B and T cell Development Flashcards
What CD marks the first stage of B cell development? What is this cell?
CD34+ (pluripotent hematopoeitic stem cell)
What are the 2 main role of the one marrow stroma in the development of B cells?
Make contact with B cells via adhesin: ligand interactions; Produce growth factors for attached B cells
What is the earliest distinguishable B cell in the B lineage?
Pro-B cell
In what stage of B cell development does the first VDJ recombination take place? What Ig is produced?
Pro-B cell; Surface IgM
How does the principle of allelic exclusion apply to the development of B cells? Why is this necessary?
When pro-B cells undergo the first round of VDJ recombination to produce IgM, if the rearrangement is successful then the rearrangement on the second chromosome is stopped; If this process did not occur then a B cell could make and express 3 different Ig such that it couldn’t bind efficiently to multivalent antigens?
What is the first checkpoint of B cell development?
Once the mu H chain has been successfully produced, its ability to bind to light chain is tested through binding to a pre-B cell receptor/ surrogate receptor. If there is successful assembly then intracellular signaling is triggered and development continues- otherwise apoptosis
What forms the pre-B cell receptor?
VpreB and Lambda5
What event marks the transition of pro-B cell to pre-B cell?
If the mu H chains assemble with surrogate receptor successfully
What cellular events occur upon successful assembly of the mu H chain with the pre-B cell receptor?
Transcription of RAG genes stops, H cain rearrangement is shut off, and the pre-B cells go through several rounds of division
What is the order of Light chain rearrangement in the Pre-B cell?
Kappa first, then lambda
What is the second check point of B cell development?
The successful rearrangement of light chains and assembly with mu H chains to form an IgM surface receptor
What stage of B cell development follows the pre-B cell?
Immature B cells
What CD is specifically expressed by B-1 cells?
CD5
What is the predominant type of Ig produced by B-1 cells?
Low-affinity, polyspecific antibodies
Approximately what percent of immature B cells are reactive to self antigen?
~75%
What is receptor editing?
If an immature B cell binds to a multivalent self antigen it undergoes further light chain rearrangement for a 2nd chance at recognizing non-self antigen
Following receptor editing, if an immature B cell is still self-reactive, what happens?
The cell will continue rearranging until it can no longer and then it gives up and dies– clonal deletion
What is the dominant method for establishing B cell self-tolerance?
Clonal deletion
What is anergy? When does it occur with B cells?
When self-reactive B cells bind to monovalent antigens they do not undergo further light chain rearrangement or apoptosis, are signaled to express mostly IgD or non-functional IgM, and is unresponsive to antigen
What is central tolerance?
The outcome of loss of self-reactive B cells in the bone marrow
Only what kind of B cells can leave the bone marrow?
Non-self reactive or anergic
How is peripheral tolerance established?
Once immature B cells leave the bone marrow, those that recognize self-antigen will undergo apoptosis or become anergic
At the point when immature B cells enter circulation, what Ig molecules are expressed on the surface and what is the relative levels of expression of each?
High IgM and low IgD
What happens if an immature B cell cannot enter 2ndary lymphoid tissue?
It dies
At what point do immature B cells become mature B cells?
Entry into secondary lymphoid tissue
Through what molecules do B cells home to HEV via a gradient of chemokines?
CCL21 and CCL19 chemokines which binds to CCR7 receptor on B cells
Once in the secondary lymphoid tissue, to what specific area do B cells migrate? What stimulates this movement?
B cells further home to primary lymphoid follicles where follicular dendritic cells secrete CXCL13 chemokine
Once within a primary lymphoid follicle, what happens if a mature B cell does not see antigen?
it re-enters circulation as a naive B cell
What is the ‘secret of life’ for naive B cells?
Regular passage through primary follicles in 2ndary lymphoid tissue
What events are prompted by naive B cells encountering specific antigen in secondary lymphoid tissues?
B cells are detained in the T cell area and are signaled by T cells to differentiate immediately into IgM plasma cells and migrate to nearby primary follicles, which then become a secondary lymphoid follicle containing a germinal center
What events occur within germinal centers?
Isotype switching and affinity maturation
True or False: All cells within a B cell tumor will have identical Ig rearrangement.
True
At what age does the thymus begin to degenerate?
1 year old
What are the two lineages of T cells defined by TCR type?
Alpha-beta T cells and gamma:delta
At the point when T cells begin to undergo gene rearrangement, what kind of T cell is it?
Double negative T cell
What determines whether or not a cell becomes a alpha-beta or gamma-delta T cell?
The beta, gamma, and delta chain all start rearrangement simultaneously- if the gamma and delta chains successfully rearrange first, then the cell become gamma:delta cells. If the beta chain wins, then it will become an alpha-beta cell
Why is T cell chain rearrangement biased toward success of beta chain rearrangement?
There is only 1 rearrangement necessary vs. 2; there are 4 possible beta chain rearrangements
What is the first T cell developmental checkpoint?
The beta chain is tested for its ability to bind to a surrogate light chain (pTalpha)- if the cell is successful at assembling the pre-T cell receptor it continues differentiation- if not, development stops
What molecules make up the pre-T cell receptor?
Beta chain, surrogate light chain, CD3 complex, and the zeta chain
At what point does a Pre-T cell form?
If a pre-T cell receptor successfully assembles
What cellular events are stimulated by the successful assembly of the pre-T cell receptor?
Ceased expression of RAG genes, a short bout of proliferation, and expression of both CD4 and CD8
What are double positive thymocytes?
Developing T cells within the thymus that express both CD4 and CD8 on their surface
What is checkpoint 2 in T cell development?
If the alpha chain successfully rearranges before both gamma and delta, the alpha chain is tested for its ability to assemble with the beta chain and if it doesn’t- apoptosis
What is positive selection of T cells?
Double positive cells are tested for their ability to recognize self-peptides: MHC on cortical epithelial cells- if binding occurs, a positive signal is sent to the thymocyte and continues maturation
What happens if a TcR doesn’t bind to a peptide:MHC?
The alpha chain undergoes receptor editing
What stimulates a double positive T cell to become either CD4+ or CD*+ T cells?
If the cell binds to self MHC I:self peptide, it will become CD8+; If it binds to MHC II:self-peptide, it will become CD4+
What is negative selection of T cells?
Autoreactive, single-positive T cells are removed from circulation by binding self-antigens: MHC complexes on thymal dendritic cells in the medulla
What does AIRE stand for? Where is it expressed? What is its importance?
Autoimmune Regulator Gene; Expressed in thymal medullar epithelial cells; It is a transcriptional activator that induces low-level expression of thousands of tissue specific antigen genes
What results from absence/ nonfunctional AIRE?
Self-reactive T cells enter the periphery and attack cells in various tissues causing autoimmune polyendocrinopathy candidiasis
How is central tolerance established in T cells?
T cells reactive with thymic antigens and those antigens induced by AIRE are eliminated.
How is peripheral tolerance established in T cells?
T cells enter the periphery, and if it recognizes self-antigen will undergo anergy or activation-induced cell death
What is the typical, healthy ratio of CD4+ : CD8+ T cells?
2:1
