L10: T Cell Maturation and Differentiation Flashcards Preview

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Flashcards in L10: T Cell Maturation and Differentiation Deck (41)

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?



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?



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?


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?


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?



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