Abstract
Background/Immune responses initiated by T cell receptor (TCR) and costimulatory molecule mediated signaling culminate in maximal cytokine mRNA production and stability. The transcriptional responses to co-stimulatory T cell signalling involve calcineurin and NF-AT, which can be antagonized by interference with the cis-trans peptidyl-prolyl isomerases (PPIase), cyclophilin A and FKBP. Signalling molecules downstream of CD28 which are essential for the stabilization of cytokine mRNAs are largely unknown.Methodology/Principal FindingsWe now show that Pin1, a third member of the PPIase family mediates the post-transcriptional regulation of Th1 cytokines by activated T cells. Blockade of Pin1 by pharmacologic or genetic means greatly attenuated IFN-γ, IL-2 and CXCL-10 mRNA stability, accumulation and protein expression after cell activation. In vivo, Pin1 blockade prevented both the acute and chronic rejection of MHC mismatched, orthotopic rat lung transplants by reducing the expression of IFN-γ and CXCL-10. Combined transcriptional and post-transcriptional blockade with cyclosporine A and the Pin1 inhibitor, juglone, was synergistic.Conclusions/SignificanceThese data suggest Pin1 inhibitors should be explored for use as immunosuppressants and employed with available calcineurin inhibitors to reduce toxicity and enhance effectiveness.
Highlights
During and after antigen presentation, inflammatory cytokines structure the type and amplitude of the T cell response
Splenocytes from KO mice activated with anti-CD3 plus anti-CD28, which normally triggers cytokine mRNA stabilization and accumulation [4,13], showed significantly less IFN-c and IL-2 mRNA compared to WT (p,0.03 and p,0.008, respectively) while CXCL-10 mRNA was reduced by 50% but did not quite reach significance
We recently reported that Pin1 plays a role in the posttranscriptional control of GM-CSF mRNA expression by activated eosinophils and lymphocytes
Summary
During and after antigen presentation, inflammatory cytokines structure the type and amplitude of the T cell response. GM-CSF is a prototypical proinflammatory cytokine, whose mRNA is regulated by 39-untranslated AU-rich elements (AREs) These are found in and important for the posttranscriptional control of IL-2 and IFN-c mRNAs [14,15] suggesting a role for Pin in the type 1 immune response. We show that Pin KO mice show an alternated cytokine response, after co-stimulation with anti-CD3 and antiCD28 This reflects an inability of T cells to fully stabilize ARE mRNAs after cell activation. We show that Pin blockade is synergistic with calcineurin inhibitors such as Cyclosporin A These data establish a new role for Pin in the T cell immune response and point to a novel target for immunosuppression
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