T-cells, Effector Functions and the MHC

• T-cell receptors recognise foreign molecules that are bound to another self-protein. These self-proteins are encoded for by genes called the major histocompatibility complex (MHC) genes. The proteins the MHC genes code for are known as MHC proteins.
• MHC proteins are specifically responsible for presenting foreign antigens, and they are found on a certain type of cell called an Antigen Presenting Cell.
• Foreign antigens (which tend to be peptides) are displayed to T-cells by MHC molecules. MHC molecules are high polymorphic, which means that these molecules can occur in several different forms.
• There are 2 types of MHC molecules: MHC Class 1, and MHC Class 2.
• MHC 1 molecules are single-chained molecules that associate non-covalently with beta-2 microglobulin. MHC 1 molecules are endogenously expressed on all nucleated cells (meaning that MCH 1 molecules are expressed on the surface of all cells).
• MHC 2 molecules are heterodimers, made of an alpha and a beta chain. They are only expressed on the surface of specialised antigen presenting cells/cells of the immune system (monocytes, macrophages, dendritic cells, B-cells).
• Both classes of MHC molecules present peptides derived from foreign antigens. However, the source of these peptides are different between the two classes.

  MHC class 1 molecules tend to display peptides derived from proteins currently synthesised within the cell (these can be self or non-self peptides). MHC class 2 molecules (expressed solely on antigen presenting cells) will present peptides derived from antigens that have been pulled in from the external environment.
• The main function of MHC class 1 molecules is to allow the immune system to see and eliminate virally infected cells.

  A cell will break down a sample of all the proteins that it synthesises using a molecule called the proteasome. These peptides are then transported to the ER where they will be loaded into newly synthesised MHC 1 molecules. These molecules will then be transported to the cell surface to display the peptides to the immune system. A virally infected cell will synthesis, and subsequently present, viral proteins, which will be identified by the immune system, and eliminated.
• MHC Class 2 molecules primarily present peptides derived from exogenous antigens, which can either be taken up into the cell by receptor-mediated uptake, or endocytosis.

  Example: an APC takes up a bacterial antigen by endocytosis. Proteolytic enzymes contained within proteolytic vesicles will degrade the antigen into peptides. In the ER, MHC 2 molecules are being synthesised, and they will then migrate to the endosomes. There, they'll fuse with the bacterial residues, and then be transported to the cell surface in vesicles to be displayed to the immune system.
• In humans, the genes encoding for MHC 1 and MHC 2 molecules are found on the short arm of chromosome 6, which is the most polymorphic region in the human genome. This region specifically is known as the human leukocyte antigen (HLA) locus.
• The human leukocyte antigen (HLA) locus is polygenic, meaning that there are many MHC 1 and MHC 2 genes encoding for separate molecules.

  Three different genes code for MHC 1 molecules, leading to 3 different, but related, HLA proteins. These are known as HLA-A, HLA-B, and HLA-C.

  Similarly, three different geneces code for MHC 2 molecules, leading to 3 different, but related, HLA proteins. These are known as HLA-DP, HLA-DQ, and HLA-DR.
• The HLA locus is highly polymorphic and polygenic. This means that many different alleles of each gene exist within the human population. These genes are also co-dominantly expressed.

  The high number of HLA variants combined with the co-dominant inheritance means that there is a huge diversity of HLA proteins expressed on the cell surface within the human population.
• The polymorphism of the HLA locus is important when combating pathogens that constantly mutate and evolve. The polymorphism also isn't found in the structural regions of the protein, but instead in the amino acids that form the peptide-binding groove of the MHC 1 and MHC 2 molecules. The amino acids present in this peptide-binding groove determine which peptides from any foreign antigen will bind and be presented to the immune system.
• T-cells recognise peptides with their T cell receptors, and are defined by expression of the T cell receptor.
• The T cell receptor is a membrane-bound heterodimer consisting of two chains bound together by disulphide bridges; the two chains are coded for by different genes. There are two types of T cell receptor: alpha-beta receptors and gamma-delta receptors.

  Each chain consists of a variable region and a constant region, and each region of the TCR is encoded for by separate gene pools. TCR genes undergo gene rearrangements before translation occurs.
• The alpha and beta chains of the TCR are composed of segments.

  The alpha chain as a variable segment (of which there are 50 possible forms of the segment), a junctional segment (of which there are 50 possible forms), and a constant segment (of which there is only 1 form).

  The beta chain has a variable segment (50 possible forms), a diversity segment (2 possible forms), a junctional segment (13 possible forms), and a constant segment (2 possible forms).
• The combinations of different forms of each segment within the TCR alpha and beta chains, plus the diversity in the mechanisms of imprecise joining of the segments means there is a high variability in TCR shapes.
• Once the TCR has fully formed, it remains in that form. Affinity maturation, which occurs with antibodies, doesn't occur with TCRs.
• The greatest site of variability in a TCR is at the site where the TCR binds to the peptide-MHC complex. It's this tripartite interaction between the TCR and peptide-MHC complex that defines the two types of alpha-beta T cells: CD8 (cytotoxic) T cells, and CD4 (helper) T cells.
• CD8 T cells preferentially interact with peptides presented by MHC 1 molecules. These T-cells co-express a receptor called CD8 which interacts with a conserved part of the MHC 1 molecule.

  CD4 T cells preferentially interact with peptides presented by MHC 2 molecules. These T-cells co-express a receptor called CD4 which interacts with a conserved part of the MHC 2 molecule.
• CD4 and CD8 T cells need to be activate before they can induce an immune response. The activation of these T cells requires 2 signals, known as Signal 1 and Signal 2/the co-stimulatory signal.

  When a T cell receives both these signals, it can begin to divide, and start to produce cytokines. (Cytokines are the molecules through which T-cell function is determined).
• The first signal of T cell activation (Signal 1) is the binding of the correct specific T cell to the peptide-MHC complex. (The binding has to be strong enough to be long enough to cause sustained signalling in that T cell, which can only happen when the correct T cell binds to the complex).

  The second signal (Signal 2) is a molecule of CD80 or CD86 located on the surface of the antigen present cell binding to a molecule of CD28 on the surface of the T cell. The production of co-stimulatory molecules CD80 and CD86 on an APC is only upregulated in the presence of inflammation or infection.
• CD8 T cells kill virally infected cells and cancerous cells so they are unable to divide further.
• A naive T cell (a T cell that hasn't encountered a peptide-MHC complex yet), when activated, can develop a range of different activates that can serve different, distinct functions in the immune response, helping other cell types to perform their immune function. As a result CD4 T cells are also referred to as helper T cells.
• The function of different subsets of helper T cells is closely associated with the cytokines they secrete. Some of the different helper T cell subsets include Th1, Th2, and Th17. These cells are categorised based on the cytokines they secrete, and the function they serve in the immune response.

  Naive T cells can also differentiate into regulatory T cells. Regulatory T cells prevent immuno-pathologies by modulating the activity of other immune cells.
• Th1 cells are characterised by secretion of interferon gamma and IL-2. They are mainly involved in responses against viruses and other intracellular pathogens, such as listeria, tuberculosis, and leprosy.
• One of the main effector functions of Th1 cells is to help CD8 T cells via secretion IL-2 and interferon gamma. These cytokines help to allow CD8 cells to proliferate, differentiate, and start to express their cytolytic cytokines (porphyrin and granzymes).

  A second important function of Th1 cells is to aid macrophage function by secretion of IL-2 and interferon gamma. These cytokines promote the differentiation and activation of macrophages, and helps to direct them to sites of infection.
• Th2 cells are largely involved in responses to extracellular parasites. These cells:

  • Aid the antibody response via production of IL-4 and IL-3 cytokines.
  • Help B-cells by promoting their division, class switching, and affinity maturation of the antibodies.
  • Allow for the differentiation of B cells into plasma cells.
  • Promote parasite clearance through the activation of cells like eosinophiles, which is done via the secretion of IL-4 and IL-5.
• Th17 cells are involved in responses to extracellular bacteria. These cells secrete cytokines interleukin 17, interleukin 21, and interleukin which provide help at epithelial and fibroblast cell surfaces, promoting secretion of antimicrobial peptides and aiding in wound-healing.

  Th17 cells also provide help for neutrophiles by promoting their maturation and directing them to the site of infected by chemotaxis.
• Regulatory T cells are responsible for modulating the immune responses to prevent immunopathology, and they regulate both the innate and adaptive immune response. These cells do this by downregulating other immune responses by either cell-to-cell contact, or by secretion of cytokines TGF-beta and interleukin 10.

  Regulatory T cells:

  • supress stimulating activity of APCs
  • Stop proliferation and cytokine production of responder T cells,
  • Supress antibody production in B-cells.
  • Supress the function of other immune cells like NK and NKT cells.