Type 1 diabetes is a pancreatic autoimmune disease affecting children and results from both genetic and environmental factors where coxsackievirus B4 (CB4) is the most associated pathogen. Genome-wide association studies have linked variants in MDA5, an RNA virus sensor, with T1D protection. As CB4 is an RNA virus and a likely factor in T1D etiology, we chose to use CB4 to study the role of MDA5 in T1D. CB4 infection enhances T1D in NODs through activation of autoreactive T cells. We hypothesized that MDA5 signals the strength, polarization and regulation of the T cell response after stimulation by agents like CB4 and dampening MDA5 function would alter the T cell response to favour T1D protection. MDA5ko(-/-) were backcrossed to the NOD background and confirmed by SNP analysis. NOD-MDA5ko(10/10) failed to develop spontaneous T1D by 24 weeks when T1D occurred in MDA5het(+/-)(2/10) and wt(+/+)(9/33). While decreased MDA5 expression (confirmed by Western) in MDA5het did not affect spontaneous T1D, it protected MDA5het(4/4 ) from CB4 induced T1D compared to infected wt(2/4). FACS analysis revealed significantly fewer activated effector CD4+ T cells in the spleen and PLNs of MDA5hets. Further, MDA5het PLNs had increased numbers of natural Tregs. These results support our premise that reduced MDA-5 expression alters the T cell response limiting the development of autoreactive effectors and T1D and suggests that dampening MDA-5 function could be a key therapeutic target.
- Copyright © 2013 by The American Association of Immunologists, Inc.