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

Cell Rep. 2018 Aug 21;24(8):2112-2126. doi: 10.1016/j.celrep.2018.07.067.


Mechanisms implicated in robust transplantation tolerance at the cellular level can be broadly categorized into those that inhibit alloreactive T cells intrinsically (clonal deletion and dysfunction) or extrinsically through regulation. Here, we investigated whether additional population-level mechanisms control T cells by examining whether therapeutically induced peripheral transplantation tolerance could influence T cell populations' avidity for alloantigens. Whereas T cells with high avidity preferentially accumulated during acute rejection of allografts, the alloreactive T cells 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 T cells at the population level, in addition to the individual cell level. Controlling expansion or eliminating high-affinity, donor-specific T cells long term may be desirable to achieve robust transplantation tolerance in the clinic.

Keywords: T cells; TCR; affinity; avidity; costimulation; mouse; pMHC multimer; tolerance; transplantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Graft Rejection / immunology*
  • Humans
  • Immune Tolerance / immunology*
  • Mice
  • Transplantation Tolerance / immunology*