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.

FIGURE 1.

Development of CD4⁺ T-cell subsets and their phenotypic markers. Naive CD4⁺ T cells differentiate into phenotypically and functionally distinct subsets upon MHC-II-dependent activation via antigen-presenting cells. TCR signaling strength determines development of Teff or Tfh cells. Subtype lineage fate is driven by the cytokine environment (not shown for Tfh subsets). Each subset is displayed with characteristic markers. Created with BioRender.com. IFN-γ, interferon gamma; IL, interleukin; IRF4, interferon-regulatory factor 4; MHC, major histocompatibility complex; ROR, RAR-related orphan nuclear receptor; TCR, T-cell receptor; Teff, T effector; Tfh, T follicular helper; TGF-β, transforming growth factor beta; Th, T helper cell; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cell.

FIGURE 2.

Overview of T-cell subset insights and characteristics. CTL, cytotoxic T lymphocyte; γδ, gamma-delta; IFN-γ, interferon gamma; IL, interleukin; IRF4, interferon-regulatory factor 4; NKT, natural killer T cell; ROR, RAR-related orphan nuclear receptor; Tfh, T follicular helper; Tfr, T follicular regulatory cell; TGF-β, transforming growth factor beta; Th, T helper cell; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cell.