Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance

Abstract

Mechanisms implicated in robust transplantation tolerance at the cellular level can be broadly categorized into those that inhibit alloreactive Tcells intrinsically (clonal deletion and dysfunction) or extrinsically through regulation. Here, we investigated whether additional population-level mechanisms control Tcells by examining whether therapeutically induced peripheral transplantation tolerance could influence Tcell populations' avidity for alloantigens. Whereas Tcells with high avidity preferentially accumulated during acute rejection of allografts, the alloreactive Tcells in tolerant recipients retained a low-avidity profile, comparable to naive mice despite evidence of activation. These contrasting avidity profiles upon productive versus tolerogenic stimulation were durable and persisted upon alloantigen re-encounter in the absence of any immunosuppression. Thus, peripheral transplantation tolerance involves control of alloreactive Tcells at the population level, in addition to the individual cell level. Controlling expansion or eliminating high-affinity, donor-specific Tcells long term may be desirable to achieve robust transplantation tolerance in the clinic.