Major Histocompatibility Complex I- Structure, Mechanism, Functions

Major Histocompatibility Complex I (MHC I) is a type of molecule that plays a key role in presenting antigens to T cells and thus activating the adaptive immune system. MHC I molecules are expressed on the surface of almost all nucleated cells in the body, except for red blood cells, nervous tissues and platelets.

The structure of MHC I molecules consists of two polypeptide chains: a longer alpha chain (45 kDa) and a shorter beta-2 microglobulin chain (12 kDa). The alpha chain has three domains: alpha-1, alpha-2 and alpha-3. The alpha-1 and alpha-2 domains form a cleft that binds to a peptide antigen, while the alpha-3 domain anchors the molecule to the cell membrane. The beta-2 microglobulin chain is non-covalently attached to the alpha-3 domain and does not span the membrane.

The peptide-binding cleft of MHC I molecules can accommodate peptides of 8 to 10 amino acids in length. These peptides are derived from the degradation of endogenous proteins, such as viral or tumor antigens, by the proteasome in the cytoplasm. The peptides are then transported to the endoplasmic reticulum (ER) by a transporter associated with antigen processing (TAP), where they are loaded onto MHC I molecules with the help of other proteins, such as tapasin, calreticulin and ERp57. The loaded MHC I molecules then travel to the cell surface via the Golgi apparatus.

The structure of MHC I molecules allows them to present antigens to CD8+ T cells, also known as cytotoxic T cells. CD8+ T cells have receptors (TCRs) that recognize both the peptide antigen and the MHC I molecule on the target cell. When this recognition occurs, CD8+ T cells are activated and can induce apoptosis (programmed cell death) of the target cell. This mechanism is important for eliminating infected or transformed cells and mediating cellular immunity.

In humans, there are three main types of MHC I molecules: HLA-A, HLA-B and HLA-C. These molecules are highly polymorphic, meaning that there are many different variants (alleles) of each gene in the population. This diversity ensures that different individuals can present a wide range of antigens and mount an effective immune response against various pathogens. However, it also poses a challenge for organ transplantation, as mismatched MHC I molecules can trigger immune rejection by the recipient`s CD8+ T cells.

MHC class I molecules are involved in presenting antigens of endogenous origin to CD8+ T cells. Endogenous antigens are peptides derived from the degradation of intracellular proteins, such as viral or tumor antigens, by the proteasome. The proteasome is a large protein complex that recognizes and cleaves ubiquitinated proteins into short fragments. The ubiquitin system is a way of tagging proteins for degradation by attaching a small protein called ubiquitin to them.

The proteasome-generated peptides are then transported from the cytoplasm to the endoplasmic reticulum (ER) by a transporter associated with antigen processing (TAP). TAP is a heterodimeric protein composed of TAP1 and TAP2 subunits that form a channel in the ER membrane. TAP binds to peptides that are 8-16 amino acids long and have hydrophobic or basic residues at their C-termini. TAP transports these peptides across the ER membrane using ATP as an energy source.

In the ER, the peptides are loaded onto newly synthesized MHC class I molecules with the help of a peptide-loading complex (PLC). The PLC consists of several proteins that facilitate the assembly and quality control of MHC class I-peptide complexes. These include tapasin, which bridges TAP and MHC class I molecules; ERp57, which catalyzes disulfide bond formation and rearrangement; and calreticulin, which acts as a chaperone and stabilizes MHC class I molecules. The PLC also contains a protease called ERAP1 that trims longer peptides to fit into the MHC class I binding groove.

The MHC class I-peptide complexes are then released from the PLC and transported to the cell surface via the Golgi apparatus. On the cell surface, they can interact with CD8+ T cells that express T cell receptors (TCRs) specific for the presented peptide. CD8+ T cells also express CD8 co-receptors that bind to the α3 domain of MHC class I molecules and enhance the recognition and signaling of TCRs. When a CD8+ T cell encounters an MHC class I-peptide complex that matches its TCR, it becomes activated and initiates an immune response against the infected or transformed cell. This process is called antigen presentation and is essential for cellular immunity.

MHC class I molecules have two main functions: to present endogenous antigens to CD8+ T cells and to regulate the expression of NK cell receptors.

Presentation of endogenous antigens to CD8+ T cells

MHC class I molecules present peptides derived from the degradation of intracellular proteins, such as viral or tumor antigens, to the T cell receptors (TCRs) of CD8+ T cells. CD8+ T cells are also known as cytotoxic T lymphocytes (CTLs) because they can kill the target cells that express the foreign antigens. This process is essential for the elimination of infected or transformed cells and for the protection against intracellular pathogens.

The presentation of endogenous antigens by MHC class I molecules involves several steps:

• The intracellular proteins are degraded by the proteasome, a complex of proteolytic enzymes in the cytoplasm.
• The resulting peptides are transported from the cytoplasm to the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP), a heterodimer of TAP1 and TAP2 proteins.
• In the ER, the peptides are loaded onto the MHC class I molecules with the help of a peptide-loading complex that consists of tapasin, ERp57, calreticulin, and ERp29. Tapasin bridges the MHC class I molecule and TAP and facilitates the peptide binding. ERp57 and calreticulin are chaperones that stabilize the MHC class I molecule and assist in quality control. ERp29 is an enzyme that removes a signal peptide from the MHC class I molecule.
• The loaded MHC class I molecules are transported from the ER to the Golgi apparatus and then to the plasma membrane by vesicular transport.
• On the cell surface, the MHC class I molecules display the peptides to the TCRs of CD8+ T cells. The interaction between the MHC class I molecule and the TCR is stabilized by a co-receptor called CD8, which binds to a conserved region of the MHC class I molecule. The recognition of the foreign peptide by the TCR triggers a cascade of signaling events that leads to the activation and proliferation of CD8+ T cells.

Regulation of NK cell receptors

MHC class I molecules also play a role in regulating the activity of natural killer (NK) cells, which are innate lymphocytes that can kill virus-infected or tumor cells without prior sensitization. NK cells express a variety of receptors that can recognize MHC class I molecules on target cells. Some of these receptors are inhibitory and some are activating.

The inhibitory receptors bind to self-MHC class I molecules and prevent NK cell activation. This mechanism ensures that NK cells do not attack normal cells that express adequate levels of MHC class I molecules. The inhibitory receptors belong to two families: killer cell immunoglobulin-like receptors (KIRs) and C-type lectin-like receptors (CD94/NKG2A).

The activating receptors bind to non-self or altered MHC class I molecules and trigger NK cell activation. This mechanism allows NK cells to detect and eliminate cells that have downregulated or modified their MHC class I expression due to viral infection or tumor transformation. The activating receptors include some members of KIRs and CD94/NKG2 family, as well as NKG2D, which recognizes stress-induced ligands.

The balance between inhibitory and activating signals determines whether NK cells will be activated or not. This process is called "missing self" recognition because it is based on the absence or alteration of self-MHC class I molecules on target cells.

Antigen processing and presentation is the process by which cells degrade and display peptides derived from foreign or self-proteins on their surface in association with MHC molecules. This allows the recognition and activation of specific T cells that can respond to the antigen.

There are two main pathways of antigen processing and presentation: the endogenous pathway and the exogenous pathway. The endogenous pathway is used by MHC class I molecules to present peptides from proteins synthesized within the cell, such as viral or tumor antigens. The exogenous pathway is used by MHC class II molecules to present peptides from proteins taken up by the cell from the extracellular environment, such as bacterial antigens.

The endogenous pathway involves the following steps:

• Proteins are degraded by proteasomes, which are large protein complexes that recognize and cleave ubiquitinated proteins. Proteasomes can generate peptides of 8-10 amino acids in length that fit into the peptide-binding groove of MHC class I molecules.
• Peptides are transported from the cytosol to the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP), which is a heterodimer of TAP1 and TAP2. TAP is embedded in the ER membrane and forms a channel that allows peptides to enter the ER lumen.
• Peptides are loaded onto newly synthesized MHC class I molecules in the ER with the help of several accessory proteins, such as tapasin, calreticulin, and ERp57. Tapasin bridges the peptide-binding groove of MHC class I molecules with TAP and facilitates peptide binding. Calreticulin and ERp57 act as chaperones that stabilize MHC class I molecules and assist in peptide editing.
• Peptide-MHC class I complexes are transported from the ER to the Golgi apparatus and then to the plasma membrane via vesicles. Along the way, they may encounter other proteins that modulate their expression or stability, such as endoplasmic reticulum aminopeptidase 1 (ERAP1), which trims peptides to optimal length, or human leukocyte antigen (HLA) class I histocompatibility antigen (HLA-E), which binds to some MHC class I molecules and protects them from degradation by natural killer (NK) cells.
• Peptide-MHC class I complexes are displayed on the cell surface where they can be recognized by CD8+ T cells that express T cell receptors (TCRs) specific for the peptide-MHC class I complex. This leads to the activation of cytotoxic T lymphocytes (CTLs) that can kill infected or transformed cells.

The exogenous pathway involves the following steps:

• Proteins are internalized by phagocytosis or endocytosis into phagosomes or endosomes, which are membrane-bound vesicles that contain acidic enzymes and proteases that degrade proteins into peptides of 13-18 amino acids in length that fit into the peptide-binding groove of MHC class II molecules.
• Peptides are loaded onto newly synthesized MHC class II molecules in specialized vesicles called MIICs (MHC class II compartments) or late endosomes. MHC class II molecules are synthesized in the ER with an invariant chain (Ii) that blocks their peptide-binding groove and directs them to MIICs. In MIICs, Ii is cleaved by cathepsins, leaving a small fragment called CLIP (class II-associated invariant chain peptide) that still occupies the peptide-binding groove. CLIP is then exchanged for peptides with the help of an accessory protein called HLA-DM, which acts as a catalyst and stabilizer for peptide binding.
• Peptide-MHC class II complexes are transported from MIICs to the plasma membrane via vesicles. Along the way, they may encounter other proteins that modulate their expression or stability, such as HLA-DO, which inhibits HLA-DM activity in some cell types, or HLA-DP, which binds to some MHC class II molecules and protects them from degradation by NK cells.
• Peptide-MHC class II complexes are displayed on the cell surface where they can be recognized by CD4+ T cells that express TCRs specific for the peptide-MHC class II complex. This leads to the activation of helper T cells that can secrete cytokines and provide co-stimulation for other immune cells.

Antigen processing and presentation is essential for adaptive immunity, as it allows T cells to recognize and respond to specific antigens. However, it also poses challenges for self-tolerance, as it exposes potentially self-reactive T cells to self-peptides. Therefore, mechanisms of central and peripheral tolerance are required to eliminate or regulate autoreactive T cells and prevent autoimmune diseases.

Transplant rejection is a process in which the recipient`s immune system attacks the transplanted organ or tissue as foreign and tries to eliminate it. Transplant rejection can lead to graft failure and loss of function, and may require removal of the transplant or additional treatment.

One of the major factors that determines the risk of transplant rejection is the degree of similarity or difference between the donor and the recipient in terms of their major histocompatibility complex (MHC) molecules. MHC molecules are proteins that are expressed on the surface of almost all nucleated cells and present peptides derived from self or foreign antigens to T cells. In humans, MHC molecules are also called human leukocyte antigens (HLAs), and they are highly polymorphic, meaning that there are many different variants of them in the population.

The immune system can recognize foreign MHC molecules as non-self and mount an alloreactive response against them. This response can involve both cellular and humoral immunity, mediated by cytotoxic T cells and antibodies, respectively. Cytotoxic T cells can directly kill cells that express foreign MHC molecules, while antibodies can bind to them and activate complement-mediated lysis or antibody-dependent cellular cytotoxicity.

The degree of mismatch between donor and recipient MHC molecules can vary depending on the type of transplant and the availability of compatible donors. For solid organ transplants, such as kidney, liver, heart, or lung, the donor and recipient are usually matched for at least some of the major HLA alleles, especially those encoded by the HLA-A, HLA-B, and HLA-DR loci. These alleles are inherited in a linked fashion on each chromosome 6, forming a haplotype. Ideally, the donor and recipient should share both haplotypes (identical match), or at least one haplotype (haploidentical match), to reduce the risk of rejection. However, due to the scarcity of organs and the urgency of transplantation, sometimes mismatched donors are used, especially for life-saving procedures.

For hematopoietic stem cell transplants (HSCT), such as bone marrow or cord blood transplants, the donor and recipient are usually matched for all of the major HLA alleles, as well as some minor ones, such as those encoded by the HLA-C, HLA-DQ, and HLA-DP loci. This is because HSCT involves replacing the recipient`s immune system with that of the donor, and any mismatch can result in severe complications, such as graft-versus-host disease (GVHD) or graft failure. GVHD occurs when the donor-derived immune cells attack the recipient`s tissues as foreign, while graft failure occurs when the recipient`s residual immune cells reject the donor-derived stem cells.

To prevent or treat transplant rejection, immunosuppressive drugs are used to dampen the recipient`s immune response against the donor tissue. These drugs can target different aspects of the immune system, such as T cell activation, proliferation, differentiation, or migration; antibody production; complement activation; or inflammation. Some examples of immunosuppressive drugs are corticosteroids, calcineurin inhibitors (such as cyclosporine and tacrolimus), antimetabolites (such as azathioprine and mycophenolate), mTOR inhibitors (such as sirolimus and everolimus), monoclonal antibodies (such as basiliximab and rituximab), polyclonal antibodies (such as antithymocyte globulin), and fusion proteins (such as belatacept).

Immunosuppressive drugs have to be carefully dosed and monitored to achieve a balance between preventing rejection and avoiding infection or malignancy due to immunosuppression. Moreover, some drugs may have adverse effects on the transplanted organ or other organs, such as nephrotoxicity or hepatotoxicity. Therefore, transplant recipients have to follow a strict regimen of medication and regular check-ups to ensure the optimal functioning of their grafts.

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