Yager concepts

What is the function of Th-PoK?

Acts as a transcription factor during the transition from double positive thymocytes to single positive CD4 cells.

Which of the following is characteristic of individuals homozygous for defective alleles of the interleukin (IL-7) receptor?

They have no T-cells.

Which of the following describes the ligand for the receptor protein Notch1?

It is a transmembrane protein on epithelial cells of the thymic stroma.

In a pre T-cell receptor, what is the function of pTa?

In the superdimer configuration, each of two pTa molecules interacts with the variable region of one B chain and the constant region of the other B chain.

What would happen to a thymocyte that failed to cleave Notch1?

The thymocyte would continue to block the T-cell lineage genes.

Why is it necessary for mature T-cells to be MHC restricted?

To recognize self-MHC molecules presenting pathogen derived peptides.

Which of the following is true of MHC class I and II molecules on the surface of thymic epithelial cells?

Present peptides derived from self proteins present in the thymus.

Which of the following is true of receptor editing of the T-cell receptor?

It occurs to ensure reactivity with self-MHC molecules.

Double negative thymocytes express which of the following cell-surface markers?

CD2, CD5, CD127, (IL-7) receptor, CD1A, RAG complex

What is the route that developing T-cells take through the thymus, beginnnig with their most immature state?

Subcapsular region, cortex, corticomedullary junction, medulla.

What is the mechanism of the bias favoring commitment to the a:B T cell lineage?

Only one productive rearrangement is required at both the double negative and double positive stages of T-cell development.

In contast to peripheral tolerance, central tolerance has what result?

It signals continuation of light chain gene rearrangement

What are the phases of B-cell development?

Repertoire assembly, negative selection, positive selection, searching for infection, finding infection, attacking infection.

Why are the immunoglobulin loci in non-B cells transcriptionally silent?

Pax-5 is not made in those cells.

Which of the following occurs on the subendosteum region of the bone marrow?

A high proportion of hematopoietic stem cells reside there.

How do B-cells circulate through a lymph node?

Blood, high endothelial venule, T-cell area, primary lymphoid follicle, T-cell area, medullary cords, efferent lymphatic vessel.

What is the normal situation whereby the immune system does not respond to self antigens?

Self-tolerance

A complete and functional immunoglobulin chain is made onkly if what circumstance occurs?

A correct reading frame in the variable region is produced.

Which of the following is a type of B-cell tumor that arrises from a germinal center B-cell and does not express antigen receptor?

Hodgkin's lymphoma

Upon reaching what stage is a developing B-cell irreversibly committed to the B-cell lineage?

Pro-B-cell

What happens if the B-cell receptor of an immature B-cell does not interact with multivalent self antigens present in the bone marrow?

The cell is exported to the peripheral circulation as an immature B-cell.

You would like to obtain a B-cell line from a tumor that has a single receptor specificity and resembles a naïve B-cell. Which tumor type would most-likely serve your needs?

Mantle cell lymphoma

RNA tumor viruses that directly mediate the development of cancer in their vertebrate hosts contain oncogenes originating from what phenomenon?

The genome of the host.

What occurs following cell division of large pre-B-cells?

u chains are synthesized and remain inside the cell.

Assume that an early pro-B-cell has productively rearranged D to J segments on both chromosomes. What happens if there is then a non-productive V-DJ rearrangement of the heavy-chain locus on the first chromosome?

Rearrangement of V-DJ occurs on second chromosome.

The second checkpoint in B-cell development that tests the quality of the light chain occurs at what stage?

Small pre-B-cell

A patient is found that her antibodies are overwhelmingly targeting a single antigen. What would you expect to find in the B-cell populations?

Clonal population derived from a single ancestral cell.

Although the pre-B-cell receptor resembles the B-cell receptor, it differs by containing a surrogate light chain that is composed of what?

VpreB and l (upside down Y)5

Which of the following refers to events that join DNA sequences from two different chromosomes?

Translocation

The first checkpoint in B-cell development that tests the quality of the u chain occurs at what stage?

Late pro-B-cell

Which molecule do all human hematopoietic stem cells express?

CD34

In B-cell development, what is it called when the quality of the immunoglobulin chains arising from gene rearrangement is tested?

Checkpoint

When looking at chromosomes using a light microscope during metaphase, what would you expect to see in a burkitt's lymphoma cell?>

Chromosome 8 is too short and either chromosome 2, 14, or 22 is too long.

Why are T cells with an initially nonproductive a-chain gene rearrangement very likely to be rescued by a further productive rearrangement?

The a-chain locus contains large numbers of both V and J gene segments.

Systemic lupus erythematosus is an autoimmune disorder in which damage to small blood vessels occurs when immune complexes of self antigens and autoreactive antibodies form and deposit there, The self antigens include DNA, RNA, and components of nucleoprotein particles. Which of the following explains why self reactive B-cells in SLE have escaped immunological tolerance?

Self-tolerance is readily induced to accessible self-antigens, but not to inaccessible self-antigens

Which of the following is a transcription factor that causes tissue-specific genes to be transcribed in medullary epithelial cells in the thymus?

Autoimmune regulator (AIRE)

If an individual is homozygous for defective TAP-2, one of the proteins needed to transport peptides into the lumen of the endoplasmic reticulum, then what would be observed in the T-cell repertoire of this individual?

It will lack cytotoxic T-cell function

What comprises the pre-T-cell receptor?

CD3 complex, pTa, B-chain, S chain

In what ways does T cell development differ from B-cell development?

Developing T cells form 2 lineages distinguished by different types of T-cell receptors and T cells develop in the thymus.

Which of the following are correct regarding expression of a pre-T-cell receptor at the cell surface?

Expression confirms that a functional B-chain has been produced and that the B-chain produced can bind a-chains

Which of the following correctly describes the functional form of the pre-T-cell receptor?

It is a superdimer composed of two heterodimers of pTa and a B-chain

True or false, Naive T cells can be activated anywhere in the body

False.

True or false, a very small proportion of developing T cells emigrate from the thymus as mature T-cells

True

What occurs durinng successive rearrangments at a T-cell receptor a-chain locus?

The nonproductively arranged V and J segments are deleted.

What is the end effect of the cytokines released by effector T-cells on their target cells?

Gene expression

What is the funciton of TH1?

Activates macrophages (IFN-y)

What is the function of TH2?

Activates responses to parasites (IL-4)

What is the funciton of TH17?

Enhances neutrophil response (IL-6, IL-21, IL-17)

What is the function of Treg?

Suppresses effector T-cells (TGFB)

What is the function of TFH?

Promotes B-cell differentiation into plasma cells.

What is used to divide effector T-cells into their functional classes?

The transcription they express, which control different differentiation pathways, the type of cytokines they secrete, their function in adaptive immunity, and, the cytokines that influence their activation and differentiation

What characteristic defines anergic T-cells?

They are unable to produce IL-2

What cytokine is expected to predominate in lesions analyzed form an individual with the tuberculoid, rather than the lepromatous, form of leprosy?

IFN-y

What are the advantages of apoptosis over necrosis?

The breakdown of viral nucleic acids prevents the assembly of infectious viral particles, prevents the release of pathogen from the infected cells and cells killed via. apoptosis do not lyse or disintegrate.

Other than blood, through whicb other structure can naive T cells enter lym-ph nodes?

Afferent lymphatic vessels

What forms a dimer during cytokine induced signaling?

Janus kinases (JAKs), signal transducers and activators of transcription (STATs) and cytokine receptor subunits.

What cell surface molecule ensures that effector T cells home to infected tissues?

VLA-4

What is induced in shaping the effector CD4 T cell response?

Cytokines made during the innate immune response, tissue of origin of the activated dendritic cell and the nature of the pathogen.

In the lymph node, what is the primary role of macrophages?

Filter the lymph; macrophages remove pathogens and their breakdown products from the afferent lymph that drains sites of infection.

Circulating naive T cells gain access to lymph nodes through high endothelial venules (HEVS), which are located where?

The cortex

What is not required to activate a naive T cell?

CTLA4

What delivers the main signal leading to dendritic cell activation?

Toll-like receptors.

If DNA rearrangement occurs within the a-chain locus, then which of the following will occur?

The D-chain locus is permanently deleted from the chromosome

What is the reason why MHC molecules are able to bind to a variety of peptides?

A small number of amino acids in the peptide bind specifically to complementary pockets in the MHC molecules peptide-binding groove.

Which domains exhibit the highest degree of polymorphism between members of the HLA-B isotype?

a1 and a2

Other than the T-cell receptor, why is it important that the other components of the T-cell reeptor complex are invariant?

Polymorphisms in CD3y, d or e, or the s chain could compromise other components their ability to bind to and stabilize the T-cell receptor and transduce signals to the cell's interior.

What is directional selection?

A type of natural selection that replaces older alleles with newer variants; favors certain alleles at the expense of others.

What is interallelic conversion?

Mechanism of genetic recombination between two alleles of a gene in which a segment of one allele is replaced with the homologous segment from the other. This mechanism generates new HLA class I and class II alleles. It is also called segmental exchange.

What is balancing selection?

A type of evolutionary selection that acts to maintain a variety of phenotypes such as different variants of MHC molecules in a population

What is the responsibility of TAP?

This transporter moves peptides produced in the cytosol to the ER to be bound to MHC class 1 molecules.

What are the proteins associated with the MHC1 peptide-loading complex?

MHC class 1, B2-microglobulin, Calnexin, Tapasin, Calreticulin, ERp57.

What is the name of the enzyme responsible for trimming peptides that are "too long" for MHC class 1 molecules?

Enzyme endoplasmic reticulum aminopeptidase (ERAP)

How does Tapasin increase the affinity of peptides bound by MHC class 1?

This enzyme widens the peptide binding groove, reducing affinity, causing the release of most peptides; only peptides with the highest affinity persist.

True or false, TCR complexes undergo somatic hypermutation.

False

What are the enzymes involved in genetic recombination?

RAG 1 & 2, DNA-PK, Artemic, TdT

What is TREC and why is it important?

These are the DNA circles resulting from rearrangement which are a marker for T cells that have left the thymus.

What is the importance of the invariant chain for MHC class 2?

Since MHC class 2 is made in the ER, the chain binds to the groove of MHC 2 to prevent peptides from binding. It also delivers the MHC 2 molecules to the MHC 2 compartment (MIIC).

About how long do the MHC class 2 receptors last?

Days

What are the molecules associated with MHC class 2 peptide loading?

Invariant chain, Cathepsin S, CLIP, HLA-DM

What type of T cell is activated when bound to MHC 2?

CD4+ T cell

True or false, virtually all cells express MHC class 2.

False.

What are the cells MHC class 2 is restricted to?

Professional antigen presenting cells (APCs): B cells, macrophages, and dendritic cells; atypical APCs: mast cells, basophils, eosinophils, ILC3s.

Where are the genes key for antigen processing and presentation (including genetic information for TAP, tapasin, and proteasome components) located?

Human chromosome 6, within the MHC class 2 region.

Why is genetic diversity important for MHC isotypes?

Without it, pathogens could evade immunity by simply escaping MHC antigen presentation.

What is an allotype?

A protein coded by different forms of an allele

What is an allele?

Alternative forms of a gene.

What are the genes associated with antigen presentation for MHC class 1?

HLA-A, HLA-B, HLA-C

What are the genes associated with antigen presentation for MHC class 2?

HLA-DP, HLA-DQ, and HLA-DR

What are anchor residues? Where are they located?

They are a preference for certain amino acid sequences. They are located at positions 2 and 9 for MHC class 1.

What are superantigens?

Molecules that stimulates 2-20% of all T cells causing massive production of cytokines, systemic toxicity and suppression of adaptive immunity. (Kawasaki Disease?)

Where are y:d T cells primarily located?

Tissues, especially the gut.

What is EPCR and what is it involved with?

Endothelial protein C receptor is a ligand for Vd4:Vy5 T cells. This receptor is found on virally infected cells and tumors. It also binds phospholipids.

What cells recognize antigens presented by CD1D?

Vy:Vd1 T cells. They resemble MHC class 1 and are expressed by epithelial cells in tissue, dendritic cells, and monocytes. The antigen is a microbial lipid.

What provide the signals that switch on key genes that direct B-cell development?

The bone marrow; specifically E2A, the B-lineage specific transcription factor.

What stage(s) of B cell development does VDJ rearrangement occur for the heavy chain genes?

The first step of rearrangement begins in early pro-B cells and the final step of rearrangement in late pro-B cells.

What stage(s) does VJ rearrangement occur for light chain genes?

Rearrangement occurs in the small pre-B cell stage.

True or false, D to J rearrangements occur on BOTH alleles during heavy chain rearrangement on the pro-B cell.

True

What is the surrogate light chain and why is it important?

This complex is part of the pre-B cell receptor to test if a functional heavy chain was produced. It is made of the lamda (upside down Y) and VpreB proteins which are controlled by E2A and EBF.

What is Pax-5?

B-cell specific transcription factor that opens and closes chromatin to allow transcription.

What is the importance of Bruton's tyrosine kinase (Btk)?

It is critical for B cell development and survival of immature B cells in the bone marrow.