T cell Receptors?
Have a similar structure to immunoglobulins: transmembrane region, constant region, variable (binding) region. They have two parts: alpha and beta. They are signal transducing molecules and are co-expressed with CD3. CD3 mediates teh signalling function. TcR's sense for MHC molecules on APCs and linear epitopes.
What are the functions of T cells?
T cells function by making contact with macrophages, infected cells and B cells.
What is the MHC?
A cluster of closely linked genes on Chromosome 6 that encodes proteins which: control T cell mediated response, determine the fate of transplanted tissues. The key molecules encoded by MHC are the Human Leukocyte Antigen (HLA) molecules.
What kinds of HLA molecules exist as MHC's?
MHC Class I: HLA-A, HLA-B, and HLA-C, which are highly polymorphic.
MHC Class II: HLA-DP, HLA-DQ, and HLA-DR, which are polymorphic (less so).
The HLA molecules differ in the cell types they are expressed on, peptides displayed, peptide generation pathways, and the T cells that they talk to.
This is why it is so difficult to match tissue/organ donors.
What are the molecular characteristics of MHC I?
α1, α2, α3, and β2-micro globulin. Binds T cells via CD8.
What hematopoietic cells present MHC I?
T cells, B cells, Macrophages, Dendritic cells, Neutrophils.
What are the molecular characteristics of MHC II?
α1, α2, and β1, β2. Binds T cells via CD4
What hematopoietic cells present MHC II?
B cells and Dendritic cells present strongly, but they are also on T cells and macrophages.
What is the function of MHC molecules?
MHC class I and II molecules bind peptides and present them to T cells.
How do peptides bind to MHC molecules?
There is a small peptide binding grove at the top of the molecule. Peptides bind to the MHC molecules via anchor residues. TcR's see both the MHC and the bound peptide.
What are the steps in T cell development and Where do they take place?
In the bone marrow, CD34 uncommitted T cells turn into CD2 committed double negative T cell progenitor cells (lacking both the CD4 and CD8 signal molecule. Next, in the cortex of the thymus αβ and γδ T cells arise from rearrangements of a common double-negative T cell progenitor. TcR rearrangement occurs in the thymus. Double positive (CD4, CD8) T cells go thru MHC recognition testing with dendritic cells. Mature self-tolerant, self-restricted, single positive (CD4 or CD8) naive T cells migrate to the thymic medulla and then to the periphery. Once mature, they travel to secondary lymphoid tissues (spleen, lymph node, GALT in the GI)
How do T cells decide to be CD4 or CD8?
Positive selection determines the expression of either the CD4 or CD8 molecule. If selection occurs on a MHC class I molecule, then the cell is committed to the CD8+ subset (cytotoxic T lymphocyte or CTL). If the selection occurs on a MHC class II molecule, then the cell is committed to the CD4+ subset (T helper lymphocyte, Th1 or Th2).
Conversely, negative selection deletes T cells that react against self peptides (on self MHC molecules).
What is an alloantigen?
What are the functions of gamma-delta T cells?
What do regulatory T cells do? T-Reg's
What are the two types of TcR's?
alpha/beta and gamma delta. 95% of all TcR are alpha/beta.
Genetic characteristics that increase the diversity of MHC molecules:?
MHC molecules are highly polymorphic; MHC are co-dominant and inherited as haplotypes (from different alleles); polymorphism determines the peptides that they bind;
How is the MHC specific for the TcR?
The TcR is restricted to seeing one particular peptide with the particular MHC molecule that the peptide is bound to for recognition.
List the functional subsets of T cells?
CD8 T cell: Cytotoxic T Lymphocytes; CD4 T Cell: Th1, Th2, T-Reg
What do CD8 T cells do?
CTLs kill their targets by inducing apoptosis. After recognizing and binding virus infected cell, CTL secretes PERFORINS and GRANZYMES into target cell inducing cell death pathways. Target cell dies by apoptosis without harming neighboring cells. Apoptosis can also be triggered by interaction of CTL FasL with target cell's Fas.
What do Th1 cells do?
Th1 cells help out with cellular immunity (CD8+, macrophages). Th1 CD4 cells activate macrophages to be highly microbiocidal via CD40 ligand interacting with the CD40 on the macrophage. Th1 CD4 induce granuloma formation when intracellular pathogens cannot be totally eliminated (ex: Tuberculosis has become macrophage resistant)
What do Th2 cells do?
Th2 cells support humoral immunity (B cells). Th2 cells talk to B cells via IL-4 and IL-5 and interaction of CD40L/CD40 which activates the B cell into proliferation and differentiation to antibody-secreting plasma cells.
How are memory cells differentiated?
Both T and B cell effector and memory cells are produced in the primary immune response. Memory B cells are more abundant and make better antibodies than naïve B cells. The amount and affinity of antibodies increases with repeated exposure.
What are the key types of antigen presenting cells?
Dendritic cells, Macrophages, B cells
Most are found in the skin or mucosal tissues as Langerhans cells; located in the lymph node everywhere except the follicles. Dendritic cells are the best APCs. They present peptides, viral antigens and allergens.
How are T cells activated by antigens?
Antigens and APCs activate T cells in the T cell regions of lymphoid tissues. T cells enter a lymph node across a endothelial venules in the cortex. T cells monitor antigen presented by macrophages and dendritic cells. T cells that do not encounter specific antigen leave the node in the efferent lymph. T cells that encounter specific antigen proliferate and differentiate to effector cells.
How do T cells know where to go?
T cells home to lymph nodes via adhesion molecules. Selectins and ICAMs are crucial adhesion molecules. Selectins allow lymphocytes to home to lymph nodes or to sites of infection. ICAMs allow T cells to talk to APCs.
What is required for clonal expansion of T cells?
Co-stimulation delivers required second signal for T cell activation. Binding of TcR and CD4 to MHC Class II delivers signal to T cell. Clonal expansion of T cell can occur only after second signal is delivered by CD80/86:CD28 interaction. This process is downregulated on T cells by CTLA4. IF either the CD80/86 or the MHCII is missing, the T cell becomes anergic (permanently turned off. Following this, IL-2 stimulates proliferation of effector T cells.
How does calcineurin up-regulate IL-2 and increase the activity of T-helper cells?
When an antigen-presenting cell interacts with a T cell receptor on T cells, there is an increase in the cytoplasmic level of calcium, which activates calcineurin, by binding a regulatory subunit and activating calmodulin binding. Calcineurin induces different transcription factors (NFATs, Nuclear Factor of Activated T cell) that are important in the transcription of IL-2 genes. IL-2 activates T-helper lymphocytes and induces the production of other cytokines. In this way, it governs the action of cytotoxic lymphocytes and NK cells. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly.
What is the significance of up-regulating CTLA-4 following immune response?
CLTA4 is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells. It binds to CD80/86 on antigen presenting cells competing with CD28, which transmits a stimulatory signal to T cells. It is also found in Regulatory T cells. T cell activation through the TcR and CD28 increases expression of CTLA-4.