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.