells is a promising approach for preventing or reversing Type 1 diabetes (T1D). Regulatory T cells are likely critical for the maintenance of long-term tolerance. At present, it is unclear how co-stimulatory blocking agents affect the activity of regulatory T cells. To better understand the mechanism of costimulation blockade induced tolerance in murine autoimmune diabetes, we evaluated the effect of CD28 and CD154 blockade on both beta cell-specific effector and regulatory T cell responses.
Diabetes transferred by lymphocytes isolated from BDC2.5.NOD mice could be prevented if cells were antigenactivated ex vivo in the presence of CTLA4Ig and anti- CD154. Following antigen-stimulation, both effector (Teffs; FoxP3-) and regulatory (Tregs; FoxP3+) CD4+ T cells upregulated CD25, divided and accumulated. Co-culture with CTLA4Ig and anti-CD154 dampened the quantitative and qualitative Teff response (i.e. cell cycling and CD25 expression), but there was little effect on the Treg response. Adding exogenous IL-2 to such cultures reversed the diabetes protective effect of CD28/CD154 blockade.
These findings suggest that Tregs do not only respond vigorously to antigen, but they rely less on traditional costimulatory signals than Teffs. Understanding the different signaling requirements of Teff and Tregs may facilitate the development and investigation of rational therapeutic interventions in Type1 diabetes that will both quiet diabetogenic effector T cells and enhance regulatory pathways.