Allorecognition by T Lymphocytes and Allograft Rejection

Abstract

Recognition of donor antigens by recipient T cells in secondary lymphoid organs initiates the adaptive inflammatory immune response leading to the rejection of allogeneic transplants. Allospecific T cells become activated through interaction of their T cell receptors with intact allogeneic major histocompatibility complex (MHC) molecules on donor cells (direct pathway) and/or donor peptides presented by self-MHC molecules on recipient antigen-presenting cells (APCs) (indirect pathway). In addition, recent studies show that alloreactive T cells can also be stimulated through recognition of allogeneic MHC molecules displayed on recipient APCs (MHC cross-dressing) after their transfer via cell-cell contact or through extracellular vesicles (semi-direct pathway). The specific allorecognition pathway used by T cells is dictated by intrinsic and extrinsic factors to the allograft and can influence the nature and magnitude of the alloresponse and rejection process. Consequently, various organs and tissues such as skin, cornea, and solid organ transplants are recognized differently by pro-inflammatory T cells through these distinct pathways, which may explain why these grafts are rejected in a different fashion. On the other hand, the mechanisms by which anti-inflammatory regulatory T cells (Tregs) recognize alloantigen and promote transplantation tolerance are still unclear. It is likely that thymic Tregs are activated through indirect allorecognition, while peripheral Tregs recognize alloantigens in a direct fashion. As we gain insights into the mechanisms underlying allorecognition by pro-inflammatory and Treg cells, novel strategies are being designed to prevent allograft rejection in the absence of ongoing immunosuppressive drug treatment in patients.

Keywords: T cell tolerance; T cells; allograft rejection; allorecognition; exosomes; major histocompatibility complex; regulatory T cells.

Figure 1

Potential mechanisms involved in semi-direct allorecognition by recipient CD4⁺ and CD8⁺ T cells. Recipient cells are shown in blue and donor cells and peptides are shown in red. (A) depicts the classical four-cell cluster model in which CD4⁺ T cells activated indirectly [via recognition of recipient major histocompatibility complex (MHC) class II⁺ donor peptide, displayed on recipient antigen-presenting cells (APCs)] may provide help for CD8⁺ T cells activated directly (via recognition of donor MHC class I on donor APCs). (C) depicts the traditional four-cell cluster model in which CD4⁺ T cells activated indirectly (via recognition of recipient MHC class II⁺ donor peptide, displayed on recipient APCs) and CD4⁺ T cells activated directly (via recognition of donor MHC class II on donor APCs). (B,D) describe different mechanisms by which semi-direct allorecognition could allow for a three-cell cluster model in which different T cells recognize different antigens on the same recipient APCs. This process would optimize T cell help by CD4⁺ T cells activated indirectly for CD8⁺ T cell activated directly (recognition of acquired MHC class I) (B) and enhance cooperation between CD4⁺ T cells activated directly (via recognition of acquired donor MHC class II) and indirectly (recipient MHC class II⁺ donor peptide) (D).