Abstract
The treatment of nonobese diabetic (NOD) mice with anti-CD137 monoclonal antibody prevented diabetes by increasing the number of T regulatory cells, which transferred protection from disease. We show here that two subsets of Tregs, CD137pos and CD137neg, differ phenotypically and functionally. CD137pos Tregs are distinctly CD69hi, CD62Llow and produce significantly higher levels of IL-10 and ICOS. There is significant decline in the number of CD137pos Tregs in NOD spleen but not thymus with age. This decline is not observed in an NOD.Idd9.3 congenic strain that is protected from diabetes and has a B10 Cd137 allele. The NOD.Idd9.3 strain has significantly higher numbers of CD137pos Tregs in both spleen and thymus compared to NOD mice. Functionally, NOD CD137pos Tregs are more suppressive than CD137neg cells. Here we dissect the mechanism of suppression and find that in a contact independent transwell system, the combination of anti-IL-10R and anti-TGF-β blocking antibodies decreases but does not abolish suppression of CD137pos Tregs. The loss of peripheral CD137pos Tregs with age in NOD mice, the increase in the frequency of CD137pos Tregs with anti-CD137 antibody treatment, and the persistently higher numbers of CD137pos Tregs in NOD.Idd9.3 congenic mice suggest that this functionally superior Treg subset could act to prevent diabetes when increased by genetic or environmental means. Therefore CD137pos Tregs are a therapeutic target in T1D and other autoimmune diseases.
