Pathways of major histocompatibility complex allorecognition

Abstract

Purpose of review: Here, we review the pathways of allorecognition and their potential relevance to the balance between regulatory and effector responses following transplantation.

Recent findings: Transplantation between nonidentical members of the same species elicits an immune response that manifests as graft rejection or persistence. Presentation of foreign antigen to recipient T cells can occur via three nonmutually exclusive routes, the direct, indirect and semi-direct pathways. Allospecific T cells can have effector or regulatory functions, and the relative proportions of the two populations activated following alloantigen presentation are two of the factors that determine the clinical outcome. Regulatory T cells have been the subject of significant research, and there is now greater understanding of their recruitment and function in the context of allorecognition.

Summary: A greater understanding of the mechanisms underlying allorecognition may be fundamental to appreciating how these different populations are recruited and could in turn inform novel strategies for immunomodulation.

Figure 1. Direct, indirect and semi-direct pathways of allorecognition

(a) Direct pathway. Recognition of intact foreign MHC on donor APC primes CD4⁺ and CD8⁺ recipient T cells. CD4⁺ cells then provide T cell help for the effector function of CD8⁺ cells. (b) Indirect pathway. Recipient APCs traffic through transplanted organs, phagocytose allogeneic MHC shed from foreign cells through cell necrosis and apoptosis and present the processed peptides in the context of self-MHC class II to MHC class II-restricted CD4⁺ T cells. (c) Semi-direct pathway. Cell-to-cell contact between donor and recipient APC may transfer intact membrane components including intact allo-MHC (a). Likewise, donor APC can release small vesicles, known as ‘exosomes’ containing intact MHC (b), which fuse with the membrane of recipient APCs (c). Recipient APCs, now chimeric for MHC, stimulate direct pathway CD4 and CD8 responses through intact foreign MHC and indirect responses through processing and presentation of peptides of foreign MHC acquired from necrotic and apoptotic cell material. Given that the same APC stimulates both CD4 and CD8 cells, linked help can occur. APC, antigen-presenting cells; dAPC, donor APC; MHC, major histocompatibility complex; rAPC, recipient APC. Modified from [1].

Figure 2. The three and four cell models of T cell cross-talk

(a) The three-cell model of T cell cross-talk. The traditional dogma of CD4⁺ T cell help to or suppression of a CD8⁺ cell stipulates that both T cells should be primed by the same APC, thereby resulting in ‘linked’ help or suppression. (b) The four-cell problem. To explain the observation that recipient CD8⁺ T cells stimulated through the direct pathway by donor APC can receive T cell help or suppression from CD4⁺ T cells activated via the indirect pathway by recipient dendritic cells, it is necessary to invoke a four-cell or ‘unlinked’ model. APC, antigen-presenting cells; dAPC, donor APC; rAPC, recipient APC. Modified from [1].