B and T cell Maturation Flashcards
Where in the body do B cells mature? WHen do they leave?
Bone marrow - they leave when they’re in the immature transitional stage
What acts as the initial BCR? What are the components?
membrane-bound IgM and signaling chains Ig-alpha and Ig-beta (CD79a and CD79b)
What will happen to the immature B cells in the periphery if they don’t experience antigen?
they’ll undergo apoptosis in a few weeks
What is the earliest stage of antigen-independent B cell development?
the progenitor B cell = pro-B cell
The pro-B cells are divided into three groups how?
early pro-B: express Tdt alone
intermediate pro-B: express both TdT and B220
Late pro-B: express B220, but downregulated Tdt
As the cell progresses through the pro-B cell stage, what else does it begin to express?
CD43, CD19, RAG-1 and RAG-2
As the late pro-B cell passes into the pre-B cell stage, what do they downregulate?
TdT, RAG1, RAG2 and CD43
What do pro-B cells express to allow them to bind to stem cell factor expressed on bone marrow stromal cells? What does this induce?
c-Kit
This induces the pro-B cell to proliferate and differentiate into pre-B cells
What are the two groups of pre-B cells?
large mitotically active
small non-dividing
What do both the large and small pre-B cells express in their cytoplasm? on their surfaces?
IgM heavy chains in the cytoplasm and a receptor complex on their surface (no light chain yet)
What do the large pre-B cells do as they pass into the small group?
They upregulate RAG1 and RAG2 so they can rearrange their Ig light chain genes
pre-B cells have a receptor for which cytokine that stimualtes them to divide and differentiate?
IL-7
What do Immature B cells express that pre-B cells didn’t?
Finally express surface IgM (with successfully rearranged heavy and light chains)
When the immature B cells further develop into mature B cells, what else do they express on their surface?
surface IgD
What phase do the mature B cells go thorugh when they first exit the bone marrow and migrate to the periphery?
thr transition phase
What cytokine signals through the BR3 receptor for the survival of pre-immune B-cell stages from the transition stage onwards?
B-lymphocyte stimulator (Blys)
What are some of the transcription facotrs involved in B cell generation?
- E2A and EBF (turned on by STAT5 ignalling)
- Pax5
- Sox4 and LEF1
- IRF4 and IRF8
- Bcl6
What happens in immunodeficiency XLA?
It’s a mutation in Bruton’s tyrosine kinase, which is a key enzyme involved in signal transduction downstream of the pre-BCR and BCR
Without that signalling, these patients have very vew circulating B cells and negligible serum Ig
(this agammaglobulinemia!)
What happens to the B cells in CVID?
You have reduced serum Ig, reduced memory B cells and less class switch recombinaiation or B cell activation
What happens to the B cells when there’s a mutation in CD40 ligand on T cells?
You don’t get the costimulatory signal from the Th to the B cells, so you have issues with class switching
WHat happens first for the B cells - negative or positive selection? WHere
negative happens first - in the bone marrow (mostly)
What are the three populations of B cells in the periphery? Which is most numerous?
Follicular B2 C cells - most common (and what we usually think of for the immune response)
B-1 B cells
Marginal zone B cells
What are the two types of T-independent antigens that can activate B cells without Th help?
TI-1 - bacterial cell wall components like LPS
TI-2 - large polysaccharide molecules with repeating antigenic determinants (like bacterial flagellin)
What class of B cells are activated by the TI antigens?
the B-1 B cells
What does the B-1 B cell use to bind to the type 1 TI antigen? How does this affect what expansion occurs?
TLR4 - you get polyclonal activation
BCR - you get clonal activation
What antibody is produced in response to type 1 TI antigens? Can you develop memory this way?
IgM - no memory
How does the B1 B cell bind to type 2 TI antigens? So what kind of activation/expansion is possible?
through cross-linking of the BCR only.
so you only get clonal activation (not polyclonal)
What Ig type is formed in response to type 2 TI antigen? Is there a potential for a full B cell response?
IgM mostly, but there IS a potential for full B cell response as CD4+ T cells can be innvolved and produce the right cytokines for class switching
Where are B1 B cells generally found in the body?
peritoneum
What are the two ways the BCR can be stimulated?
- By having antigen cross-linking multiple IgM or IgD on the surface of the cell
- By having antigen bind one Ig and complement binding to both the antigen and CD21 on the B cell - so the complement binding does the cross stimulation
What cytokines does the Th2 cell make to push B cell proliferation and differentiation?
IL2, IL4, and IL5
How does the memory B cell response differ from the naive B cell response?
- faster - only 1-3 days to start producing antibody and peak is reached in 3-5 days
- stronger - makes more antibodies and the antibody affinity is much higher
- IgG and IgA (not IgM)
- thymus dependent (no independent - remember its membory)
- long-lived
In the germinal centers, T and B cells that have recognized antigen try to find each other. What happens to the B cell if it doesn’t get Th help after SHM? WHat happens if it does - specifically, how does it become long-lived?
Doesn’t meet it’s T cell - dies by Fas-independent apoptosis
Does meet - starts to make Bcl-2 so it’s protected from apoptosis and becomes long-lived
What signalling molecule must be made by thymic stromal cells in order for T cells to develop?
Notch
DUring T cell development, there are multiple stages denoted by “double negative” which means?
they have neither the CD4 or CD8 (They’re starting to make the TCR, but don’t have the costimulators yet)
What stage comes after the double negative stages?
Double positive - they have both CD4 and 8
What CD marker is required for the T cells to relocalize to the thymus for education?
CD44
What does the T cell undergo first - negative or positive selection?
positive selection in the thymus
Positive selectio nis also known as what?negative selection?
positive = restriction negative = self-tolerance
How many TCRs must be bound to activate the T cell? What’s the maximum?
Only one is necessary; 10 is the max
What cytokine is the activated T cell use as an autocrine to increase further proliferation?
IL-2 - help generate the clone
What do superantigens do and how do they do it?
They can bind both the MHC and TCR outside of the antgen groove by binding directly to CD28
Thus, they can provide the co-stimulatory signal to the T cell without the need of B7 - triggering a non-specific interaction to stimulate many T cells of different antigen specificity
What does superantigen binding lead to?
shock - via massive release of IFN gamma and TNF alpha
What cytokines will trigger formation of Treg cells? What do they secrete?
Trigger: IL-2 and TGF beta
Secrete: IL-10 and TGF beta
What cytokines will trigger formation of Th17 cells? What do they secrete?
trigger: IL-1, IL-6, IL-23, TGF beta
secrete: IL17A< IL17F, IL22
What cytokines will trigger formation of Th2 cells? What will they secrete?
Trigger: IL-4
Secrete: IL4, IL-5, IL-13
What cyotokines will trigger formation of Follicular T cells/ What will they secrete?
trigger: IL-6 and IL-21
secrete: IL4, IL-21
What cytokines will trigger formation of Th1 cells/ What will they secrete?
trigger: il-12, IFN gamma, IL-18
secrete; IFN gamma, TNF
