Mechanisms of allorecognition and xenorecognition in transplantation

Abstract

Foreign antigen recognition is the ability of immune cells to distinguish self from nonself, which is crucial for immune responses in both invertebrates and vertebrates. In vertebrates, T cells play a pivotal role in graft rejection by recognizing alloantigens presented by antigen-presenting cells through direct, indirect, or semidirect pathways. B cells also significantly contribute to the indirect presentation of antigens to T cells. Innate immune cells, such as dendritic cells, identify pathogen- or danger-associated molecular patterns through pattern recognition receptors, thereby facilitating effective antigen presentation to T cells. Recent studies have shown that innate immune cells, including macrophages and NK cells, can recognize allogeneic or xenogeneic antigens using immune receptors like CD47 or activating NK receptors, instead of pattern recognition receptors. Additionally, macrophages and NK cells are capable of exhibiting memory responses to alloantigens, although these responses are shorter than those of adaptive memory. T cells also recognize xenoantigens through either direct or indirect presentation. Notably, macrophages and NK cells can directly recognize xenoantigens via surface immune receptors in an antibody-independent manner, or they can be activated in an antibody-dependent manner. Advances in our understanding of the recognition mechanisms of adaptive and innate immunity against allogeneic and xenogeneic antigens may improve our understanding of graft rejection.

Keywords: Alloimmunity; Nonself recognition; Transplantation; Transplantation rejection; Xenotransplantation.

Fig. 1

Various mechanisms of allorecognition of T cells. Mature APCs activate CD4⁺ and CD8⁺ T cells by presenting donor-derived peptides via MHC molecules through three pathways: direct, indirect, and semidirect. (A) In the direct pathway, recipient T cells recognize donor MHC-peptide complexes on donor APCs, and CD8⁺ T cells are assisted by CD4⁺ T cells. (B) In the indirect pathway, CD4⁺ T cells interact with recipient MHCs presenting peptides from processed donor MHCs. Meanwhile, ^ⓐ CD8⁺ T cells interact with recipient APCs via cross-presentation (three-cell model) or ^ⓑ donor APCs (four-cell model) and receive assistance from CD4⁺ T cells. (C) The semidirect pathway involves CD8⁺ T cells recognizing intact donor MHC class I on recipient APCs and receiving assistance from CD4⁺ T cells that recognize recipient MHC class II with processed peptides on recipient APCs. APC, antigen-presenting cell; MHC, major histocompatibility complex; TCR, T cell receptor; IL, interleukin.

Fig. 2

Allorecognition of B cells and B–T interaction. Naive B cells exit the circulation, enter B cell follicles in the secondary lymphoid organ and survey antigens in the environment. (1) Antigens are encountered on B cells through the B cell receptor, and the antigens are (2) internalized, and then (3) processed and presented to T cell receptors on T cells at the T–B cell border, driving naive B cells to proliferate and differentiate into plasma cells or memory B cells. Ig, immunoglobulin; MHC, major histocompatibility complex.

Fig. 3

Primary and secondary allorecognition of macrophages. (A) Mismatches of MHC I and SIRPα between donor and recipient and expressions of both PIR-A and CD47 molecules on recipient monocytes are required for establishing allospecific monocyte memory. (B) Recipient monocytes are primed by increased binding strength of CD47 with allogeneic SIRPα. Primed myeloid cells engage with mismatched MHC class I molecules through PIR-A (mouse) or LILR (human), leading to proliferation and increased responsiveness. SIRPα, signal regulatory protein alpha; PIR-A, paired immunoglobulin-like receptor-A; MHC, major histocompatibility complex; LILR, leukocyte immunoglobulin-like receptor; HLA, human leukocyte antigen.

Fig. 4

Allorecognition of NK cells via missing-self. Recipient NK cells are suppressed by the binding of NK inhibitory receptor, such as KIR, to self HLA class I on the membrane of recipient cells. In contrast, recipient NK cells are activated by binding of NK activating receptor to activating ligands on donor cells in the absence of self HLA class I, so-called missing-self mechanism. NK cell, natural killer cell; KIR, killer cell Ig-like receptor; HLA, human leukocyte antigen.

Fig. 5

Xenorecognition of T cells. (A) Direct xenorecognition. Xenogeneic APCs present xenogeneic peptides to the recipient CD4⁺ T cells via the xenogeneic MHC class II molecules. This led to the production of IL-2 by the CD4⁺ T cells. IL-2 acts on CD8⁺ T cells, which themselves recognize xenogeneic peptides presented via the MHC class I on the xenogeneic APC. (B) Indirect xenorecognition. Shed xenogeneic antigens from the xenogeneic cell are taken up by the recipient APC to be presented to the CD4⁺ T cell via MHC class II molecule, which results in generation of the effector functions. IL-2, interleukin 2; APC, antigen-presenting cell; MHC, major histocompatibility complex; TCR, T cell receptor.

Fig. 6

Antibody-dependent and -independent xenorecognition of macrophages. Monocytes or macrophages can trigger the destruction of porcine cells through two immune mechanisms. In the antibody-dependent process, macrophages are activated via FcR-mediated signaling during their interaction with cells coated by xenoreactive antibodies. In contrast, in the antibody-independent process, monocytes are activated through direct recognition of xenogeneic antigens, such as α-Gal, via cell surface receptor, such as galectin-3. Molecular incompatibility of myeloid inhibitory molecules, such as CD47 and CD200, between pigs and humans contributes to weak negative feedback on macrophage activation and leads to overactivation of macrophages after xenotransplantation. α-Gal, α-galactosidase; FcR, Fc receptor; DAMP, danger-associated molecular pattern; TLR, Toll-like receptor; SIRPα, signal regulatory protein alpha.

Fig. 7

Antibody-dependent and -independent xenorecognition of NK cells. (A) NK cells can facilitate the destruction of porcine cells through antibody-dependent cytotoxicity and (B) antibody-independent direct cytotoxicity. In the antibody-dependent cellular cytotoxicity process, NK cells interact with the Fc region of antibody complexes via FcRs, leading to the release of cytotoxic granules. In the antibody-independent, direct cytotoxicity, the inhibitory receptors on human NK cells, including KIR, ILT2, and CD94/NKG2A, fail to effectively recognize SLA-I and the pig HLA-E counterpart, which blocks the inhibitory signals that would typically suppress NK cell activity. Additionally, the engagement of pULBP1-NKG2D and pCD58-CD2 signaling pathways, along with an unknown ligand interacting with NKp44, can induce the direct cytotoxic activity of NK cells. NK, natural killer; FcR, Fc receptor; α-Gal, α-galactosidase; KIR, killer cell immunoglobulin-like receptor; SLA, swine leukocyte antigen; HLA, human leukocyte antigen.