Human FOXP3+ T regulatory cells suppress mouse T cell activation by targeting mouse dendritic cells via a human LFA‐1/mouse ICAM‐1 mediated interaction

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We have developed a novel in vitro T suppressor cell assay in which the responders are mouse CD4+CD25‐ T cells (mCD4+) stimulated by mouse T‐depleted splenocytes and soluble anti‐mouse CD3, and the T suppressors are human CD4+FOXP3+CD25hi cells (nTreg) activated with plate‐bound anti‐human CD3/CD28. Human nTreg were almost as efficient as mouse nTreg in suppressing the responses of mCD4+ cells. Suppression was not abrogated by neutralizing human IL‐10 or TGFbeta, and was not observed when responders and suppressors were separated in a transwell. Cell contact between the human nTreg and the mouse cells was required as blocking human CD11a or CD18 completely abrogated suppression. Mouse mCD4+ cells deficient in ICAM‐1 were suppressible, suggesting that the nTreg targeted the mouse dendritic cells through the binding of human LFA‐1 with mouse ICAM‐1. Mouse nTreg could not suppress human CD4+ T cells most likely due to the fact that mouse LFA‐1 could not bind to human ICAM. Under suboptimal stimulatory conditions, hIL‐2 was required for activation of nTreg suppressor function. Since the human IL‐2R does not bind mouse IL‐2, IL‐2 consumption is ruled out as a mechanism of suppression. Our results indicate that one of the mechanisms of nTreg‐mediated suppression functions across species and that this cross‐species assay should prove to be a valuable tool for studying the mechanisms of action of human nTreg.