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

Background and aims: T cells are main mediators in allogeneic immune responses. Specific T cell clones can be tracked by their unique T cell receptor (TCR), but specificity and function remained elusive thus far and have not been investigated in liver biopsies after orthotopic liver transplantation.Methods: TCR repertoire analysis of CD4+, CD8+ T cells and regulatory T cells (Tregs) of the peripheral blood and liver graft was performed in seven liver transplant recipients with either stable course (NR), subclinical cellular rejection (SCR) or acute cellular rejection (ACR) in an observation period from pre-transplant to six years post-transplantat. Furthermore, donor-reactive T cells, identified by their expression of CD154 and GARP after allogeneic activation, were tracked longitudinally in the peripheral blood and within the liver allograft. Results: While overall clonality of the TCR repertoire did not increase in the peripheral blood after liver transplantation, clonality of donor-reactive CD4+ and Tregs increased and these clones accumulated within the liver graft. Surprisingly, the TCR repertoires between the liver graft and the peripheral blood were distinct and showed only little overlap. Notably, during ACR TCR repertoires aligned suggesting either graft-specific homing or release of activated T cells from the graft. Conclusion: This is the first study comparing TCR repertoires between liver graft and peripheral blood in patients with NR, SCR and ACR. Moreover, we attributed specificity and function to a subgroup of intragraft T cell populations. Given the little 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. For this purpose, protocol biopsies of patients with normal graft function and subclinical rejection have to be taken into account.