Major Histocompatibility Complexes (MHC) are key players in our immune system. They're like tiny flags on cells that show what's going on inside. MHC I molecules are on all cells, while MHC II molecules are on special immune cells.

These molecules help our body recognize and fight off invaders. They work with different immune cells, like T cells, to start an immune response. Understanding MHC is crucial for grasping how our body defends itself against diseases.

Major Histocompatibility Complexes (MHC)

Structure and expression of MHC molecules

• MHC I molecules
  • Heterodimers composed of a polymorphic α chain and a non-polymorphic β2-microglobulin (light chain)
  • Expressed on the surface of all nucleated cells (somatic cells and leukocytes)
  • Present intracellular antigens such as viral proteins (influenza) and tumor antigens (melanoma) to CD8+ T cells to initiate cytotoxic immune responses
  • Contain a peptide-binding groove that accommodates antigenic peptides
• MHC II molecules
  • Heterodimers consisting of polymorphic α and β chains that form a peptide-binding cleft
  • Expressed on professional antigen-presenting cells (APCs) including dendritic cells, macrophages, and B cells
  • Present extracellular antigens like bacterial proteins (lipopolysaccharides) to CD4+ T cells to stimulate helper T cell responses and antibody production

Key antigen-presenting cells

• Dendritic cells (DCs)
  • Most potent APCs with the unique ability to activate naive T cells and initiate primary immune responses
  • Myeloid DCs specialize in antigen uptake, processing, and presentation to T cells in lymph nodes
  • Plasmacytoid DCs produce large amounts of type I interferons (IFN-α and IFN-β) in response to viral infections (influenza, HIV)
  • Capable of cross-presentation, presenting exogenous antigens on MHC I molecules to CD8+ T cells
• Macrophages
  • Phagocytose and degrade pathogens (bacteria, fungi) and present antigens to T cells to stimulate adaptive immunity
  • Secrete cytokines (IL-1, TNF-α) and chemokines to modulate immune responses and recruit other immune cells
  • Involved in tissue repair (wound healing) and maintaining homeostasis by clearing apoptotic cells
• B cells
  • Primary function involves producing antibodies (immunoglobulins) to neutralize pathogens and toxins
  • Act as APCs by presenting antigens to T cells via MHC II and receiving co-stimulatory signals (CD40-CD40L interaction) for activation and differentiation into plasma cells

Antigen Processing and Presentation

MHC I vs MHC II pathways

• MHC I pathway
  1. Processes intracellular antigens such as viral proteins (influenza nucleoprotein) and tumor antigens (mutated p53)
  2. Antigens are degraded by the proteasome in the cytosol into peptide fragments
  3. Peptide fragments are transported into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP)
  4. Peptides bind to MHC I molecules in the ER lumen and the stable MHC I-peptide complex is transported to the cell surface
  5. MHC I-peptide complexes are recognized by CD8+ T cells to initiate cytotoxic T lymphocyte (CTL) responses
• MHC II pathway
  1. Processes extracellular antigens such as bacterial proteins (tetanus toxoid) and allergens (pollen)
  2. Antigens are endocytosed by APCs and degraded in endosomes/lysosomes by proteases (cathepsins)
  3. MHC II molecules are synthesized in the ER and transported to the endosomal compartment
  4. Peptide fragments bind to MHC II molecules in the endosome and the stable MHC II-peptide complex is transported to the cell surface
  5. MHC II-peptide complexes are recognized by CD4+ T cells to stimulate helper T cell responses (Th1, Th2) and antibody production by B cells
  • The invariant chain protects the peptide-binding groove of MHC II molecules during transport from the ER to endosomes

Genetic basis and diversity

• MHC molecules are encoded by HLA genes in humans, which are highly polymorphic
• This genetic diversity allows for recognition of a wide range of antigens and contributes to individual differences in immune responses

T cell recognition

• T cell receptors (TCRs) on T cells recognize and bind to specific MHC-peptide complexes on APCs
• This interaction is crucial for initiating and regulating adaptive immune responses