Immunology Starved into Submission?

Elizabeth M. Adler

Science's STKE, AAAS, Washington, DC 20005, USA

CD4⁺CD25⁺ thymus-derived regulatory T cells (T_reg cells) suppress the activity of naïve and effector T cells, limiting the immune response and helping guard against autoimmune activity. The mechanisms whereby they inhibit the activity of target cells, however, have been controversial and unclear (see Scheffold et al.). Pandiyan et al. found that T_reg cells elicited the apoptosis of activated "responder" CD4⁺ T cells with which they were cocultured, without blocking their proliferation or the early production of interleukin-2 (IL-2). Apoptosis of responder T cells occurred in the presence of T_reg cells from perforin-deficient or Fas ligand mutant mice, occurred over several days (peaking 3 to 4 days after activation), depended on the proapoptotic protein Bim, and was blocked by cytokines that signal through the common chain. Pharmacological analysis of the cytokine-dependent Akt pathway indicated that the ability of IL-7 to rescue responder T cell survival depended on phosphatidylinositol-3-OH kinase (which activates Akt), whereas Akt phosphorylation in responder T cells was decreased in the presence of T_reg cells, as was phosphorylation (and thereby deactivation) of the proapoptotic protein Bad. Bad phosphorylation was enhanced during IL-7 rescue. In a mouse model of inflammatory bowel disease involving the transfer of colitogenic CD4⁺CD45RB^hi T cells, T_reg cells protected against colitis and stimulated the Bim-dependent apoptosis of the transferred T cells. The authors thus conclude that T_reg cells can inhibit effector T cell responses both in vitro and in vivo by depriving them of cytokines and eliciting their apoptotic death.

P. Pandiyan, L. Zheng, S. Ishihara, J. Reed, M. J. Lenardo, CD4⁺CD25⁺Foxp3⁺ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4⁺ T cells. Nat. Immunol. 8, 1353-1362 (2007). [PubMed]

A. Scheffold, K. M. Murphy, T. Höfer, Competition for cytokines: T_reg cells take all. Nat. Immunol. 8, 1285-1287 (2007). [PubMed]