The TLR-MyD88 signaling pathway enables the innate immune system to sense inflammation and promote adaptive immune responses. TLRs are expressed on T cells as well, and we have previously demonstrated that T cell intrinsic MyD88 signaling promotes T cell survival and is required for optimal responses to pathogens such as T. gondii and LCMV. Surprisingly however, we have observed that mice with a targeted T cell deletion of MyD88 (MyD88fl/fl x CD4-Cre, termed MyD88ΔT) reject bm12 skin allografts in the presence of ΑCD154 and rapamycin at a higher frequency than wild type (WT) mice (mean survival time of 19 and >100 days respectively). As Tregs are critical for graft prolongation following costimulatory blockade, we hypothesized a “defect” in MyD88ΔT Tregs in the above model. Indeed, while the frequency of Tregs is similar in unmanipulated WT vs. MyD88ΔT mice, we observe a higher frequency of WT Tregs in comparison to MyD88ΔT Tregs 7 and 14 days after bm12 skin transplantation with ΑCD154 and rapamycin, without any obvious changes in the total frequency of CD4 T cells. As MyD88ΔT mice do not allow us to differentiate the effect of MyD88 deletion specifically on Tregs versus the T cell compartment as a whole, we created mice with a targeted deletion of MyD88 specific to Tregs (MyD88fl/fl x FoxP3-Cre-YFP, termed MyD88ΔTreg). MyD88ΔTreg mice, like MyD88ΔT mice have a similar Treg frequency when compared to WT mice and have no observable signs of autoimmunity. To determine whether the failure of MyD88 deficient Tregs to accumulate following skin transplant and costimulatory blockade might be a result of an inability to activate pro-survival pathways, we analyzed sorted FoxP3+ cells from MyD88ΔTreg mice for Bcl-xL. Paradoxically, we observe higher levels of Bcl-xL in MyD88ΔTregs compared to control Tregs. This suggests that Bcl-xL may be acting in a compensatory manner for another defect in the pro-survival or anti-apoptotic pathways. Skin transplants using MyD88ΔTreg mice as recipients are currently in progress to determine whether Treg specific MyD88 deletion prevents allograft survival in our model. Taken together, these data suggest that T cell intrinsic MyD88 signaling promotes Treg accumulation following skin transplantation in the presence of costimulatory blockade, which may be associated with long-term allograft survival.

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