An increase in tolerogenic dendritic cell and natural regulatory T cell numbers during experimental autoimmune encephalomyelitis in Rras-/- mice results in attenuated disease.
R-Ras is a member of the Ras superfamily of small GTPases, which are regulators of various cellular processes, including adhesion, survival, proliferation, trafficking, and cytokine production. R-Ras is expressed by immune cells and has been shown to modulate dendritic cell (DC) function in vitro and has been associated with liver autoimmunity. We used Rras-deficient mice to study the mechanism whereby R-Ras contributes to autoimmunity using experimental autoimmune encephalomyelitis (EAE), a mouse model of the CNS autoimmune disease multiple sclerosis. We found that a lack of R-Ras in peripheral immune cells resulted in attenuated EAE disease. Further investigation revealed that, during EAE, absence of R-Ras promoted the formation of MHC II(low) DC concomitant with a significant increase in proliferation of natural regulatory T cells, resulting in an increase in their cell numbers in the periphery. Our study suggests a novel role for R-Ras in promoting autoimmunity through negative regulation of natural regulatory T cell numbers by inhibiting the development of MHCII(low) DC with tolerogenic potential.
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201;
Avijit
A
Ray
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201; Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; and.
Sreemanti
S
Basu
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201;
Nichole M
NM
Miller
Division of Hematology and Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226.
Andrew M
AM
Chan
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201; Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; and bonnie.dittel@bcw.edu.
Bonnie N
BN
Dittel
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018631:ras Proteins / Q000235:genetics / Q000276:immunology*
D000949:Histocompatibility Antigens Class II; C513254:Rras protein, mouse; D018631:ras Proteins