*Purpose: CD4⁺ regulatory T cells (Treg) maintain transplantation tolerance through the suppression of immunity in both secondary lymphoid organs and allografts. However, the signals promoting Treg migration to allograft are not fully understood. Specifically, the role of effector T cells (Teff) in this process remains unknown.

*Methods: To address this, we adoptively transferred activated Treg alone or with Teff into splenectomized B6.LTβR^-/- (H2b) mice transplanted with allogeneic Balb/c islets (H2d), and enumerated graft-infiltrating cells on day 3 after cell transfer by flow cytometry. These recipient mice are lymphoid-replete but lack secondary lymphoid organs, prohibiting endogenous adaptive immune responses to allografts.

*Results: We found that Treg remained in the circulation and readily migrated to lungs and liver independently of the presence of Teff. In sharp contrast, few Treg were found within islet allografts when transferred alone. However, the presence of Teff led to a 30-fold increase in Treg migration to allografts. Similar results were observed in B6 recipients of B6.Ova islet grafts transferred with either OTII Treg alone or OTII Treg + OTI Teff. We then investigated whether Teff potentiate Treg migration through chemokine receptor signaling in Treg. Pre-treatment of Treg with pertussis toxin (PTx) before cell transfer with Teff drastically reduced their migration to allografts by 22-folds. Consequently – and unlike untreated Treg -, PTx-treated Treg were unable to suppress Teff responses and prevent rejection in splenectomized B6.LTβR^-/- recipients. Given that chemokines can be induced by pro-inflammatory cytokines, we investigated whether Teff potentiate Treg migration to allografts through interferon-λ (IFNλ) secretion. Interestingly, we found that Treg equally migrated to allografts when transferred with either WT Teff or IFNλ^-/- Teff.

*Conclusions: Overall, our findings demonstrate that Treg minimally migrate to inflamed allografts in absence of a parallel effector T cell response. In turn, these data establish an unexpected role for effector T cells in potentiating chemokine receptor-dependent Treg migration to allografts, which has implications for Treg therapy.

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