97 Specific (Adaptive) Immune Response – Role of MHC Class 2 Complexes

How do MHC Class II proteins compare to MHC Class I in terms of location, structure and function?

MHC Class II (MHC II) – Location

Unlike MHC I, which are expressed by all nucleated cells and platelets, MHC II are synthesized only by Antigen-Presenting Cells (APCs) such as macrophages and dendritic cells as well as B lymphocytes (B cells) and some thymic cells.  MHC II are comprised of 4 polypeptides that are transcribed and translated from the MHC Class II (HLA II) coding region on chromosome 6.  The MHC coding region is polygenic, in that it is made of many genes (in this case over 160 genes).  There are polymorphisms within certain genes in this region (e.g. MHC I and MHC II genes), meaning that there are many different alleles of these genes, such that each individual human is likely to have a unique set of alleles for MHCII and MHCII genes, just like a unique set of fingerprints.  Each individual inherits between 3-6 different MHC I genes and 3-12 MHC II genes.  Plus, there are over 19,000 different alleles of MHC I and 1000s of different MHC II alleles.

Crunching the Numbers – How many Self and/or Non-Self Peptides are Displayed by MHC I and MHC II?

Assessing the binding regions of MHC II, it is estimated that MHC II molecules for each individual can present more than a trillion different peptides.  This helps to protect individuals from many types of pathogens.

However, each cell does have a limit as to how many MHC I and MHC II molecules are present on their cell surface at any one point in time.  For B and T cells, it is estimated that there are 200,000 MHC I and 20,000 MHC II molecules on their cell surface.  In calculating how many different peptides can be displayed at once on each cell, and keeping in mind that it is known that some peptides are present in high numbers, and others are not, it is estimated that there are <10,000 different peptides displayed on each cell with a half-life of peptide-loaded MHC molecules being hours to days.

Notably, if activated, the half-lives of APCs, B cells and T cells are lengthened, and the half-lives of their cell surface peptide-bound MHC molecules are also prolonged.

Role of MHC II: Presentation of Non-Self Antigens by APCs and B cells

MHC II polypeptides are synthesized and folded in the rough endoplasmic reticulum (RER) and they are transmembrane glycoproteins that specialize in presenting antigens on the cell surface.

However, while MHC I molecules present intracellular peptides on the cell surface, the main role of MHC II is to present extracellular peptides.  APCs and B cells are responsible for phagocytosing pathogens and when they do so the pathogens are ingested in a vesicle termed a phagosome.  The phagosome fuses with a lysosome and the lysosomes’ lytic enzymes digest and degrades the pathogen.  The MHC II molecules once folded in the RER are sent to the Golgi apparatus where they are transported by vesicles to the maturing phagolysosome.  Embedded in the membrane of the late (mature) phagolysosome, the MHC II molecules meet and bind with the degraded pathogen peptides.  The peptide-loaded MHC II are then delivered to the cell surface for display.   APCs that display non-self peptides on their MHC IIs travel to lymphoid tissue and present these non-self peptides to Helper CD4+ T cells in order to stimulate an adaptive immune response.  APCs will release cytokines such as monokines in order to fully activate specific Helper CD4+ T cells, that have TRCs that can successfully bind to the peptide-loaded MHC II on the surface of the macrophage.  Once triggered, Helper CD4+ T cells play a crucial role in activating B cells and stimulating B cell antibody production.  Activated Helper CD4+ T cells also enhance the CD8+ T cell mediated immune response.

*It should be noted that APCs, such as monocytes and macrophages, can release cytokines, sometimes termed monokines as they are produced by monocytes and macrophages.   There are a range of monokines that macrophages will release which include interleukins (to activate WBCs), tumor necrosis factor-alpha TNF-α (to stimulates WBC production and activity as well as induce fever, inflammation, and apoptosis of cancerous cells), alpha and beta interferons (in general, α-IFN stimulates anti-viral defenses and β-IFN supresses the immune response), and colony stimulating factors, CSFs (which induce WBC production in the bone marrow).

Summary:

Comparison of MHC Class I and MHC Class II in Terms of Location, Structure, and Function

MHC Class I

• Location
  • Expressed by all nucleated cells and platelets.
• Structure
  • Composed of 4 polypeptides including polymorphic region.
• Function
  • Presents intracellular peptides (e.g., viral peptides) to CD8+ T cells.
  • Helps the immune system recognize and destroy infected or cancerous cells.
• Peptide Presentation
  • Displays a variety of peptides with an estimated <10,000 different peptides per cell.
  • Each cell has about 200,000 MHC I molecules on its surface.

MHC Class II

• Location
  • Synthesized only by Antigen-Presenting Cells (APCs), such as macrophages, dendritic cells, B lymphocytes, and some thymic cells.
• Structure
  • Genes located in the MHC Class II (HLA II) region on chromosome 6.
  • Highly polymorphic with thousands of different alleles
  • Comprised of four polypeptides, form transmembrane glycoprotein
  • Synthesized and folded in the rough endoplasmic reticulum (RER)
• Function
  • Present extracellular peptides (e.g., bacterial peptides) to CD4+ Helper T cells.
  • Activates CD4+ T cells, which in turn help activate other immune cells, including B cells and CD8+ T cells.
• Peptide Presentation
  • Can present more than a trillion different peptides.
  • Each cell has about 20,000 MHC II molecules on its surface.

Role in Adaptive Immune Response

• MHC Class I
  • Intracellular pathogen (e.g., virus) infects host cell.
  • Proteins are processed and presented on the cell surface by MHC I.
  • Recognized by CD8+ T cells, leading to destruction of infected cells.
• MHC Class II
  • APCs phagocytose extracellular pathogens (e.g., bacteria).
  • Phagosomes fuse with lysosomes, digesting the pathogen
  • Pathogens are processed in phagolysosomes
  • MHC II molecules from RER to Golgi, then to maturing phagolysosome
  • MHC II binds with degraded pathogen peptides in the phagolysosome
  • Peptide-loaded MHC II delivered to cell surface of APCs for display
  • Recognition of non-self peptide on MHC IIs by the binding of CD4 receptor and TCR of CD4+ T cells, provides 1st and 2nd confirmation to becoming activated
  • Release of cytokines by APCs provides 3rd and final confirmation for CD4+ T cells to becoming fully activated
  • Activation of CD4+ T cells leads to activation of adaptive immune response.
  • CD4+ T cells help activate B cells (antibody production) and CD8+ T cells.

T Cell Activation

• CD8+ T cells (activated by MHC Class I on host cells)
  • CD8+ T cells bind to MHC I-peptide complex on aberrant cells, via TCR and CD8 co-receptor.
  • Proliferate and differentiate into cytotoxic T cells and memory T cells.
  • Destroy infected or cancerous cells by releasing cytotoxic molecules.
• CD4+ T cells (activated by MHC Class II on APCs)
  • CD4+ T cells bind to MHC II-peptide complex on APCs via TCR and CD4 co-receptor.
  • Proliferate and differentiate into helper T cells and memory T cells.
  • Helper T cells activate B cells and CD8+ T cells, and release cytokines to enhance immune response.

Genetic Diversity

• MHC Class I and II
  • Polygenic: Many genes encoding MHC molecules.
  • Polymorphic: Numerous alleles exist, leading to a high degree of individual variability.
  • Each individual inherits a unique set of MHC I and II genes, contributing to immune system diversity and effectiveness.

Clinical Relevance

• MHC Class I
  • Essential for immune surveillance and response to intracellular infections.
• MHC Class II
  • Critical for coordinating the immune response to extracellular pathogens.
  • Key in vaccine responses and immune memory formation.

Overview

• MHC Class I: Present in all nucleated cells, presents intracellular antigens to CD8+ T cells.

• MHC Class II: Present in APCs, presents extracellular antigens to CD4+ T cells, crucial for activating the broader immune response.
• Memory Trick:
  • MHC Class I activates CD8 T cells (1 x 8 = 8)
  • MHC Class II activates CD4 T cells (2 x 4 = 8)