Regulatory T-cell Status in Red Cell Alloimmunized Responder and Nonresponder Mice

Red blood cell alloimmunization remains a major complication for transfusion-dependent patients, but immune factors governing risk for alloimmunization are unknown. We hypothesized that CD4+ regulatory T cells (Tregs), which we have shown control the rate and the frequency of red blood cell alloimmunization in mouse models, may dictate responder/nonresponder status. Using a transfusion regimen in which more than 50% of mice develop alloantibodies to human glycophorin A antigen, we found reduced in vitro and in vivo Treg-suppressive activity in responders compared with nonresponders that was the result of impaired Treg suppressor function. Moreover, responders were prone to developing additional alloantibodies to strong immunogens, whereas nonresponders were resistant to alloimmunization. Altogether, our data raise the possibility that Treg activity may be used as a marker for identifying responder/nonresponder status in transfusion recipients.