T cell development - Generation of receptor repertoire diversity Flashcards
What are the main events in lymphocyte development?
- Commitment
- Proliferation
- Selection
- Differentiation into distinct functional effector (mature cell to perform a function) subpopulations
What key factors are needed for lymphocyte development?
Key factors: Stem cell factors (c-KIT)
Cytokines (IL-7, IL-3)
Tissue specific signals (Notch and thymic stromal cells)
What do multipotent HSCs give rise to?
What are the two types of T-cells (they are named after there receptor)?
Multipotent HSCs give rise to distinct B and T cell lineages
Alpha beta
gamma delta t-cells
Describe the stages of T-cell development
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Describe the journey of T-cells through development
T-cell progenitors develop in the bone marrow and migrate to the thymus
Positive and negative selection in the thymus
Mature T-cells migrate to the peripheral lymphoid organs
Activated T-cells migrate to the sites of infection
What are the successive stages in T cell development?
- 1 week after arrival of precursors into the thymus progenitors commit to the T cell lineage
- Express early markers of the T cell lineage (CD2 and Thy1)
- Do not express any of the markers that define T cells later in development or after in the periphery (CD3, CD4, CD8)
- Because of the absence of CD4 and CD8 early developing T cells are called DN (double negatives)
- At DN stage developing T cells (thymocytes) re-arrange the TCR locus
- Stages post DN are characterized by the expression of both CD4 and CD8 and later just one or the other
Describe the acquisition of either CD4 or CD8 receptors
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Describe the structure of a T-cell receptor
- Upon successful rearrangement and in the periphery (if selected) T cells express high levels of TCR
- TCR is a heterodimer consisting of two transmembrane polypeptide chains covalently linked to each other by disulphide bonds
- Two types alpha-beta and gamma-delta
- Each chain has one Ig-like N terminal variable domain (V) and one Ig-like constant domain (C), a hydrophobic transmembrane region and a short signaling cytoplasmic region
- The V regions of both chains contain short stretches of amino acid sequence that is highly variable between receptors. These regions form the CDRs or complementary determining regions. The 3 CDRs of the alpha chain and 3 of the beta chain form the peptide-MHC binding site
Compare and contrast TCR and Ig
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What does the binding of the charged residues of the transmembrane region allow?
- The C regions have cysteines residues that bring the chains together
- Charged residues in the transmembrane region bind to CD3 and the zeta chain to form the TCR signaling complex
- CD3 and zeta allow for the transduction of signals upon MHC-peptide binding
How do most T-cells recognise peptides and no other molecules?
Only peptides bind to MHC molecules
How do T-cells recognise linear peptides and not conformational determinants of protein antigens?
Linear peptides bind to the clefts of MHC molecules, and protein conformation is lost during the generation of these peptides
How do T-cells recognise cell associated and not soluble antigens?
Most T-cells recognise only peptide MHC complexes and MHC molecules are membrane proteins that display stably bind peptides on cell surfaces
What do cells do MCH class 1 and 2 express peptides to?
MHC 1 = Cytotoxic T-cell (CD8+)
• MHC class I molecules present peptide antigens derived from pathogens that replicate inside the cell, such as viruses.
MCH2- T-helper cell (CD4+)
• MHC class II molecules present peptides from pathogens and antigens that are present outside the cell taken up by endocytic vesicles of phagocytic cells.
What is MHC?
MHC is the Major Histocompatibility Complex
