T cell receptor repertoires within liver allografts are different to those in the peripheral blood

Abstract

Background & aims: T cells are the main mediators of allogeneic immune responses. Specific T cell clones can be tracked by their unique T cell receptor (TCR), but specificity and function remain elusive and have not been investigated in human liver biopsies thus far.

Methods: TCR repertoire analysis of CD4⁺, CD8⁺, and regulatory T cells of the peripheral blood and liver graft was performed in 7 liver transplant recipients with either stable course (non-rejector, NR), subclinical cellular rejection (SCR), or acute cellular rejection (ACR) during an observation period from pre-transplant to 6 years post-transplant. Furthermore, donor-reactive T cells, identified by their expression of CD154 and glycoprotein A repetitions predominant (GARP) after allogeneic activation, were tracked longitudinally in peripheral blood and within the liver allograft.

Results: Although overall clonality of the TCR repertoire did not increase in peripheral blood after liver transplantation, clonality of donor-reactive CD4⁺ and regulatory T cells increased and these clones accumulated within the liver graft. Surprisingly, the TCR repertoires between the liver graft and the periphery were distinct and showed only limited overlap. Notably, during ACR, TCR repertoires aligned suggesting either graft-specific homing or release of activated T cells from the graft.

Conclusions: This is the first study comparing TCR repertoires between liver grafts and blood in patients with NR, SCR, and ACR. Moreover, we attribute specificity and function to a subgroup of intragraft T cell populations. Given the limited overlap between peripheral blood and intragraft repertoires, future studies investigating function and specificities of T cells after liver transplantation should focus on the intragraft immune response.

Lay summary: In solid organ transplantation, T cells are key mediators of the recipient's immune response directed at the transplanted organ. In our study, we characterised the T cell repertoire in a cohort of 7 liver transplant recipients. We demonstrate that donor-specific T cells expand clonally and accumulate in the transplanted liver. Moreover, we show that the composition of T cells in peripheral blood differs from the T cells in the liver allograft, only aligning in the context of acute cellular rejection but not in normal graft or subclinical cellular rejection. This indicates that the intragraft immune response is not mirrored in the peripheral blood. Our findings clarify the importance of protocol liver biopsies in identifying intragraft immune responses for future investigations of allo-directed immune responses.

Keywords: Allogeneic immune response; Graft rejection; Liver transplantation; T cell receptor repertoire analysis.