Non-depleting anti-CD4 monoclonal antibodies potently induce dominant infectious tolerance and Foxp3+ regulatory T cells (Tregs) have recently been implicated as a crucial underlying mechanism. However, it has not been explored whether anti-CD4 treatment has residual activity in the complete absence of Foxp3+ Tregs. Utilizing DEREG mice which allow for the inducible depletion of Foxp3+ Tregs by diphtheria toxin (DT), we found that the anti-CD4 clone YTS177.9 is able to fully inhibit CD4+ T cell activation in the absence of Foxp3+ Tregs in vitro. Moreover, anti-CD4 treatment of neonatal scurfy (sf) mice genetically devoid of functional Foxp3+ Tregs resulted in a rescue of the autoimmune phenotype. We thus discovered a novel Foxp3-independent mechanism of anti-CD4-induced tolerance. Foxp3-independent tolerance was recessive as opposed to classical dominant infectious tolerance requiring Foxp3+ Tregs. Given that anti-human CD4 antibodies are currently developed as therapeutics, our results provide valuable insights into anti-CD4-mediated tolerance and unexpectedly highlight a potential synergy of anti-CD4 antibodies with Foxp3+ Treg-modulating regimens for the treatment of human inflammatory diseases. Beyond, anti-CD4 antibodies might represent a novel therapeutic option for the human IPEX syndrome which is caused by Foxp3 mutations similar to the autoimmune disease of sf mice.
- Copyright © 2013 by The American Association of Immunologists, Inc.