When antigens are inside of cells, they are cleaved into peptides, and those peptides bind to MHC class I or class II molecules. MHC molecules then carry the antigen to the plasma membrane and form a complex that can be recognized by T cells. Each MHC molecule can bind to various peptides and present those antigens to T cells. Class I MHC molecules primarily present peptide products that are synthesized inside of the cell to cytotoxic (CD8) T cells.[6] In contrast, class II MHC molecules primarily present exogenous proteins that were taken up and degraded by the cell to helper (CD4) T cells.[7] Therefore, class I molecules are responsible for presenting viral, tumor, or parasitic antigens and class II molecules are responsible for initiating the immune response in bacterial infections.

Major histocompatibility complex molecules are initially synthesized in and anchored to the rough endoplasmic reticulum (ER). After MHC class I chains are synthesized, they are first bound to calnexin, a membrane-bound molecule in the rough ER that stabilizes the chain until it can bind to beta2-microglobulin. After synthesis, chaperone proteins calreticulin, tapasin, and ERp57 additionally stabilize the molecule until an antigenic peptide binds. Proteins synthesized in the cytoplasm are then cleaved into peptides about 8 to 10 amino acids long and transported to the ER by ATP-dependent transporter proteins TAP1 or TAP2, where they can bind to MHC class I molecules. Any antigen that produces intracellular proteins, whether viral, bacterial, or tumor in etiology, could bind to MHC. Also, defective proteins that did not fold correctly and are digested by proteasomes, also known as defective ribosomal products (DRiPs) could bind to MHC. Tapasin is a molecule involved in stabilizing the transfer of peptides from TAP transporters to MHC molecules. Once the MHC I-peptide complex forms, it is transported to the cell surface, where it could potentially bind to a cytotoxic T cell and induce a response. In most healthy cells, if the complex contains a self-antigen, no immune response will be triggered. However, if the CD8 T cell identifies a non-self antigen, then it will trigger cell lysis.[1]

The mechanism of class MHC molecule function is similar; however, class II molecules first get transported to an endosome before binding to a peptide. In the endoplasmic reticulum, they are bound to an invariant chain that prevents them from binding to any peptides inside the ER. After binding to the invariant chain, the MHC-invariant chain complex is transported to an endosome. Most of the invariant chain is cleaved by a protease, and a small molecule named class II invariant chain peptide (CLIP) remains at the peptide-binding cleft. Meanwhile, the antigen-presenting cell, such as a dendritic cell, will phagocytize an exogenous peptide antigen, creating another endosome. The endosome containing the digested peptide will then fuse with the MHC-CLIP endosome. After fusion, preferential binding of the exogenous peptide displaces CLIP. Additionally, HLA-DM molecules help remove CLIP. After the MHC-peptide complex forms, it is transported to the cell surface. It can then bind to the T-cell receptor on a CD4 T cell, which will eventually result in antibody formation by B cells. Note that binding of the MHC-peptide complex to the T cell receptor is one of two interactions required for a successful immune response. The other is the binding of the B7 receptor on the antigen-presenting cell to the CD28 receptor on the CD4 T cell.[2]

(Figures 3 and 4)

Both major histocompatibility complex class I and class II molecules are responsible for the acute immune response that progresses to graft rejection. Because of the significant genetic variability in HLA antigens between individuals, donor organs can contain highly immunogenic antigens. It is the donor’s HLA molecules themselves that get recognized as non-self HLA, which leads to the generation of anti-HLA antibodies and subsequent graft damage.[8] In fact, antibody-mediated rejection is the most common cause of kidney or heart transplant loss. These antibodies can cause necrotic cell death in endothelial cells. The mechanism of cell damage is via both complement-dependent and complement-independent pathways. The complement-dependent antibody response involves the classical complement cascade while the complement-independent response involves intracellular signal transduction cascades.[9]

Donor organs are often preferentially taken from siblings or close family members and tested for HLA compatibility to minimize this risk. Patients typically undergo crossmatching to identify any preexisting HLA antibodies. However, post-transplant monitoring for anti-HLA antibodies is still required as they can develop even years after the transplant.[10]