Chapter 7- Development and Activation of T Lymphocytes Flashcards
Where do T cells travel as they mature?
T cells originate in the bone marrow and then travel to the thymus, where VDJ recombination occurs. Mature T cells will leave the thymus and travel to secondary lymphoid tissues.
Self MHC
A person’s own set of MHC class 1 and class 2 molecules. A major function of the thymus is to ensure that a person’s mature T cells have T cell receptors that recognize the self MHC to prevent autoreactivity
2 lineages of T cells
- αβ T cells
- γδ T cells
Both develop in the thymus from a common T-cell precursor
CD4 and CD8
Cell surface glycoproteins found on T cells, which act as co-receptors. These glycoproteins begin to be expressed in the thymus. They differentiate the two lineages of αβ T cells- CD4 recognizes MHC class 2, and CD8 recognizes MHC class 1
Where is the thymus located?
In the upper anterior thorax, right above the heart
T cell developmental precursors
Common lymphoid precursor, then NK/T cell precursor, then the cell can differentiate into a T cell. It can also further differentiate into an effector T cell
Thymus organization
The thymus is a primary lymphoid organ that contains immature T cells (thymocytes) that are embedded in a network of epithelial cells (the thymic stroma). These 2 components form a closely packed cortex (outer) and more loosely packed medulla (inner). The thymus does not receive lymph from other tissues, the blood is the only route for progenitor cells to enter the thymus and for mature T cells to leave
DiGeorge syndrome
Prevalence is 1-2 in 4,000 people. It is a genetic disease where the thymus doesn’t develop and T cells are absent. Caused by a chromosome 22q11 deletion- T-box transcription factor TBX1. B cells are still made. These patients have almost no adaptive immunity and are frequently infected with a wide range of opportunistic infection.
Thymic involution
The maximal size of the thymus is reached at puberty, and then atrophy begins and steadily continues throughout life. The T cell producing tissue of the thymus is gradually replaced with fatty tissue. With atrophy, fewer naive T cells are produced, but this does not grossly impair T cell immunity. The repertoire of mature peripheral T cells seems to be long lived, self renewing, or both, in contrast to the short-lived B cell repertoire.
Immunosenescence
A gradual reduction of immune function with age
DiGeorge syndrome symptoms (6)
- Cardiac abnormalities
- Learning problems
- Specific facial features
- Thymic hypoplasia
- Cleft palate
- Opportunistic infections
Thymocyte commitment to the T cell lineage
T cell progenitors are not committed to becoming a T cell when they enter the thymus. At this point, they express markers like CD34 that identify them as stem cells. When they interact with the thymic stroma, the cells are signaled to divide, proliferate, and differentiate. After a week, the cells have lost all stem-cell markers and become committed thymocytes. They express CD2, CD5, and other T cell markers.
Double-negative thymocytes
Immature T cells at a very early stage of development in the thymus, which don’t have CD4 or CD8. T-cell receptor gene rearrangement up to the pre T-cell receptor stage occurs in double-negative thymocytes. DN thymocytes are the progenitor for both T cell lineages
Interleukin-7 (IL-7)
An important cytokine in T cell development. It is secreted by thymic stromal cells and binds to IL-7 receptors on CD34-bearing progenitor cells.
Notch1
An important regulator in T cell development- it is a thymocyte cell-surface receptor. It interacts with transmembrane protein ligands on thymic epithelial cells. Signals from Notch1 are necessary to drive cells along the path to T cell development in all stages. Notch1 keeps cells away from the pathway of B cell differentiation
Notch1 structure
The extracellular domain binds to its ligand on the thymic epithelium. This induces proteolytic cleavage which releases the Notch1 intracellular domain from the thymocyte plasma membrane. The intracellular domain then goes to the thymocyte nucleus. It becomes part of the transcription factor complex, which initiates the transcription of genes for T cell development
T-cell progenitors
Both αβ and γδ cell lineages come from a double negative thymocyte precursor. Rearrangement of the antigen receptor genes are then initiated to commit the cells to a certain lineage.
Which T cell lineage predominates?
αβ TCRs predominate, γδ T cells make up around 2% of total T cells
TCR gene rearrangement
Proliferation of T cell progenitors is followed by rearrangement of the β, γ, and δ chain genes. Cells that productively rearrange both a γ and δ chain gene, but not a β chain gene commit to the γδ lineage. Once the γδ TCR appears on the cell surface, the cells exit the thymus and travel in the blood to other tissues. In other cells, rearrangement of the β chain shuts down the recombination machinery. When this occurs, the β chain is made and is quality tested. If it passes, the cell proliferates and makes a clone of β chain positive cells. If these cells, the recombination machinery is reactivated at the α, γ, and δ chains occurs. When a productive α chain is made, an αβ receptor is assembled and the cell commits to the αβ lineage
Competition in TCR rearrangement
Rearrangement of the β, γ, and δ chain genes occurs at the same time. The γ and δ chain genes compete with the β locus to make productive gene rearrangements and functional T cell receptor chains. If a thymocyte makes a functional γδ receptor before a function β chain, it commits to the γδ lineage. A functional β chain predisposes the cell to the αβ lineage, but does not commit it. Gene rearrangement stops at this point, and the cell expresses CD4 and CD8 receptors
Double-positive thymocytes
A T cell at an intermediate stage of development in the thymus. It expresses both CD4 and CD8. The final steps of TCR receptor gene rearrangement to produce an αβ TCR gene occur in double positive thymocytes.
What happens to cells that don’t make a productive TCR gene rearrangement?
They die by apoptosis and are phagocytosed by macrophages in the thymic cortex. Apoptosis occurs with all except around 2% of thymocytes
β chain and δ chain rearrangements
β chain and δ chain loci contain V, D, and J gene segments. The first rearrangement joins D to J and the second joins V to VDJ
α and γ chain rearrangements
These loci only contain V and J segments. A single rearrangement joins V to J.
δγ cell development
If a thymocyte first makes productive δ and γ rearrangements, the δ and γ chains are made and form δγ heterodimers in the endoplasmic reticulum. Each heterodimer assembles with a CD3 signaling complex and moves to the cell surface. It also generates signals that stop β chain gene rearrangement. The cell is then committed to becoming a δγ cell. These cells do not undergo positive and negative selection. They leave the thymus through the blood and enter the circulation.
αβ cell development
A productive β chain gene rearrangement occurs more commonly. The β chain is made, translocated to the endoplasmic reticulum. There, it is tested for its capacity to bind to PTα. If heterodimers form a superdimer, PTα makes extensive contacts with the C and V regions of the β chain in order to test the β chain conformation and make sure it can interact with α chains and make a functional TCR. Then, a functional pre-T cell receptor is formed and checks the quality of the β chain
PTα
An invariant polypeptide that acts as a surrogate α chain. If the β chain binds to PTα, two of these heterodimers will form a superdimer.
Pre-T cell receptor
A receptor that is present on the surface of some immature thymocytes. It’s made of a TCRβ chain associated with PTα. To form it, each heterodimer superdimer assembles with the CD3 complex and ζ chain
Lck
An intracellular protein tyrosine kinase associated with the CD4 and CD8 co-receptors of T cells. It is involved in transmitting signals from these receptors
Pre-T cell receptor signaling
This receptor generates intracellular ligands rather than using an exogenous ligand. The signals are mediated by the CD3 complex and Lck. Assembly of the pre-T cell receptor signals the thymocyte to stop the rearrangement of the β, γ, and δ chains. Once a thymocyte has passed the pre-T cell receptor developmental checkpoint, it becomes a pre-T cell and moves on to the next stage of development.
Which factors bias thymocytes in favor of the αβ lineage? (2)
- Commitment to the αβ lineage occurs after the first productive β chain gene rearrangement, while commitment to the γδ lineage requires productive rearrangement of both chains
- The β chain locus has two different CB genes and their associated Db and Jb segments. Therefore, a nonproductive rearrangement of the β chain can be followed by a second, productive rearrangement at the same locus. Each person has 2 copies of the locus, so can make 4 rearrangements in total
Allelic exclusion in T cell development
Once the pre-T cell receptor is made, it signals the pre-T cell to stop gene rearrangements. This causes the degradation of the proteins of the RAG complex, and prevents the expression of RAG genes. This ensures that only one β chain gene has a productive rearrangement and is expressed, leading to allelic exclusion at the β chain locus. The pre-T cell is signaled to proliferate and makes clones of the cells with the same β chain
Rearrangement of the α-chain gene
This only occurs in pre-T cells- CD4 and CD8 are both expressed, and RAG1 and RAG2 are re-expressed after proliferation ends. Vα gene to Jα gene rearrangement
occurs on both alleles, similar to light chain rearrangement in B cells. Several α chains can be expressed until one is produced that can pass positive selection
RAG proteins
Essential for gene rearrangement, selectively expressed at the two stages in which β and α rearrangements are made.
ZAP70
A cytoplasmic tyrosine kinase in T cells that forms part of the signal transduction pathway from T cell receptors. Involved in signals from the pre-T cell receptor
Steps of the initial development of αβ T cells (7)
- Uncommitted progenitor cell enters the thymus through HEVs
- Proliferation
- DN T cells commit to the T lineage
- β genes are rearranged, the cell goes through the checkpoint for pre-TCR
- Proliferation of DN pre-T cells, immature double positive cells develop
- α genes are rearranged, the cell goes through the checkpoint for TCR
- Mature double positive cells
Positive selection
The process in the cortex of the thymus that selects for developing T cells with receptors that recognize peptide antigens presented by self-MHC molecules. Only cells that are positively selected are allowed to continue their maturation. Successful positive selection results in a single positive CD4 or CD8 cell
When does positive selection occur?
When the αβ receptor of a double positive thymocyte recognizes the complex of a self-peptide and a self-MHC molecule on a cortical epithelial cell. MHC class 1 and class 2 are both expressed by the epithelium, and thymocytes express CD4 and CD8, so the epithelial cells can select double positive thymocytes whose TCRs interact with a self-MHC class 1 or MHC class 2
What happens to a thymocyte with a TCR that doesn’t bind to self-MHC?
If the cell has run out α chain recombination options and there is no recognition of self-MHC, positive selection is unsuccessful. The cell is signaled to die by apoptosis. This occurs in 95% of thymocytes
How long does positive selection take?
A few hours up to 3-4 days if rearrangements are needed
MHC restriction
The property that a given TCR recognizes its peptide antigen only when the peptide is bound to a specific form of MHC molecule. This restriction is a consequence of positive selection in the thymus. The MHC class that mediates positive selection of a T cell is the one to which it becomes MHC restricted
Thymoproteasome
A version of the proteasome that is present in cortical epithelial cells of the thymus. It produces self peptides that are particularly effective at positive selection when bound to MHC class 1.
