98 Specific (Adaptive) Immunity – Role of Helper T Lymphocytes

CD4+ Helper T cell Activation by APCs that are Displaying Non-Self Antigens:

APCs present pathogen (non-self) antigens on their cell surface MHC II molecules.  These peptide-bound MHC II molecules are able to stimulate CD4+ Helper T lymphocytes.

In order to describe the process by which MHC II is able to trigger an effective C4+ T cell adaptive immune response, let’s consider the steps involved in an infection with most types of bacteria (as well as other pathogens).

1. Bacteria exposure: Host cells are exposed to bacteria frequently, particularly on the skin and in the respiratory and gastrointestinal tracts.
2. Bacteria Infection: Some types of bacteria are able to adhere to host cells and cause damage.
3. Phagocytosis: Bacteria are phagocytosed by APCs and once the phagosomes fuse with lysosomes, the bacteria are enzymatically degraded.
4. MHC II display of bacterial antigens: The MHC II molecules are sent from the RER to the Golgi, where they are packed in vesicles that fuse with the mature phagolysosome. Bacterial peptides bind to MHC II molecules and sent to the cell surface of APCs for display.  The APCs then travel to lymphoid tissues to find and activate CD4+ Helper T cells.
5. CD4+ T cell co-receptors: It should be noted that CD4+ T cells require two co-receptors (CD4 and TCR) to bind to the MHCII-antigen complex.
   1. a) The Cluster of Differentiation 4 (CD4) transmembrane glycoprotein co-receptor on CD4+ T cell helps T cells to bind to MHC II molecules on APCs.
   2. b) The other co-receptor, T cell receptor (TCR) is used to bind the antigen peptide displayed by the MHC II molecule. As discussed previously with MHC I TCRs:
      • It should be noted that TCRs are coded from a unique region of DNA that is able to undergo DNA rearrangements. This ability to create millions of uniquely sequenced TCRs is beneficial as the immune system must be able to potentially recognize millions of non-self antigens.
      • This genetic rearrangement of TCR occurs only once in each T cell and it occurs during the maturation process. Therefore, each T cell produces only one version of the TCR gene product.
      • As such, each T cell will produce 100s of identical TCRs and place them on their cell surface in close proximity to the CD4 co-receptors, in order for these co-receptors to perform their role of binding the peptide-loaded MHC II of other cells (APCs) and provide surveillance for non-self (e.g. bacterial) peptides.
      • Background:
      • The creation of each T cell occurs in the bone marrow. As mentioned above, every T cell is different from every other T cell, because each T cell displays a different version of TCR. Therefore, there are millions of different Helper CD4+ T cells (each with a different TCR).
      • The next step in CD4+ Helper T cell maturation occurs in the thymus.
      • Within the thymus, it is important for CD4+ T cells to go through positive selection and negative selection.
      • Positive selection ensures that T cells are able to bind to MHC self-antigen complexes with low affinity. T cells that can’t bind these MHC self-antigen complexes at all, are triggered to go through apoptosis.
      • Negative selection ensures that T cells do not bind MHC self-antigen complexes too strongly. If this occurs, the T cell is stimulated to go through apoptosis. If these T cells did not go through apoptosis, autoimmunity could develop.
   3. CD4+ T cell bind to MHC-II displaying non-self antigen: CD4+ (Helper) T lymphocytes with T cell receptors (TCRs) that successfully bind the displayed non-self antigen will be stimulated to launch an adaptive immune response specifically against the bacteria (or other pathogen), which involves the clonal expansion (proliferation) of the Helper CD4+ T cells with the TCR that binds those specific bacterial antigens.  Additionally, stimulated CD4+ T cells can activate CD8+ T cells and B cells, as well as release a range of cytokines, some of which are anti-viral, anti-bacterial, anti-protozoal, and/or anti-cancer.  The release of cytokines also recruits, attracts, and activates WBCs such as macrophages.  Enhancing CD8+ T cell activity boosts the cell-mediated immune response.  Plus, the stimulation of B cells allows for the production of antibodies and therefore launches the humoral adaptive immune response as a further mode of defense.
   4. CD4+ T cell mitosis (cell division): CD4+ T cell with bacteria-antigen-binding-TCR proliferates (goes through several rounds of mitosis, also known as cell division) to produce many daughter CD4+ T cells that have this same TCR, and that have 2 different roles:  Activated Helper CD4+ T cells and Memory Helper CD4+ T cells.

• Memory CD4+ T cells as the name suggests, hold a ‘memory’ of the pathogen, as it will continue to express the specific TCR that recognizes the specific antigens of the pathogen.  These memory cells will continue to proliferate and maintain a ‘memory pool’ that persists in the body, giving “memory” of the non-self antigen for many years.  This is helpful in that it serves to speed up the adaptive immune response upon subsequent exposure to the same non-self antigen.  
• Activated Helper CD4+ T cells embark on a ‘help activate’ mission – they activate sensitized B cells and further activate CD8+ Cytotoxic T cells by inducing further proliferation.

Summary:

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

• Phagocytosis by APCs and B cells
  • APCs and B cells phagocytose pathogens, forming phagosomes
  • Phagosomes fuse with lysosomes, digesting the pathogen
  • 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 for display
• Activation of Helper CD4+ T Cells
  • APCs display non-self peptides on MHC II, travel to lymphoid tissues
  • Present non-self peptides to Helper CD4+ T cells, stimulating adaptive immune response in CD4+ T cells that have a complimentary (matching) TCR that binds to the non-self peptide.  CD4 receptor binding to the MHC II serves as the 1st confirmation step.   TCR binding of non-self peptide serves as the 2nd confirmation step
  • APCs release cytokines (e.g., monokines) to fully activate Helper CD4+ T cells (and is the 3rd or final confirmation step of activation).
• Example of Helper CD4+ T Cells Activation Process
  • Bacteria Exposure and Infection
    • Frequent exposure on skin, respiratory, and gastrointestinal tracts
    • Some bacteria adhere to host cells and cause damage
  • Phagocytosis and Antigen Presentation
    • Bacteria phagocytosed, degraded in phagolysosome
    • Bacterial peptides bind to MHC II, displayed on APC surface
    • APCs travel to lymphoid tissues, activate CD4+ Helper T cells
  • CD4+ T Cell Co-Receptors
    • CD4 co-receptor helps T cells bind to MHC II molecules on APCs
    • TCR binds pathogen antigen peptide displayed by MHC II molecule
    • TCRs undergo genetic rearrangement during maturation
  • T Cell Maturation in Thymus
    • Positive selection: T cells bind to MHC self-antigen complexes with low affinity
    • Negative selection: T cells that bind too strongly undergo apoptosis
  • CD4+ T Cell Binding and Activation
    • CD4+ T cells bind MHC-II displaying non-self antigen
    • Trigger adaptive immune response, clonal expansion of CD4+ T cells
    • Activated CD4+ T cells activate CD8+ T cells, B cells, release cytokines