T Cell Maturation Flashcards
When does the maturation of B cells from progenitors occur?
Before birth in the foetal liver.
After birth in the bone marrow
Final steps completed in the spleen.
Where do the precursors of T lymphocytes emerge from?
Foetal liver before birth primarily precursors of gammadelta TCell Receptor (TCR)
Bone marrow primarily alphabeta TCR later in life.
They then circulare to the thymus to complete their maturation.
What signals induce expression of genes required for alphabeta TCR’s?
Notch1 anf GATA3
What are the major events of lymphocyte maturation?
Growth factor mediated commitment, proliferation.
Initiation of antigen receptor gene rearrangement
Selection of cells that express pre-antigen receptors
Selection of repertoire
Maturation of functionally distinct T and B cell subsets
Where do the major events of lymphocyte maturation occur?
Bone marrow
What does cortex region of the thymus do?
Proliferation of the thymus
What can you use cell lineage marker proteins for?
Immunophenotyping cells
Diagnostically
Cancer therapies can be antibodies against these
How does the thymus T cells mature?
It starts with double negative thymocytes (CD3-4-8-) and some will become CD4- and CD8- whilst others become CD4+ and CD8+.
What happens to CD8- and CD4- T cells?
They export to the periphery and stay there
What happens to CD4+ and CD8+ T cells?
Exported to the periphery and can identify an respond to danger or damage.
What MHC does CD8+ cells have?
MHC1
What MHC does CD4+ cells have?
MHC2
What drives maturation of T cells?
Transcription factors, epigenetic modifications and cytokines. To become CD4+ cells epigenetic changes must occur to silence the CD8+ gene and vice versa.
What do mutations in the human gene encoding the common gamma chain receptor shared by receptors do?
Gives rise to x-linked severe immunodeficiency (X-SCID) characterised block in T cell, NK cell and normal B cell development.
What does somatic recombination of the T cells lead to in the thymus?
Variable regions
What are T-cell receptors structurally similar to?
Ig encoded by homologous genes
What is the difference between Ig and T-cell receptors?
They have similar varaible regions but different J regions in the VDJ recombination Rag complex.
They also have more distinct junctions.
What do T-cells not undergo?
somatic hypermutation
How many TCR recombinations can arise?
1000000000000000000
The TCR complex is found where?
On the surface of the cell
What does surface expression of the TCR require assembly off?
TCR alpha: beta with signalling subunits of CD3
What is constant in TCR complexes despite the specificity?
CD3 proteins and zeta
What is the TCR complex required for and not involved in?
Signalling and not involved in antigen recognition
How does CD3 bind to TCR?
Through charge interactions in the transmembrane domains to form the TCR complex.
What happens if there is no TCR complex?
The cell undergoes apoptosis
What is DiGeorge Syndrome (SCID)?
This is an autosomal dominant disease caused by large deletion leading to a small or no thymus resulting in no mature T-cells and few B cells. This makes patients susceptible to mycobacterial, viral and fungal infections. T-cells improve with age.
What do matured but naive T cells subsets interact with\/
Innate immune cell in secondary lymphoid organs
What do naive T cells have?
Many copies of one type of TCR in a complex with CD3 and will leave the thymus and circulate looking for antigens and will mature further into effector T cells.
What are the mature T cell subsets?
CD4+ and is naive also express CD45RA+
CD8+ T lymphocytes
How does the lymphatic system work?
The lymphatics - fluid drains through lymph nodes and into thoracic duct which empties into subclavian vein
What are the primary lymphoid organs?
Bone marrow and thymus
What are the secondary lymphoid organs?
Adenoids tonsil, lymph node, appendix, spleen, peters patch in the small intestine
Is the lymphatic system one way?
Yes
How do cells get into the blood stream?
Through the thoracic duct into the vena cava and into the blood stream
How fast do lymphocytes make a full circuit of the body?
Once of twice a day
What does disruption of the lymphatic system by tumours or parasitic infections cause?
Severe tissue swelling due to fluid accumulation
What does the lymphatic system not have?
Red cells, granulocytes
What does the lymphatic system have,
Lymphocytes, monocytes, dendritic cells
What is the structure of the lymph node?
Naive lymphocytes enter lymph node through artery. Chemokines then attract the correct lymphocyte to the correct area (whether it needs to go to the B or T cell section).
How do dendritic cells enter the lymph node?
The afferent vesicle
How do lymphocytes go from the blood into the lymphoid tissue?
This is a step by step process with lots of letters and numbers
Lymphocytes enters the endothelial venule in the lymph node
L selection binds to GlyCAM-1 and CD34 allows rolling interactions.
CCR7 (in response to CCL21 and CCL19) activates LFA-1which binds to ICAM-1 and the lymphocyte can enter lymph node via diapedesis
Where do naive lymphocytes migrate to?
Secondary lymphoid organs
Where do effector lymphocytes and myeloid cells home into?
Tissues where there is infection or tissue injury
Where do memory lymphocytes migrate to?
Lymphoid organs, mucosal tissues, skin and other tissues
What is the spleen?
The spleen is the largest secondary lymphoid, capsulated organ.
How is the spleen unique?
It has unique entry into the white pulp via marginal sinus, not HEVs
What is the white pulp?
It is where you find T and B cells
What is PALS?
Peri-arterial lymphoid sheath made of mostly T cells
Can the spleen be enlarged during some infections?
Yes as the lymphocytes proliferate
What does the spleen do?
Captures antigens that enter the bloodstream.
How are circulating T and B cels initially delivered to spleen?
Through the marginal sinus with is designed for capture of blood burn antigens or intact microbes
What is found in the marginal sinus?
Specialised populations of macrophages, dendritic cells and the marginal zone B cells, which didn’t recirculate
How are pathogens trapped in the marginal sinus?
Dendritic cells and macrophages which deliver antigen to the white pulp.
Marginal zone B cells which are adapted to provide rapid responses to pathogens that enter the marginal zone
What happens if the spleen is damaged? - people born without a spleen?
Liver can take over removing ages and damaged blood cells and particles.
Secondary lymphoid organs can still protect against many pathogens
What are you susceptible to if you don’t have a spleen?
Blood borne pathogens
Why are people more lively to get blood borne pathogens without a spleen?
The spleen has T-independent B cells to make antibodies against polysaccharide capsules and lots of macrophages to phagocytose optimised bacteria in blood
What do people without a spleen require?
Lifelong prophylactic antibiotics and relevant vaccines
What is MALT?
Mucosal associated lymphoid tissues
What happens if a dendritic cell shows an antigen on its MHC to a T cell?
Activation of naive T cells in lymph node, development of effector cells which go to site of infection and eradicate the microbe
Where are MHC class 1 expressed?
All nucleated cells
Where are MHC class 2 cells found?
Dendritic cells, macrophages and B cells
What do MHC 1 cells trigger?
CD8 CTLs which can kill any type of virus infected cell
What do MHC 2 trigger?
CD4+ helper T lymphocytes interact with dendritic cells, macrophages, B lymphocytes
How big is MHC 1?
Small - can recognise antigens 8 - 11 residues long
How big is the MHC2 biding peptide?
It’s open so can bind large antigens (10 - 30+)
How are intracellular antigens processed on MHC1
The cytosine protein is digested in the proteasomes and the peptides released into the cytosol. These are taken to the Endoplasmic reticulum via TAP proteins to bind with MHC1. They are then showed to CD8 T cells
How are extracellular antigens processed for MHC 2?
Endogenous of extracellular protein where it is digested by proteins in lysosome/endosome. An invariant chain sits inside MHC2 and when these merge together (the lysosome with the peptide and the MHC2) they remove the invariant chain and the peptide can sit in the MHC2. This is taken to CD4 cells.
What does TCR only recognise?
Antigens presented by MHC1 and is interacts with its peptide
What causes tissue matching problems in transplantation?
The TCR
