Inflammation - Immunology - B cell & T cell Maturation Flashcards
True/False.
Primary B cell development is antibody-dependent.
False.
Primary B cell development is antibody-independent.
Antibody constant regions differ between antibody _________.
Classes
(IgG, IgA, IgM, IgE, IgD)
True/False.
Antibody variable regions differ between antibody class only.
False.
Antibody variable regions differ between all antibodies.
What determines an antigen’s class (IgG, IgA, IgM, IgE, IgD)?
The constant region
(constant within each class)
What term refers to the mixing up and reassembling of DNA to form the code for a diverse variety of B cell antigen receptors (surface antibodies)?
VDJ recombination
What do the V, D, and J of B cell antibody DNA stand for?
Variable region,
diversity region,
joining region
What process is shown here?
VDJ recombination
True/False.
VDJ recombination (genetic formation for synthesizing new antibodies) is selectively directed by whatever antigens are presented to the B cell.
False.
VDJ recombination is completely random.
Which parts of VDJ recombination are relevant to light chain variable regions?
Which parts of VDJ recombination are relevant to heavy chain variable regions?
V, J;
V, D, J
What might be a potential cause of agammaglobulinemia and/or SCID involving defects in antibody production?
Defects in VDJ recombination
(e.g. a defect in RAG1 or RAG2)
True/False.
The human body is constantly synthesizing new, random antibodies.
True.
Via random VDJ recombination.
True/False.
Both T cells and B cells use random genetic recombination to increase diversity of their surface receptors.
True.
What is a B cell antigen receptor?
A B cell surface antibody
Describe the basic structural difference between B cell and T cell antigen receptors.
What type of enzyme cleaves recombination signal sequences (RSSs) to start the VDJ recombination process?
RAG (1 and 2)
(recombination activating gene)
With all the V, D, and J sequences available in both heavy chains and light chains (no Ds) for recombination, how many different antibodies can the body potentially produce?
50 trillion
(obviously, we can only have a small fraction of this total potential)
All B cells start out with what B cell antigen receptor class?
IgM
Light chains usually have a VJ section that is either classified as a __ or a __.
Heavy chains usually have one VDJ type, classified as __.
κ, λ;
H
What is the ratio of κ to λ chains in our B cells?
3:1
After a pre-B cell has formed a potential heavy chain variable region, what happens?
It presents this region to a bone marrow stromal cell as the CDR3;
if it is a productive arrangement, the B cell is allowed to proceed to light chain production
What is portrayed in this image?
A pro-B cell presenting its heavy chain CDR3 to a bone marrow stromal cell;
if it is a productive (correctly made heavy chain) arrangement, the B cell is allowed to proceed to light chain production
How many antigen-binding sites are present on a single antibody?
3
(2 on the sides of the variable regions; 1 in the middle)
True/False.
Antibodies bind to their respective antigens through weak, non-covalent interactions.
True.
These are reversible interactions.
True/False.
Every individual has their own unique antibodies that react to unique antigenic epitopes.
True.
All antibody production is randomly generated.
Pre-B cells express cytoplasmic and surface __ chains.
Immature B cells express surface __.
μ;
IgM
What type of B cell can express Ig types other than IgM?
Mature B cells
If a pro-B cell presents a non-productive (non-useful) CDR3 to a bone marrow stromal cell, what happens next?
Apoptosis
(the cell may try one more round of heavy chain production first)
True/False.
Antigens may drive the production of B cells and plasma cells, but the antibody production is still completely random and independent.
True.
The default for B cell and T cell precursors is ________, unless they are activated or maintained via extracellular preservation signalling (from nurturing / checkpoint cells in the bone marrow and/or thymus).
Apoptosis
What two cell proteins are indicative of a B cell lineage?
(And a T cell lineage?)
CD19, CD20, CD40;
(CD3, CD4 or CD8)
What cell type sends survival signals to developing B cells keep them from undergoing apoptosis?
Bone marrow stromal cells
What survival signal do bone marrow stromal cells constitutively secrete to maintain developing pro-B cells?
Interleukin-7
(NOTE: the stromal cells induce IL-7 receptor up-regulation on B cells with useful CDR3 production. So, while IL-7 is always present, only chosen cells are maintained by it.)
What is the difference between B cell antigen receptors and secreted antibodies?
Location only
(cell surface or free in serum)
Pro-B cells display what to stromal cells in the bone marrow?
And pre-B cells?
Heavy chain surrogates (CDR3);
light chain surrogates
Describe the timing of heavy chain and light chain production by pro- and pre- B cells.
How can a bone marrow stromal cell tell if a pro-B cell has created a useful heavy chain?
Correct electrical charges present
(not specific recognition)
Lipopolysaccharide (LPS) is on the surface of what?
Gram-negative bacteria
Which type of antigen creates better B cells, T-dependent or T-independent antigens?
T-dependent
What are the two main types of T-independent antigens?
Type 1:
polyclonal activators (e.g. mitogen, LPS);
Type 2:
large, polysaccharide molecules (cross-link B cell receptors)
Describe the differences in the first and second B cell response to a T-dependent antigen (according to speed, how much antibody production occurs, and what type of antibodies are produced).
How are self-recognizing B cells prevented from entering general circulation (very simple mechanism)?
Via a bone marrow self-antigen check
(self-reactive cells will stick to the bone marrow cells)
Not all self substances are present in the bone marrow.
Does a simple self-antigen check help check for B cells sensitive to T-dependent or T-independent antigens? Why?
T-independent;
most body cells are not mitogens or large polysaccharides
(i.e. once these have been screened for, there is little chance of reactivity to another part of the body unless it is T cell -induced.)
Which is more common, autoreactivity to T-dependent or T-independent substrates?
(I.e., are most autoimmune disorders likely to come from reactivity from B cells alone?)
T-dependent
(B cells are screened for T-independent reactivity before they leave the bone marrow.)
Where (specifically!) do B cells typically differentiate into memory or plasma cells?
Lymph node germinal centers
Do plasma cells still have antibody receptors on their surfaces?
Not typically;
they have been induced for producing their specific antibody until they die
What are the three main types of immunoglobulin produced by plasma cells?
IgG, IgA, IgE
__ cells recognize ‘native’ antigens.
__ cells recognize processed antigens.
B;
T
What are the two primary lymphoid organs?
Bone marrow;
thymus
What maturation happens in primary lymphoid tissues?
What maturation happens in secondary lymphoid tissues?
Antigen-independent lymphocyte maturation;
antigen-dependent lymphocyte maturation
What are the two basic processes of lymphocyte maturation that occur in the thymus?
Acquisition of antigen-specific cell-surface receptors (cortex);
elimination of auto-reactive lymphocytes (thymus)
Where do T cell precursors travel after they are formed in the bone marrow?
What do they become?
The thymus;
thymocytes
When are T cells considered mature?
After leaving the thymus to enter secondary lymphoid tissues
What general term can be used to describe both corticothymic and medullothymic cells?
They are of what origin?
Epithelioreticular cells;
thymic
Why are there plenty of macrophages and dendritic cells in the thymus?
They are of what origin?
To destroy rejected T cell precursors;
bone marrow
When has T cell maturation virtually stopped in the thymus?
≥ 50 years of age
(thymus most active during childhood and childbearing years)
What percent of T cells have αβ TCRs (as opposed to γδ)?
95%
What percent of T cell precursors are destroyed in the thymus?
98%
What cortical thymic hormones stimulate TCR acquisition on T cell precursors?
Thymosin, thymulin, thymopoeitin
What is the purpose of the CD3 in T cells?
Intracellular signal transduction
(relating information from the CD4 or CD8 into the cell)
What surface receptors do T cell precursors gain in the thymic cortex?
CD3, TCR, CD4, CD8
What surface receptors do T cell precursors lose in the thymic medulla?
EITHER CD4 or CD8
(leaving either CD4+, CD8- or CD4-, CD8+)
Which part of the T cell receptors signals the inside of the cell?
CD3
How do T cell precursors enter the thymic subcapsular space (then cortex)?
How do T cells leave the thymic medulla?
High endothelial venules (HEVs);
HEVs, lymphatics
When T cell precursors enter the thymic cortex, they are double-____________.
When T cell precursors enter the thymic medulla, they are double-____________.
Negative;
positive
How does the structure of a T cell antigen receptor compare to that of a B cell antigen receptor?
(Like one arm of the antibody)
True/False.
T cell receptors are produced in the same way as B cell antigen receptors / antibodies.
True.
VDJ recombination
Will a defect in VJ recombination or RAG enzymes affect T cells or B cells?
Both equally
(both have surface receptors generated via the same VDJ recombination mechanism)
True/False.
Defects in VDJ recombination can cause SCID.
True.
Due to severe deficiencies in both T cells and B cells
Which interleukin serves as a survival signal for B cell precursors?
Which interleukin serves as a survival signal for T cell precursors?
IL-7;
IL-2
A double-negative T cell is CD__ and CD__.
A double-positive T cell is CD__ and CD__.
4-, 8-;
4+, 8+
What are CD4 and CD8?
Co-receptors for TCR/CD3
Precursor B cells express their immature heavy chain with a light chain __________ to be checked by bone marrow stromal cells.
A light chain surrogate
Precursor T cells express their immature β-subunit with what when they are being checked by thymic epithelioreticular cells.
An α-subunit surrogate
Which T cell receptor subunit (α or β) is analogous to antibody heavy chains and has V, D, and J genetic portions?
Which has only V and J (like antibody light chains)?
β-subunits;
α-subunits
Which of the following is most responsible for MHC binding?
TCR
CD3
CD4
CD8
TCR
(CD3 allows for intracellular signal transduction)
(CD4 and CD8 are coreceptors)
Which of the following is(are) described as a cofactor for MHC binding?
TCR
CD3
CD4
CD8
CD4, CD8
(CD3 allows for intracellular signal transduction)
(TCR is the main receptor)
Which of the following are relevant to both T cell receptors and B cell antigen receptors?
Recombination activating gene (RAG1, RAG2)
VDJ recombination
Synthesis of random receptors
All three
The __- and __-subunits of a T cell receptor are analagous, respectively, to the B cell receptor _______ chains which use VDJ recombination and the _______ chains which use VJ recombination.
β, heavy (VDJ)
α, light (VJ)
TC cells are CD__+ and bind MHC class __.
8; 1
TH cells are CD__+ and bind MHC class __.
4, 2
What percent of T cell precursors are discarded in the thymus?
98%
What percent of T cells produced by the thymus bind MHC class I?
What percent of T cells produced by the thymus bind MHC class II?
50%;
50%
True/False.
Only thymocytes with a very high affinity for either of the MHC classes are allowed to become mature T cells.
False.
Only thymocytes with affinities that have a medium-to-high affinity for either of the MHC classes are allowed to become mature T cells.
(Goldilocks selection)
What will happen to thymocytes with very low affinity for either of the MHC classes?
What will happen to thymocytes with a mid-range affinity for either of the MHC classes?
What will happen to thymocytes with very high affinity for either of the MHC classes?
Apoptosis;
preserved;
apoptosis
Major histocompatability complexes (MHCs) are known as ___ in humans.
HLAs
(human leukocyte antigens)
How is a double-positive thymocyte selected to become either a TC or a TH cell?
(I.e., how does the thymus select for which CD the cell keeps and which it loses?)
Whether or not that thymocyte happens to bind a MHC class I or MHC class II
A double-positive thymocyte happens to bind MHC class II with a moderate affinity.
What will happen next?
Loss of CD8
(i.e. the cell becomes a TH cell; CD4+, CD8-)
What is the ‘Goldilocks’ selection of the thymus in regards to thymocyte affinities for MHCs?
Only those with moderate-to-strong affinities are preserved
(very high or low binding cells are lost)
The MHCs that a thymocyte can bind are located on which type of cell found in the thymus?
Cortical epithelioreticular cells
Where are MHC class I normally expressed?
All nucleated cells
Where are MHC class II normally expressed?
Specific APCs
(dendritic cells, macrophages, B cells)
What cell type has an abundance of MHC class I and MHC class II on its surface to stimulate thymocyte maturation?
Thymic epithelioreticular cells
What is found between an MHC and a TCR?
A peptide fragment
MHC class I receptors present what type of antigens on their surfaces?
MHC class II receptors present what type of antigens on their surfaces?
Self (endogenous) proteins;
non-self (exogenous) proteins
True/False.
A variety of tissue- and cell-specific proteins from all around the body (e.g. pancreatic, gut, renal, ocular, and ECM antigens) can be found in the thymus.
True.
Presented on MHC complexes so T cells that are overreactive to self will be identified and removed.
Why do thymocytes develop via a ‘Goldilocks’- like system?
(No low or very high MHC-binding cells allowed)
The TCRs need to have a strong enough affinity to recognize the MHCs, but not too strong that it results in autoimmunity
Where does positive T cell selection occur?
Where does negative T cell selection occur?
Thymic cortex;
thymic medulla
What is the purpose of positive T cell selection in the thymic cortex?
To make sure T cells can recognize MHCs (and thus, foreign antigens)
What is the purpose of negative T cell selection in the thymic medulla?
To make sure T cells don’t bind too tightly to self-antigens
Positive T cell selection ensures that the cells will recognize self-_____ (allowing for immune response).
Negative T cell selection ensures that the cells won’t recognize the self-_____/MHC complexes too tightly (preventing autoimmunity).
MHCs;
antigens
Positive T cell selection: “can it bind ____ at all? Will it be a useful immune cell?”
Negative T cell selection: “does it bind the ____-____ complex too tightly? Will is cause autoimmunity?”
MHC;
MHC, antigen
What cell type(s) perform(s) positive selection of T cells?
What cell type(s) perform(s) negative selection of T cells?
Cortical epithelioreticular cells;
dendritic cells, macrophages, medullary epithelioreticular cells
What thymic protein causes expression of MHC within the thymus displaying a huge variety of body proteins (e.g. pancreatic, gut, renal, ocular, ECM antigens, etc.) to screen for T cells with a high affinity for body antigens (negative selection)?
Aire
(autoimmune regulatory protein)
What happens to thymocytes with little affinity for the MHC-antigen complex?
And high affinity?
Apoptosis (by neglect);
apoptosis (by negative selection)
The purpose of CD4 and CD8 is to enhance what?
TCR/CD3 binding to MHCs
Which peripheral T cells are CD3+?
All of them
(necessary for intracellular TCR signal transduction)
True/False.
T cell receptors have a potential diversity (after VDJ recombination) of over 1013.
B cell antigen receptors have a potential diversity (after VDJ recombination) of over 1018.
False.
T cell receptors have a potential diversity (after VDJ recombination) of over 1018.
B cell antigen receptors have a potential diversity (after VDJ recombination) of over 1013.
Thymic Aire protein is responsible for MHC presentation of what in the thymus?
Why?
A huge variety of body antigens (e.g. pancreatic, gut, renal, ocular, ECM antigens, etc.);
to screen for T cells with a high affinity for body antigens (negative selection)
