An Immune Atlas of T Cells in Transplant Rejection: Pathways and Therapeutic Opportunities

Abstract

Short-term outcomes in allotransplantation are excellent due to technical and pharmacological advances; however, improvement in long-term outcomes has been limited. Recurrent episodes of acute cellular rejection, a primarily T cell–mediated response to transplanted tissue, have been implicated in the development of chronic allograft dysfunction and loss. Although it is well established that acute cellular rejection is primarily a CD4+ and CD8+ T cell mediated response, significant heterogeneity exists within these cell compartments. During immune responses, naïve CD4+ T cells are activated and subsequently differentiate into specific T helper subsets under the influence of the local cytokine milieu. These subsets have distinct phenotypic and functional characteristics, with reported differences in their contribution to rejection responses specifically. Of particular relevance are the regulatory subsets and their potential to promote tolerance of allografts. Unraveling the specific contributions of these cell subsets in the context of transplantation is complex, but may reveal new avenues of therapeutic intervention for the prevention of rejection.

Elucidating T cell dynamics and molecular mechanisms in syngeneic and allogeneic islet transplantation through single-cell RNA sequencing

“…Moreover, the significant role of MIF in various biological processes and immune responses, particularly its impact on different T-cell types, underscores its potential as a biomarker or therapeutic target in islet transplantation. Compared to findings from the previous study ( 11 ), our study further elaborates on the role of γδ T cells in graft environments, providing a deeper understanding of their dual role in immunoregulation and inflammation.…”

“…The heterogeneity of T-cell subpopulations and their distinct roles in transplantation immunobiology has been studied. For instance, regulatory T cells have been shown to promote graft tolerance ( 12 ), while effector T cells contribute to graft rejection ( 11 ). The phenotypic characterization of T-cell subpopulations in the context of islet transplantation has revealed potential targets for immunomodulatory therapies, indicating the potential of these cell types for improving transplantation outcomes ( 13 ).…”

“…Allogeneic islet transplantation has demonstrated efficacy in restoring insulin independence in T1DM patients; however, donor scarcity and the necessity for chronic immunosuppression limit its widespread application ( 8 – 10 ). Moreover, allogeneic islet transplantation is also accompanied by significant immunological challenges, primarily due to robust T-cell-mediated rejection ( 11 ). The critical role of T-cell dynamics in islet transplantation is underscored by their central involvement in immune tolerance and rejection processes.…”

Imaging and monitoring of granzyme B in the immune response

“…The recognition and rejection of allografts are the result of complex interactions between various cells. Modern transplantation immunology studies have found that GzmB plays an important role in CTL killing of donor cells (Short et al, 2023). As early as 1991, Clément et al reported that GzmB could be used as a predictive marker of acute GVHD or cardiac rejection after bone marrow or heart transplantation (Clément et al, 1991).…”

Multiple Shades of Gray—Macrophages in Acute Allograft Rejection

“…Historically, the research addressing allograft rejection mainly focused on the adaptive immune system, increasing the knowledge regarding different cell subsets involved in this process [15,16]. This goes back to early publications showing that T-cells played a crucial role in allograft rejection [17,18].…”