T-Cell Specific Adapter Protein (TSAd) Mediates Immunoregulation in Alloimmunity.

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An understanding of the alloimmune response and events leading to immunoregulation is required to optimize long-term allograft survival. TSAd, an SH2 domain containing intracellular adapter molecule, functions to elicit T cell receptor-mediated signals that result in effector T cell (Teff) cytokine production including IL-2, IL-4 and IFN-γ. Here, we initially performed heterotopic heart transplants using fully mismatched BALB/c (H-2d) donor grafts into wild type (WT) C57BL/6 (H-2b) or TSAd KO (H-2b) recipients. Contrary to our expectation, TSAd KO recipients (median survival=8 days, n=5) did not have a survival advantage in comparison to WT recipients (p=NS). We also performed minor MHC class II mismatched B6.C-H-2bm12 grafts in WT or TSAd KO recipients and found that rejection was markedly accelerated (p<0.005) in TSAd KO recipients (median survival=22 days, n=10) vs. WT recipients (median survival >45 days). Next, we performed fully mismatched transplants and treated recipients with anti-CD40L (200 mcg i.p. on day 0 and day 2) to inhibit Teff expansion. While graft survival in WT recipients was >30 days, all grafts in TSAd KO mice failed by day 21 post-transplantation (n=6, p<0.005). FACS and ELISPOT analysis revealed that anti-CD40L-treated TSAd KO recipients had increased numbers of Teffs (n=3, p<0.001) that produced increased IFN-γ production (n=3, p=0.05) vs. WT recipient cells. To evaluate whether TSAd KO mice exhibit an inability to expand induced regulatory T cells (iTregs), we next cultured WT or TSAd KO CD4+CD25- T cells with mitogen (anti-CD3/CD28), IL-2, TGFβ, and either rapamycin or retinoic acid. We observed similar numbers of CD4+CD25hiFoxp3+ cells in both WT and TSAd KO iTreg cultures. Interestingly, however, in pilot experiments, these TSAd KO Foxp3+ iTregs failed to suppress Teffs as efficiently as WT iTregs. Also, when alloprimed CD4+CD25- T cells were cocultured with CD4+CD25+ Tregs from WT or TSAd KO recipients, we found that TSAd KO Tregs had a reduced suppressive function as compared to WT Tregs. Collectively, these findings suggest that TSAd signaling is critical for the generation of functional iTregs in vivo and in vitro, and identify TSAd as a critical mediator of immunoregulation following transplantation. DISCLOSURES:Briscoe, D.: Grant/Research Support, Pfizer.

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