Module 4 Flashcards
(37 cards)
What are the events in a lymphocyte?
- T-cell progenitors develop in the boine marrow and migrate to thymus. T-cell precursor rearranges its T-cell receptor genes in thymus.
- Immature T-cells that recognise self MHC molecules receive signals for survival. Those that interact strongly with self-antigen are removed from repertoire.
- Mature T cells migrate to peripheral lymphoid organs. Mature T cells encounter foreign antigens in peripheral lymphoid organs and are activated.
- Activated T cells proliferate and migrate into peripheral sites to eliminate infection
Main points of early lymphocyte development?
- Common lymphoid precursor found in bone marrow and gives rise to T cells and B cells.
- Early thymic progenitor may be the true T cell precursor
- Notch1 expression appears to determine whether a progenitor becomes a T cell or B cell
-> When the cell gets into the thymus, there is a coactivator that inhibits repressor and transcription starts
Is double-negative or double-positive state of t-cell development first?
Double-negative state in cortical area. CD44+ and CD25- into CD44+ and CD25+ into pre-TCR
They then enter double-positive state after proliferation and the second checkpoint occurs here. T-cell receptor formed and will decide whether they become CD4 or CD8.
What are the minority and majority double-positive thymocytes called?
Minority - gamma:delta CD3+ cells
Majority - CD3+ pTa:B4+8+
What are the two fates of when a T-cell receptor is expressed as a single-cell positive when seeing a self-antigen?
If they can recognise, die by apoptosis
If not, they go into periphery and become a mature T-cell
What does it mean when you see IL-2 expression?
The cells are proliferating
What is going on with the pre-TCR in the cortex and medulla of the thymus?
In the cortex they are immature CD3-4-8- double-negative thymocytes. They find cortical epithelial cells (from thymus). Then these cells are tested whether capable of binding self-MHC molecule. They travel to the medulla after and the APC’s (dendritic cells) express all the antigens in the body. If they dont recognise, they go through venule into periphery -> mature T-cell.
Structural features of a TCR.
- an a1 and a2
- a B1 and B2
- a1 and b1 are the constant region and therefore distal to the membrane.
- constant region
- hinge and disulfide bond.
- cytoplasmic tail
What chain is produced first of TCR gene rearrangement?
Starts in the thymus with B-chain germline DNA rearrangement. DJ recombination first selecting randomly chosen segments. Nucleotides in the junctional region are added to increase variability. RNA is produced and protein is expressed after translation and splicing. The protein is expressed on the surface of the membrane as beta-chain.
What is the difference between combinatorial diversity 1 and 2?
Combinational diversity 1 - (Heavy/light or alpha/beta chain pairing)
different segments get together from each domain. T cells: pairing of alpha chains with beta chains
Combinational diversity 2 - (V(D)J recombination) alpha-chain with any beta-chain. Amplifies options we have. Heavy chain or β chain: V (variable), D (diversity), and J (joining) segments recombine
Light chain or α chain: only V and J segments recombine
What is junctional diversity?
The process is intentionally imprecise — this creates randomness at the junctions. Variable use of P and N nucleotides.
Molecular processes to a full form TCR?
- rearrangements in the D carrying segment
- productive rearrangements lead to next step of development
- Surrogate non-variable a-chain binds to beta-chain to produce preTa
- B-chain + preTa complexes with CD3 -> excessive proliferation
- multiple a-chain rearrangements rescue non-productive VaJa joins’
What type of cell is it called before full formation of TCR?
Thymocyte
When B-chain and pre-Ta are together, what is it called?
pre-TCR
What is the pre-TCR composed of and what will start from here?
A successfully rearranged β chain
A temporary pre-Tα chain (not rearranged — it’s invariant!)
It signals the cell to stop β chain rearrangement on the other allele — this is called allelic exclusion
It triggers the start of α chain rearrangement
What combination of segments are expressed in low amounts?
Surface pre-TCR - B-chain + pre-Ta + CD3
Is it delta or gamma that will be excised when a-chain begins rearrangement?
Delta
What are the differences in rearrangement and survival chances between the TCR β-chain and α-chain during T cell development?
The β-chain rearranges first and has two chances: one on each chromosome. If both attempts fail to make a functional protein, the cell undergoes apoptosis.
The α-chain rearranges later and can undergo multiple sequential rearrangements on the same allele to get an in-frame coding sequence. If none are successful, the cell also dies.
What occurs between the change from pre-TCR to TCR?
- Proliferation occurs here
- other molecules of the CD3 dimerize
- heterodimer (pre-Ta and B-chain) -> superdimer with another pre-TCR
- The superdimer helps cluster CD3 signaling molecules around it.
- This occurs because of the zeta-chains that provides a second signal
- this physical bridge will help them process of generating a large number of copies of the cells
- a-chain rearrangement then starts.
Does positive selection or negative selection come first?
Positive selection
Explain positive selection? (self-restriction)
Start with double-negative thymocytes existing as Cd3-4-8- that recognise self-MHC. TCR will positively select for MHC molecule with higher affinity. Positive selection coordinates expression of CD4 and CD8 prerequisite is capable of binding to a MHC molecule. CD4 cells - MHC2 and CD8 cells - MHC1. If a particular cell that has a TCR capable of binding to a MHC type I molecule, it will become a CD8+ cell. Thymic cortical cells mediate positive selection.
Explain negative selection? (self-tolerance)
Start with single positive thymocytes that undergo selection against self-recognition. Cells with affinity for self-Ag will undergo apoptosis. Negative selection is driven by bone marrow-derived APC’S. Tissue specific proteins are driven by the transcription factor, Autoimmune regulator (AIRE) in epithelial cells of the thymic medulla.
Steps in life-cycle of a B-lymphocyte?
- Start in bone marrow from pre-cursors. rearrangement of genes that code for immunoglobulin.
- When B-cell matures, undergoes negative selection first. Cells test whether or not B-receptor recognises self-antigens or not. If do, they are eliminated. If not go to periphery.
- A mature B-cell will express an IgD and IgM.
They either…
Migrate to peripheral lymphoid organs and encounter an antigen. When they do, they become a factory of antibodies - plasma cells. Plasma cell will produce only one type of antibody, which is the same antibody that helped as a B-cell receptor in development of the cell. They produce the antibody as a factory for the rest of their lives.
or
They become a memory cell when they have a B-cell receptor on their surface. Will wait for contact with new or same antigen, for them to produce antibodies in form of plasma cells.
Stages of B-cell development?
- Start as stem cell. heavy chain + light chain in germline state.
- DJ rearranging starts on heavy chain in early pro-B cell
- Late pro-B cell finalises rearrangement, successful VDJ heavy chain.
- pre-B receptor produced allows Ig to go to surface. Massive proliferation. Only half receptor is formed, u-chain will be bound to surface w pre-B cell receptor.
- Light chain commences rearrangement
- produces functional IgM. If process is complete also IgD is on the surface of the B cell formed.
