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

• Published in: Cell reports (Cambridge) Vol. 24; no. 8; pp. 2112 - 2126
• Main Authors: Miller, Michelle L., McIntosh, Christine M., Williams, Jason B., Wang, Ying, Hollinger, Maile K., Isaad, Noel J., Moon, James J., Gajewski, Thomas F., Chong, Anita S., Alegre, Maria-Luisa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.08.2018
• Subjects: affinity; Animals; avidity; costimulation; Graft Rejection - immunology; Humans; Immune Tolerance - immunology; Mice; mouse; pMHC multimer; T cells; TCR; tolerance; transplantation; Transplantation Tolerance - immunology; avidity; mouse; TCR; costimulation; transplantation; pMHC multimer; T cells; tolerance; affinity
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •Alloantigen encounter results in preferential expansion of high-avidity T cells•Costimulation blockade prevents skewing of T cell populations toward higher avidity•Low-avidity alloreactive T cell populations typify transplant tolerance long term•Tolerant mice retain low-avidity T cell populations despite alloantigen rechallenge The net strength of multiple TCR binding interactions determines a cell’s avidity for antigen. Miller et al. find that high-avidity T cells preferentially accumulate following alloantigen encounter. This T cell repertoire skewing is durably prevented by tolerance induction, where lower avidity cell populations persist even upon subsequent alloantigen rechallenge.