The novel cyclophilin binding compound, sanglifehrin A, disassociates G1 cell cycle arrest from tolerance induction.
T cell anergy has been demonstrated to play a role in maintaining peripheral tolerance to self Ags as well as a means by which tumors can evade immune destruction. Although the precise pathways involved in anergy induction have yet to be elucidated, it has been linked to TCR engagement in the setting of cell cycle arrest. Indeed, rapamycin, which inhibits T cell proliferation in G(1), has the ability to promote tolerance even in the presence of costimulation. To better define the role of the cell cycle in regulating anergy induction, we used the novel cyclophilin-binding ligand, sanglifehrin A (SFA). We demonstrate that SFA can inhibit TCR-induced cytokine and chemokine production without preventing TCR-induced anergy. Our data also indicate that despite its ability to induce G(1) arrest, SFA does not induce anergy in the presence of costimulation. Furthermore, although SFA blocks proliferation to exogenous IL-2, it does not prevent IL-2-induced reversal of anergy. When we examined the phosphorylation of 4EBP-1, a downstream substrate of the mammalian target of rapamycin, we found that rapamycin, but not SFA, inhibited the mammalian target of rapamycin activity. Based on these data, we propose that the decision as to whether TCR engagement will lead to productive activation or tolerance is dictated by a rapamycin -inhibitable pathway, independent of the G(1)-->S phase cell cycle progression.[1]References
- The novel cyclophilin binding compound, sanglifehrin A, disassociates G1 cell cycle arrest from tolerance induction. Allen, A., Zheng, Y., Gardner, L., Safford, M., Horton, M.R., Powell, J.D. J. Immunol. (2004) [Pubmed]
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