B7-2 (CD86) Controls the Priming of Autoreactive CD4 T Cell Response against Pancreatic Islets

Abstract

The B7-1/2-CD28 system provides the critical signal for the generation of an efficient T cell response. We investigated the role played by B7-2 in influencing pathogenic autoimmunity from islet-reactive CD4 T cells in B7-2 knockout (KO) NOD mice which are protected from type 1 diabetes. B7-2 deficiency caused a profound diminishment in the generation of spontaneously activated CD4 T cells and islet-specific CD4 T cell expansion. B7-2 does not impact the effector phase of the autoimmune response as adoptive transfer of islet Ag-specific BDC2.5 splenocytes stimulated in vitro could easily induce disease in B7-2KO mice. CD4 T cells showed some hallmarks of hyporesponsiveness because TCR/CD28-mediated stimulation led to defective activation and failure to induce disease in NODscid recipients. Furthermore, CD4 T cells exhibited enhanced death in the absence of B7-2. Interestingly, we found that B7-2 is required to achieve normal levels of CD4+CD25+CD62L+ T regulatory cells because a significant reduction of these T regulatory cells was observed in the thymus but not in the peripheral compartments of B7-2KO mice. In addition, our adoptive transfer experiments did not reveal either pathogenic or regulatory potential associated with the B7-2KO splenocytes. Finally, we found that the lack of B7-2 did not induce a compensatory increase in the B7-1 signal on APC in the PLN compartment. Taken together these results clearly indicate that B7-2 plays a critical role in priming islet-reactive CD4 T cells, suggesting a simplified, two-cell model for the impact of this costimulatory molecule in autoimmunity against islets.

B7-1 mediated costimulation regulates pancreatic autoimmunity

“…For example, the absence of B7-2 leads to complete protection, whereas, B7-1 neutralization or deficiency causes exacerbation of disease Yadav et al, 2004). These results suggest that B7-1 may play a role in suppressing the development of autoimmunity in the NOD mouse.…”

“…1.2-2.5 × 10 7 CFSE labeled (as described previously (Yadav et al, 2004)) total splenocytes from either BDC2.5 or 8.3NODscids (4-7 week old) in 200μl of sterile PBS were injected intravenously per recipient (5-8 week old NOD, and B7-1KO mice). For monitoring cell death in adoptively transferred cells, PLN cells (1-2×10 6 ) from the recipients were also stained for annexin and Vβ4+CFSE low / Vβ8.1/8.2+ CFSE low cells were analyzed for the cells positive for annexin.…”

miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes

“…2,3 Major histocompatibility complex (MHC) class II molecules are not expressed on β-cells. 15 Thus, antigen-presenting cells (APCs), such as macrophages and DCs, take up β-cell-related autoantigens and present the respective antigens to naïve T cells with the help of the MHC II molecules expressed on the APCs. Upon excitation, T cells are expanded and differentiated into functional immune cells.…”

“…14,15 T cells (including CD4 + and CD8 + T cells), macrophages, dendritic cells (DCs), natural killer (NK) cells, B lymphocytes and a series of chemokines and cytokines released by various immune cells are involved in the autoimmune attack on β-cells. 2,3 Major histocompatibility complex (MHC) class II molecules are not expressed on β-cells.…”

“…Upon excitation, T cells are expanded and differentiated into functional immune cells. 15 Naïve CD4 + T cells eventually develop into four major phenotypes (T-helper 1 (Th1), Th2, Th17 and regulatory T (Treg) cells). 16,17 Considering the importance of these cells in autoimmunity, the pathogenic contributions of Th1 cells and protective effects of Th2 cells also play crucial roles in the pathogenesis of T1D.…”