L10: T Cell Maturation and Differentiation Flashcards
What does T cell repertoire self-MHC restriction means?
Cannot recognize foreign peptide unless it is presented by self-MHC class I or class II molecules
What does T cell repertoire self-tolerance mean?
T cells don’t recognize either self-MHC alone or self -MHC that has self peptide
Where does T cell maturation occur?
Thymus
What are the 2 sections of the thymus? What kinds of cells do they contain?
Outer cortex: cortical epithelial cells and other cells
Inner medulla: bone-marrow derived dendritic cells, medullary epithelial cells and macrophages
Where does the pluripotent stem cell enter the enter the thymus?
In the cortex
What is a pluripotent stem cell undergoing maturation called?
Thymocyte
What surrounds developing thymocytes?
Epithelial cells of the thymus form a network surrounding developing thymocytes
When stem cells enter the thymus, do they express any T cell lineage specific markers?
No
Doesn’t have TRC or CD8 or CD4
What occurs before positive and negative selection?
Once they go into cortex and proliferate, there is expression of coreceptors that occurs on cell surface and rearrangement of T cell receptor alpha, beta chain genes
Is positive or negative selection first?
Positive selection
What occurs in positive selection?
Thymocytes that recognized self-MHC class I or class II will be selected; those that don’t recognize them (or those than bind very weakly) will die by apoptosis
What occurs in negative selection?
Thymocytes that recognize self-MHC class I or II either by itself or w/ self-peptide will be eliminated
How do T cells that express gamma, delta TCR mature?
We have no idea
What process ensure that T cells are self-MHC restricted?
Positive selection
What process ensures that T cells are self-tolerant?
Negative selection
List the checkpoints in lymphocyte matureation
Apoptosed if there is failure to express pre-lymphocyte receptor
Apoptosed if failure to express antigne receptor
Apoptosed if fail to express receptors that recognize self-MHC
Apoptosed if they recognize self-MHC + self-peptide
What kind of receptor do majority of T cells express?
Alpha, beta chain receptor
What do alpha chains and beta chains consist of?
A variable and constant region and a transmembrane region
What are thymocytes that do not yet express any T cell lineage specific markers called?
Double-negative since they don’t express CD4 and CD8
Describe the stages of double-negative (DN) thymocyte development
DN1: CD44+, CD25-
CD44 is a cell adhesion molecule that could enable it to bind to the mesh of epithelial cells as they mature in the cortex
DN2: CD44+ , CD25+
After this, DN2 cells begin to rearrange the β-chain locus, becoming DN3
DN3: CD44-low, CD25+
DN3 cells are arrested until they productively rearrange the the β
-chain locus; the in-frame β
chain then pairs w/ a surrogate chain called pTα
to form the pre T-cell receptor (pre-TCR) and is expressed on the cell surface →triggers entry into the cell cycle →expression of small amounts of pTα:β in association w/ CD3 signals cessation of β-chain rearrangement and rapid proliferation, causing loss of CD25
DN4: CD44-, CD25-
Eventually, DN4 cell stop proliferating and CD4 and CD8 are expressed
Describe the stages of double-positive thymocyte development
Are CD4+ and CD8+
Small CD4+, CD8+ cells begin efficient rearrangement of α-chain locus → cells then express low levels of an α:β T-cell receptor and the associated CD3 complex and are ready for selection → most cells die by failing in positive selection or in negative selection → some are selected to mature into CD4 or CD8 single-positive cells → leave thymus
What must thymocytes express before positive and negative selection can occur?
A functional T cell receptor α:β chain on cell surface and the coreceptors CD4 and CD8
Since there is a lot of death by apoptosis occuring for T cells in the thymus, what clears up the debris?
Macrophages ingest developing T cells that undergo apoptosis in the thymic cortex
What are the 2 distinct lineages of thymocytes produced in the thymus?
α:β thymocyte receptors
γ:δ thymocyte receptor
Where are thymocytes at different developmental stages found in the thymus?
DN1: corticomedullary junction
DN2, DN3, DN4, immature double-positive in cortex
Mature CD4+, CD8- or CD4-, CD8+ thymocytes are found in medulla
Where do positive and negative selection take place?
Positive in cortex
Negative mostly in medulla
When β chain is productively rearranged and expressed on cell surface, what stabilizes it?
A pre-T α chain
What gene segements do the α and β chains have? What is the sequence of segment binding of the chain regions?
α: V, J, C
V to J
β: V, D, J, C
D to J
V to DJ
Rearrangement of which chain of the T cell receptors occurs first?
β chain
What is the role of pre-T cell receptors?
Signals→
Cell becomes permissive for TCR α-chain locus arrangement
Stimulates expression of CD4 and CD8 coreceptors
Stimulates proliferation
Stops additional TCR β-chain locus arrangements (allelic exclusion)
Describe the time course of appearance of α:β thymocytes and γ:δ thymocytes
In very early days of gestation, there is high frequencey of γ:δ thymocytes
By birth and as they become an adult, there is very low γ:δ thymocyte expression
Converse pattern is seen for α:β thymocytes
What is the signaling molecule associated w/ T cell receptors?
CD3
In positive selection, how do they known which thymocytes bind to self-MHC?
Bc self-MHC is expressed on epithelial cells of the cortex and thymocytes that can bind them will bind them
What determines co-receptor specificity of thymocytes?
MHC molecule that induce positive selection determine co-receptor specificity
MHC class I → only CD8+ T cells mature
MHC class II → only CD4+ T cells mature
What cells mediate positive selection?
Thymic cortical epithelial cells
Where can negative selection of thymocytes occur? Mediated by which cells?
In cortex or medulla
Cortical epithelium cell
Medullary epithelium cell
Thymic bone marrow-derived cell
What occurs if there is strong TCR signaling in negative selection of thymocytes?
Self-reactive thymocyte dies
What is thymocytes emigration induced by?
Sphingosine 1-phosphate receptor, S1PR1
After 3 - days n the medulla, CD4 and CD8 T cells upregulate SIP1 and exit the thymus into the blood
What does AIRE do?
Controls or regulates expression of certain self peptides
Where is AIRE expressed?
Expressed in the medulla of the thymus
Affinity model of T-cell positive and negative selection
Positive and negative selection is though to hinge on the strength of self-peptide:MHC binding by the TCR
Low-affinity interactions rescue the cell from death by neglect, leading to positive selection
High-affinity interactions induce apoptosis and thus negative selection
