Intercellular transfer of MHC molecules in T cell alloimmunity and allotransplantation

Abstract

After transplantation of allogeneic tissues and organs, recognition by recipient T cells of donor MHC molecules initiates the pro-inflammatory adaptive immune response leading to allograft rejection. T cell allorecognition has long been known to be mediated via two distinct pathways: the direct pathway in which T cells recognize intact allogeneic MHC molecules displayed on donor cells and the indirect pathway whereby T cells recognize donor MHC peptides processed and presented by recipient antigen-presenting cells (APCs). It is believed that direct allorecognition is the driving force behind early acute allograft rejection while indirect allorecognition is involved in chronic allograft rejection, a progressive condition characterized by graft vasculopathy and tissue fibrosis. Recently, we and others have reported that after transplantation of allogeneic skin and organs, donor MHC molecules are transferred from donor cells to the host's APCs via trogocytosis or extracellular vesicles. Recipient APCs having captured donor MHC molecules can either present them to T cells in their intact form on their surface (semi-direct pathway) or the form of peptides bound to self-MHC molecules (indirect pathway). The present article provides an overview of recent studies evaluating the role of intercellular exchange of MHC molecules in T cell alloimmunity and its contribution to allograft rejection and tolerance.

Fig. 1

Allorecognition by T cells is mediated via three distinct pathways. In the direct pathway, T cells recognize allogeneic MHC molecules displayed on the membrane of donor APCs. In the indirect pathway, T cells interact with allogeneic peptides (MHC and mHA) processed and presented by recipient APCs. In the semi-direct pathway, T cells recognize allogeneic MHC molecules transferred to and presented by recipient APCs.

Fig. 2

Three-cell versus four-cell models of CD4⁺T cell help for CD8⁺T cell alloresponse.In the four-cell model, CD4⁺ T cells and CD8⁺ T cells recognize recipient MHC class II molecules + donor peptides (indirect pathway) on recipeint APCs and donor MHC class I on donornAPCs (direct pathway), respectively. In the three-cell model, CD4⁺ T cells recognizing allogeneic peptides bound to recipient MHC class II molecules on recipient APCs (indirect pathway) provide help to alloreactive CD8⁺ T cells recognizing donor MHC class I molecules acquired by (MHC cross-dressing) and presented on the same recipient APCs (semi-direct pathway).

Fig. 3

Model for suppression of alloreactive effector T cells by CD4⁺regulatory T cells (Tregs).This model postulates that CD4⁺ Tregs recognizing donor peptides bound to self-MHC class II molecules on recipient APCs (indirect pathway) can suppress effector CD4⁺ or CD8⁺ effector T cells recognizing intact donor MHC molecules displayed on the same recipient APCs through MHC cross-dressing (semi-direct pathway).