Allorecognition Unveiled: Integrating Recent Breakthroughs Into the Current Paradigm

Abstract

In transplantation, genetic differences between donor and recipient trigger immune responses that cause graft rejection. Allorecognition, the process by which the immune system discriminates allogeneic grafts, targets major histocompatibility complex (MHC) and minor histocompatibility antigens. Historically, it was believed that allorecognition was solely mediated by the recipient's adaptive immune system recognizing donor-specific alloantigens. However, recent research has shown significant roles for innate immune components, such as lymphoid and myeloid cells, which are sometimes triggered by the mere absence of a self-protein in the graft. This review integrates recent breakthroughs into the current allorecognition paradigm based on the well-established direct and indirect pathways, emphasizing the semi-direct pathway where recipient antigen-presenting cells (APCs) acquire donor MHC molecules, and the inverted direct pathway where donor CD4⁺ T cells within the graft activate recipient B cells to produce donor-specific antibodies (DSAs). The review also explores the role of natural killer (NK) cells in both promoting and inhibiting graft rejection, highlighting their dual role in innate allorecognition. Additionally, it discusses the emerging understanding of myeloid cell-mediated allorecognition and its implications for initiating adaptive immune responses. These insights aim to provide a more comprehensive understanding of allorecognition, potentially leading to improved transplant outcomes.

Keywords: adaptive immunity; allorecognition pathways; graft rejection; innate immunity; pathophysiology.

FIGURE 1

Intricate innate and adaptive allorecognition pathways leading to allograft rejection. Legend: Mono, monocyte; DC, dendritic cell; NK, natural killer; EndC, endothelial cell; MHC, major histocompatibility complex; TCR, T-cell receptor; iKIR, inhibitory killer cell immunoglobulin-like receptor; SIRPα, signal-regulatory protein alpha; DSA, donor specific antibodies.

FIGURE 2

Molecular mechanisms of TCR-mediated direct allorecognition compared with syngeneic recognition. The grey area represents the location where the binding strength of the TCR to the MHC/peptide complex is strongest according to the theory described. Syngeneic recognition implies an interaction force that encompasses the whole complex. The multiple binary complex theory predicts that the ability to recognise endogenous peptides is the main factor determining alloreactivity. Finally, the high determinant density theory proposes that the TCR directly recognises the MHC polymorphism, independently of the peptide antigen. Legend: MHC, Major histocompatibility complex.

FIGURE 3

Kinetics of the different allorecognition pathways after transplantation. Legend: Mono, monocyte; DC, dendritic cell; NK, natural killer; EndC, endothelial cell; MHC, major histocompatibility complex; TCR, T-cell receptor; iKIR, inhibitory killer cell immunoglobulin-like receptor; SIRPα, signal-regulatory protein alpha.