How MHC determines the immune response
Genetic control of the immune response is based on the ability of MHC molecules to bind peptides. The structure of the antigen-binding cleft of an MHC molecule directly determines whether it can anchor a protein fragment.
- If the MHC molecule (encoded by a specific genotype) successfully binds the peptide, a highly immunogenic T-cell antigen is formed. An immune response is triggered.
- If the cleft structure is not suitable for the given peptide, binding does not occur. In this case, the antigen turns out to be non-immunogenic for the specific organism.
Thus, an individual's set of MHC genes dictates how effectively their immune system will recognize various pathogens. This rule also applies to the B-cell response: since antibody production often requires the participation of T helper cells, humoral immunity indirectly depends on the ability of epitopes to fit into MHC-II molecules.
Immunodominance and conditions of immunogenicity
An antigen molecule contains regions that elicit a stronger immune response — this phenomenon is called immunodominance. The main factor here is the affinity of specific protein fragments, generated by intracellular enzymes (cathepsins), for the MHC clefts of the given organism.
For a protein to become a fully functional T-cell antigen, it must meet two criteria:
- Susceptibility to intracellular proteases. The protein must be easily cleaved into short peptides.
- Ability to bind to MHC. The excised peptide must fit into the antigen-binding cleft (this is the key stage of genetic control).
T-cell specificity and the immune synapse
The interaction of the T-cell receptor (TCR) with the peptide-MHC complex is characterized by low baseline affinity ($10^{-5}$ to $10^{-6}$ M). Even with the involvement of coreceptors that increase affinity hundreds of times (up to $10^{-7} - 10^{-8}$ M), this binding strength is insufficient to fully activate the lymphocyte.
To solve this problem, an immune synapse is formed — a complex supramolecular contact zone between an antigen-presenting cell (APC) and a T lymphocyte. It is within the synapse that the accumulation of signals necessary to trigger the response occurs.
Different types of T cells specialize in different tasks thanks to their coreceptors:
- CD4+ T cells (T helpers): recognize peptides on MHC-II, reacting to extracellular threats (bacteria in the intercellular space or endosomes).
- CD8+ T cells (T cytotoxic cells): interact with MHC-I, detect intracellular proteins (e.g., viral proteins), and destroy infected cells.
Cross-reactivity and recognition of non-self
Due to the relatively low affinity of TCRs, T-cell epitopes exhibit pronounced cross-reactivity (especially with the involvement of CD4). This mechanism is established in the thymus, where lymphocytes with moderate affinity for self MHC complexes are selected. In adulthood, it is cross-reactivity that allows T cells to recognize self MHC molecules when they present foreign peptides.
A special case is the recognition of allogeneic MHC molecules (during transplantation). It proceeds via two pathways:
- Indirect pathway: T cells recognize fragments of donor MHC molecules presented on the host's own MHC molecules.
- Direct pathway: The TCR directly interacts with a foreign MHC molecule, perceiving it as "altered self," regardless of the peptide it carries.
Briefly: answers to topical questions
What structures participate in the formation of the immune synapse?
Specialized lipid microdomains, cytoskeleton elements, and various membrane and intracellular proteins participate in the formation of the immune synapse.
Main structural components:
- Rafts (raft) — membrane microdomains enriched in cholesterol and sphingolipids.
- Adhesion molecules — $\beta_2$-integrins (LFA-1, Mac-1) and CD2 on the killer cell side, forming physical contact.
- Receptor molecules and their targets — TCR, MHC-II molecules, CD4 and CD8 coreceptors.
- Costimulatory molecules — CD28 on T cells, CD80/86 on dendritic cells.
- Signaling and adaptor proteins — tyrosine kinases (Lck, ZAP-70, PLC$\gamma$, PI$_3$K), tyrosine phosphatase CD45, adaptor protein LAT, protein kinase C theta isoform (PKC$\theta$).
- Cytoskeleton elements — actin-containing components, microtubules, Vav factor, WASP and ARP2/3 proteins.
What other loci are included in the major histocompatibility complex besides classical class I and class II MHC genes?
In addition to classical genes, the major histocompatibility complex includes non-classical class I and class II genes, as well as class III MHC genes.
Additional loci:
- Non-classical class I genes — E, F, G, H, J, X loci, as well as the MIC gene family (MICA, MICD, MICE).
- Non-classical class II genes — TAP loci (TAP1,2), LMP loci (LMP2,7), HLA-DM (DMA, DMB), HLA-DO (DOA, DOB), DNA, DNB, and the tapasin gene (Tapasin).
- Class III MHC genes — complement system genes (C4$\beta$, C4$\alpha$, Bf, C2), tumor necrosis factor family genes (TNF, LTA, LTB), and the MICB gene.
Class and exam questions
What is the essence of genetic control of the immune response?
The bottom line is that MHC genes determine the structure of the antigen-binding cleft of the molecules. If the cleft is suitable for binding a pathogen fragment, the immune response is triggered; if not, the antigen remains unrecognized.
How is the problem of low TCR affinity solved?
To compensate for the weak bond between the TCR and the antigen, an immune synapse is formed — a special zone of tight contact between the T lymphocyte and the antigen-presenting cell, where receptors and coreceptors congregate.
What is immunodominance of T-cell epitopes?
This is the property of certain epitopes to elicit a much stronger immune response compared to others. It depends on how well a specific peptide binds to the MHC molecules of a given organism.
What else to study on this topic
- Structural features of MHC-I and MHC-II molecules
- Antigen processing and the role of intracellular proteases
- Structure and function of the T-cell receptor (TCR)
- Molecular structure of the immune synapse
- Superantigens: mechanisms of T-cell activation without processing
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