BLOCK 2 DR. SMITH Flashcards
What is VDJ recombination ?
Defining feature of the adaptative immune system that results in great antibody variability allowing us to be able to respond to many different antigens.
VDJ recombination occurs in germline DNA.
It produces a very unique variable regions in heavy & light chains of Ab.
What is junctional diversity ?
Nucleotides can be added or deleted at the junctions of cut DNA during recombination, which results in changes in antigen binding sites.
Allows for even more diversity.
80% of Ig molecules have this extra step.
What is somatic hypermutation ?
Mutations that occur in V genes of H or L chains over the life of the B cell, usually after activation/proliferation.
Adds even more diversity.
In BCR, heavy chains undergo VDJ recombination whereas light chain undergo ?
VJ recombination only.
What is the role of RAG enzymes ?
Binds to the recombination signal sequence (RSS), creates nick in the DNA, forms hairpin loop on coding segment.
Performs the recombination itself.
Without these RAG enzymes, you don’t have mature B & T cells, only precursors.
What is the role of TdT enzyme ?
Further processing and addition/substraction of nucleotides on coding ends creating** junctional diversity.**
Without TdT, you still have an immune response, but not as good as someone who would have this junctional diversity (additional protection).
B cells originate from ?
Bone marrow
Pre-B cells have what special feature ?
Recombined heavy chains
Use surrogate light chain & Ig alpha & Ig beta for signal transduction. The surrogate light chain appears to serve to form an IgM-like complex on the surface of pre-B cells which signals that a productive heavy chain rearrangement has taken place, and gives a signal to the cell to commence light chain rearrangement.
Pre-B cells becomes an Immature B when ?
Heavy chain and light chain is fully recombined and full membrane IgM present (functional BCR).
If it binds correctly, then signals to promote survival are sent, allelic exclusion of light chain occurs and subsequent shut down of RAG activity.
Mature B cell co-expresses ?
Membrane IgM & IgD
Maturation occurs either in the bone marrow or the spleen. The mature B cell is still naive.
Right after getting out of the bone marrow and spleen is the only moment where B cells are going to express 2 different types of receptors. Shortly after, IgD will be loss (never seen in serum).
What is allelic exclusion?
A process by which only one allele of a gene is expressed while the other allele is silenced. This phenomenon is most notable for playing a role in the development of B lymphocytes, where allelic exclusion allows for each mature B lymphocyte to express only one type of immunoglobulin.
Hereditary inability to make Ab due to absence of BTK causing the B cell to be stuck in the pre-B phase :
Agammaglobulinemia
The specialized precursor cells that produce gammaglobulins, fail to develop or function properly leading to the deficiency in the number of mature B cells.
Recurrent infections usually with extracellular bacterial infections.
If the rearrangment of kappa light chain fails to express a functional, or generates a potentially harmful self-reactive receptor, then recombination is attempted on the lambda light chain. What is this process called ?
Receptor editing
B cells only can do this.
What is isotype switch and who can do it ?
Mature B cell, only if they recieve a signal from T cells and specific cytokines, can undergo a final step of maturation in the germinal center where they will undergo recombination again and switch isotype and then will become a plasma cell that will only secrete this isotype for the rest of its life.
CD4+ T cell interact with ?
CD8+ T cells interact with ?
Heterodimers of a & b chains alone are unable to leave the ER for cell surface expression. The heterodimer associated with 4 invariant transmembrane proteins to form the T cell receptor complex (CD3 and zeta chains) :
CD4 & CD8 T cells co-receptors function to ?
Stabilize the TCR/peptide/MHC complex
Facilitate signal transduction (kinase cascade)
Define the function of a T cell has helper T cell or Killer T cell
Heavy chains and light chain analogues in TCR:
Beta chain (heavy chain analogue)
alpha chain (light chain analogue)
BCR or TCR can only bind antigenic peptides and MHC residues ?
TCR
The hypervariable region (CDR) of the TCR variable region interact with the peptide bound in the peptide binding groove of a MHC molecule.
Every MHC can bind to multiple types of peptides, but the TCR are specific to the MHC+ peptide complex.
Were do T cells mature ?
In the thymus
Pro-T cells proliferate in response to Il-7 secreted from stromal cells of the thymus. Pro-T cells are double negative meaning they do not yet express CD4 or CD8 on their cell surfaces. Some cells rearrange their beta chain (VDJ recombination) at this point and become pre-TCR.
Pre TCR b chain protein expressed on the cells surface in association with an invariant protein, pro-Ta, that works as a surrogate. If this process is successful you then get rearrangement of :
alpha chain & allelic exclusion
Omenn syndrome results from ?
Missense mutations in RAG genes.
Basically, you have limited T cell repertoire.
Presentation : erythroderma, failure to thrive, hepatomegaly & splenomegaly, î lymph nodes, diarrhea, î eosinophil count. NK function is okay.
B cell deficit also. Bone marrow transplant is only option.
What stage of T cell that both expresses CD4 & CD8 can undergo positive selection ?
Double positive T cells
Positive selection in the cortex of the thymus refers to what process ?
Cell lineage comittment occurs :
ensures ability of T cell to bind to MHC I or II.
Mediated by CDR1 & CDR2 in TCR ‘‘caressing the shoulders’’ of MHC.
T cells with the affinity for MHC class I molecules will have CD8 marker retained and T cells with affinity for MHC class II will have CD4 retained.
T cells that survive positive selection (5%) now undergo negative selection in the :
Medulla of thymus
T cells with a TCR that binds moderately to a self-MHC molecule on APC are signaled to survive, mature and enter the peripheral population. T cells that bind too tightly to self MHC class molecules on APC of thymus (CDR3 binding) are signaled to die. This process is not perfect however, 10% may escape this negative selection and cause auto-immunity.
2-10% of T cell pool who does not undergo selection and migrate as CD4- and CD8- cells to epithelial tissues in skin, intestines and lungs ?
gamma delta T cells
They recognize non-peptide antigens
They are NOT MHC restricted
They are important early in adaptative immune response
In general, limited diversity but help with broad response
Distinctions between B cells and T cells
Which MHC is expressed by all cells in our body?
MHC class I
Which MHC is expressed by APCs?
MHC class II
HLA-A, HLA-B & HLA-C are associated with what MHC?
Class I
HLA-DP, HLA-DQ and HLA-DR are associated with what MHC?
Class II
2 letters
Has 3 extracellular domains (a1, a2 & a3) and non-covalent association with B2 immunoglobulin ?
B2 immunoglobulin is a member of the Ig superfamily
MHC class I
Peptide binding domains accomodates 8-9 AA residues.
Internally derived protein-peptides are degraded by proteasomes and carried to the **ER **by what protein in the context of MHC class I presentation ?
TAP protein
Endogenous antigens are catabolized in the cytoplasm.
What is cross-presentation?
Specialized DC can endocytose antigen, but express it on class I MHC. Now they can interact with naive T cells, activate CD8 effector T cells for destruction of the pathogen.
This process is essential for activation of naive T cells. Helpful when a non-APC cell is infected with a virus.
Post cross-presentation by dendritic cells, naive T cells become ?
Effector T cells.
Effector T cells can then help B cell make antibodies.
Lymphocyte meeting spot ?
Lymph nodes
Naive T cells can enter a lymph node either by blood or afferent lymph vessel coming from an upstream lymph node. They patrol all lymph nodes, looking for one which has a ‘‘their’’ antigen. If the APC presents an antigen that is specific to it, the naive T cell will be activated and then leave as an effector T cell via the efferent lymphatic or bv.
T lymphocytes enter secondary lymphoid organs, attracted by IL-7.
CCR-7 receptor allows Naive T cells to extravasate into the lymph node following CCR7 chemokine gradient of DCs.
3 steps of T cell activation :
- TCR recognition
- Co-stimulation
- Cytokine signaling
T Lymphocytes only react with peptide antigens. What happens when you have lipid and glycolipid antigens ?
CD1 presentation.
CD1 is the equivalent of MHC which can bind lipids/glycopeptides and present it to T cells. It binds the lipid portion of the antigen and exposes the polar region for T cell interaction. CD1 can present to Ab OR gamma delta T cells (CD1 a,b,c) and/or NKT cells (CD1d).
CD1 molecules present foreign and self lipids to diverse T cells and natural killer T (NKT) cells. Whereas the clonally restricted diverse T cells mediate adaptive immunity to microbial lipid antigens, the invariant subset of NKT cells mediates innate immune responses, responding rapidly and en masse.
Similar to MHC class I, it has a b2 microglobulin complex.
Different fates of naive CD4+ T helper cells in the lymph nodes depending on cytokines present?
Th1
Th2
Th17
Tfh (follicular helper T cell)
Summary of all T cell associated cytokines
Mechanism of cell killing by Killer T cells ?
Activated CD8 cells kill target cells via apoptosis via release of cytotoxic granules. Biding of the TCR to the MHC class I triggers synthesis of perforins & granzymes, which are stored within the cytosol. Perforin assembles on target membranes, allowing delivery of granzymes into the target cell. Granzymes are a group of serine proteases that activate capases, leading to cell death. Direct cell-cell contact is critical for this system to function. CD8 cells can also induce apoptosis by ligation of Fas and Fas ligand, which are expressed on lymphocytes and on infected target cells and also involves activation of caspases.
Fas/FasL same as CD95/95L
What cell provide moral support to killer T cells ?
Th1 cells via cross-presentation.
* Th1 = T helper cell type 1
