Lecture 20: Early Lymphocyte Maturation - T cells Flashcards
Recall the similarities and differences between T and B cell developments.
Describe the thymus.
Recall the fates of thymocyte.
Thymocytes enter thymus via ____; interaction with ______________ initiates T cell fate decision (Thy1hi) and proliferation
Thymocytesenter thymus via HEV; interaction with thymic stroma cells initiates T cell fate decision (Thy1hi) and proliferation
Recall the concept of MHC restriction.
MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.
Describe how thymocytes at different developmental stages are found in distinct parts of the thymus
The earliest precursor thymocytes enter the thymus from the bloodstream via venules near the cortico-medullary junction. As these cells differentiate through the early CD4–CD8– double-negative (DN) stages, they migrate through the cortico-medullary junction and to the outer cortex.
DN3 cells reside near the subcapsular region, where they undergo proliferation. As the progenitor matures further to the CD4+CD8+ double-positive stage, it migrates back through the cortex. Finally, the medulla contains only mature single-positive T cells, which eventually leave the thymus.
Recall the mechanism of TCR rearrangement.
Functionality of the developed beta chain is tested by pairing with ________________.
The functionality of the developed beta chain is tested by pairing with pTalpha as surrogate heavy chain (=pre-TCR)
Pre-TCR stimulation halts _______________ and induces a ______________
Pre-TCR stimulation halts beta chain rearrangement and induces a burst of proliferation
DN cells then transition into ___________ , which rearranges ______________.
DN cells then transition into DP cells, which rearranges alpha chains
Recall the positive selection of T cells.
This failure is due to the absence of an interaction between the transgenic T-cell receptor with MHC molecules on the thymic cortex, and thus no signal for positive selection is delivered, leading to apoptotic death by neglect.
Positive selection of T cells occurs on ______________.
Positive selection of T cells occurs on thymic stroma cells
Positively selected thymocytes will be tested again for self-peptides presented by _____________. This process of negative selection occur in the ____________ or __________.
Professional APC (such as DC)
cortex or the medulla
Recall the process of T cell negative selection.
Recall the “fundamental principle” of the selection of T cells in the thymus
Recognition of specific peptide : MHC complex in the thymus leads to deletion;
Recognition of specific peptide : MHC complex in the periphery leads to activation
How is self-peptide represented in the thymus?
The expression of some, but not all, tissue-specific proteins in the thymic medulla is controlled by a gene called AIRE (autoimmune regulator). AIRE is expressed in medullary stromal cells, interacts with many proteins involved in transcription, and seems to lengthen transcripts that would otherwise terminate earlier.
Negative selection of developing T cells involves interactions with ubiquitous and tissue-restricted self antigens, and can take place in both the thymic cortex and the thymic medulla
Recall the following diagram overviewing T cell development in the thymus.
Recall the affinity model of T-cell positive and negative selection.
Some thymocytes on the higher end of the affinity spectrum become regulatory T cells
Recall the overview of T cell differentiation in the thymus (DN1-4 => DP)
At first, double-negative thymocytes express Kit and CD44 but not CD25 and are called DN1 cells; in these cells, the genes encoding both chains of the T-cell receptor are in the germline configuration.
At the DN2 stage (CD44+CD25+), cells upregulate the recombination genes RAG1 and RAG2 and re-arrange the TCRβ locus, combining V-D-J and constant region genes in an attempt to create a functional TCRβ chain.
As the developing thymocyte progresses through to the DN3 stage (CD44-CD25+), the T cell expresses an invariant α-chain called pre-Tα alongside the TCRβ gene. If the rearranged β-chain successfully pairs with the invariant α-chain, signals are produced which cease rearrangement of the β-chain (and silences the alternate allele). Although these signals require this pre-TCR at the cell surface, they are independent of ligand binding to the pre-TCR.
If the pre-TCR forms, then the cell downregulates CD25 and is termed a DN4 cell (CD25-CD44-). These cells then undergo a round of proliferation and begin to re-arrange the TCRα locus.
