T Cell Development- Generation Flashcards
What occurs during haematopoiesis, including key events and factors?
Lymphocytes come from hematopoietic stem cells which differentiate into multipotent progenitors and those within a stage of stem cell will transfer to a stage of commitment and produce committed precursors; either a lymphoid precursor, which will then differentiate down the line of lymphocytes, or a myeloid precursor which will then give rise to many cells of the myeloid lineage such as granulocytes, monoblasts etc.
Events in lymphocyte development
- Commitment- from multipotent to lymphoid lineage and later commitment to T cell lineage
- Proliferation- at the pre-T cell lineage and at the process of T cell differentiation
- Selection- Selected for the type of receptor that they produce
- Differentiation into distinct functional effector subpopulations
Key factors:
- Early on its stem cell factors such as C-KIT
- At the T cell lineage its cytokines such as Il-7 and 3
- From a common lymphoid progenitor to a T-cell progenitor signals such as Notch and the role of thymic stromal cells are really important
What are the two kinds of mature T cells?
Mature T cells are of two kinds, depending on the type of receptor that the T cell expresses:
- ab T cell receptor
- gd T cell receptor
There are also some cells that branch out from the lymphoid lineage early on and they include the ILC (innate lymphoid cells)
What are the stages of T cell maturation? (Stages, Major events and Anatomic site)
The stages are:
- Stem cell
- Pro-lymphocyte
- Pre-lymphocyte- which now has a receptor
- Immature lymphocyte
- Mature lymphocyte
The major events that happen are:
- Early on there is growth factor mediated commitment and proliferation and also the initiation of the antigen receptor gene rearrangement
- One a receptor has been rearranged successfully, it will be selected for it to work but also to avoid the detection of self-antigens
- At a later stage, immature lymphocytes that have been selected would require the acquisition of functional characteristics
Anatomic site:
- Stem cells and multipotent progenitors but very quickly they will migrate to the thymus
- At the end of development of the thymus they will exit and migrate to the peripheral lymphoid organs or tissue such as the spleen
Self-antigen are needed at the end of development for functionality
What is the thymus?
A gland above the heart
Precursors commit to the T-cell lineage in the thymus
It has a cortex and a lighter central area called the medulla
How do notch signals play a part in T cell development?
The original precursors move early on from the bone marrow to the thymus
Then thanks to notch signals they commit to the T cell lineage and differentiate into T-cell precursors
Notch signals induce activation of a transcription factor called GATA3 which is essential for the process of lineage commitment and development of early T-cell precursors
What are the successive changes in surface receptors of T cells?
1 week after arrival of precursors into the thymus, progenitors commit to the T cell lineage
They 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
What is TCR and what are its subtypes?
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
What forms the TCR signaling complex?
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
What is MHC?
MHC is the Major Histocompatibility Complex
HLA Human Leukocyte Antigen
MHC class I and MHC class II
MHC class I molecules present peptide antigens derived from pathogens that replicate inside the cell, such as viruses.
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 the structure of MHC (mostly class II) like?
2 chains, an alpha and a beta (with 2 domains in each)
It has an extracellular peptide binding cleft
Ig-like domain
Cytoplasmic tail
MHC class II has a conserved CD4 binding site
MHC class I has a conserved CD8 binding site
How are MHC molecules polymorphic and polygenic?
The MHC is highly polymorphic.
- There are multiple variants of each gene within the population.
The MHC is polygenic, it contains several different MHC class I and class II genes.
- Thus every individual possesses a set of MHC molecules with different ranges of peptide binding specificities
Thus polymorphism and polygeny lead to a high degree of polymorphism
How does MHC bind to a peptide?
Each MHC has one cleft that binds one peptide at the time but can bind different peptides
Peptides that bind one MHC share structural features that promote binding
Acquire peptides while the molecule is assembled inside the cell
Peptide-MHC interactions are storable with low off rate- so can last longer
Very small number of MHC-peptide complexes can activate a T cell- so powerful
MHC molecules can bind and display foreign and self peptide
MHC class II bids to longer peptides than class I
What cells express different MHC classes?
MHC class I- expressed by all cells but erythrocytes MHC class II- expressed by antigen presenting cells - CD4 helper T cells express TCRs that bind to MHC class II molecules - The peptides that MHC class II binds to come from the extracellular space through phagocytosis and processing within the phago-lysosome pathway - This is why only APCs have MHC class II because only those can phagocytose and present peptide
What is the pathway of antigen processing and presentation on top of the MHC class II?
A protein antigen is phagocytosed and goes through the endocytic pathway to be destroyed by enzymes and acidic environments within lysosomes And at the same time, the cell assembles MHC class II molecules in the endoplasmic reticulum and blocks the peptide binding group via the association with HLA and CLIP The MHC class II molecule is exported to the Golgi and through vesicles fuses with the lysosome And in this process the CLIP molecule is released and exchanged by a particular peptide that has affinity for the diverse binding groove When that happens the MHC molecule is exported into the plasma membrane for presentation onto a CD4+ T cell This process prevents endogenous peptides from binding to MHC class II
What are the properties of TCR?
Only one form of TCR is expressed on each T cell.
This means that each T cell and its daughter cells have only one TCR and one specificity for antigen
This is a T cell clone
However, there are an infinite number of different versions of the TCR each with a unique antigen binding site.
A TCR has only one antigen binding site.
A TCR is never secreted.
