First Aid, Chapter 2 Cells Involved in Immune Responses, Lymphocytes Flashcards
What are the 3 types of lymphocytes?
B cells, T cells, and NK cells
What are the general roles of helper T lymphocytes (CD4+ Th)? What are the markers?
Stimulate B-cell growth; secrete cytokines to activate macrophages; MHCII-restricted; markers CD3+/CD4+/CD8–.
What are the major CD4+ families?
Th1, Th2, Th17, Th9, Tfh, Treg
What are Th1 cells induced by? What do they produce? What are the transcription factors? What is the major function? What do they express? What diseases are they associated with?
Induced by: IL-12, IL-27, IL-18 Produce: IFNy, IL-2, TNF Transcription factors: Tbet, STAT4, STAT1 Major function: Intracellular defense Express: CXCR3, CCR5 Associated with: DM type 1, MS
What are Th2 cells induced by? What do they produce? What are the transcription factors? What is the major function?
Induced by: IL-4, IL-25, IL-33, TSLP
Produce: IL-4, 5, 13; IL-6, 10, 21, 25, 31, 33
Transcription factors; GATA3, STAT6, STAT5
Major function: humoral immunity, antiparasitic, allergy
What are Th17 cells induced by? What do they produce? What are the transcription factors? What is the major function? What do they express? What diseases are they associated with?
Induced by: IL-6, IL-1, 21, 23, TGFB
Produce: IL-17, IL-1, 6, 21, 22, TNFa, GM-CSF
Transcription factors: RORyT, STAT3
Major function: Extracellular defense; neutrophil recruitment; autoimmunit
Express: CCR6
Associated with: RA, IBD, MS, and psoriasis
What are Treg cells induced by? What do they produce? What are the transcription factors? What is the major function? What are the 2 Treg subsets? What do they produce to suppress other T cells?
Induced by: TGFB and retinoic acid
Produce: IL-10, TGFB
Transcription factors; FOXP3, STAT5
Major function: Immunosuppression, prevents autoimmunity
Subsets: natural Tregs, Induced Tregs
Do not make IL-2, use cytotoxic T-lymphocyte antigen 4 (CTLA4) to suppress other T cells
What are Th9 cells induced by? What do they produce? What is required for their differentiation?
Induced by: transforming growth factor beta (TGFB) and IL-4
Produce: IL-9 +/- IL-4
Require IRF4 and PU.1 for differentiation
Where are Tfh (follicular helper T cells) located? What is their role? What is it mediated by? What does it produce?
- Located in the follicles of active germinal centers.
- Play a major role in helping B cells make antibodies.
- Mediated by transcription factor Bcl-6 (which causes downregulation of CCR7 and upregulation of CXCR5)
- Produce IL-21.
Where are natural Tregs derived? What are they developed in response to? What do they express? What is their function?
Thymically derived and develop in response to thymically presented autologous antigens Constitutively express IL-2-Rα(CD25+) FOXP3+ Mediate self-tolerance
Where are induced Tregs derived? What are they developed in response to? What do they express? What types of cells do they include?
Peripherally derived and develop in response to peripherally expressed self-antigens and external antigens Inducible IL-2–Rα(CD25) expression Include: Tr1(produce IL-10; involved in mechanism of immunotherapy), Th3 (produce TGFβ; in gut; important in IgA production)
How do cytolytic T lymphocytes (CTLs and CD8) kill virally infectedcells and tumor cells? What do they express? What pathogenesis are they involved in? What do they use as a transcription factor? What markers do they have?
Kill viral-infected cells and tumor cells via perforin and granzyme; express IFN, TNF, and lymphotoxin; harder to activate than CD4s; involved in allograft rejection; use eomesodermin homologs (EOMES) as a transcription factor; MHCIrestricted; markers CD3+/CD8+/CD4–.
Where to γδ T cells develop? Do they have a large diversity? What do they bind? What are the markers and chains required for signal transduction? Are they MHC restricted? What do they produce?
γδ T cells: These cells use γ and δ chains (instead of α and β chains); they develop in the thymus and have limited diversity; they can bind lipids and heat shock proteins; they are not associated with CD4 or CD8, but do require CD3 and the zeta chain for signal transduction; they do not recognize MHCassociated peptides and are not MHC-restricted; produce IFNy and TNF.
What cells do NK cells kill? How do they know to kill them?
They kill viral-infected cells and tumor cells (due to these cells losing MHCI and gaining danger receptors).
What cytokine is important for NK cell development?
IL-15
What are markers on NK cells?
Markers include: CD16+ (FCRIII), CD56+ (NCAM), natural cytotoxicity receptors (NCRs), and killer inhibitory receptors (KIRs); do not express CD3.
What is NK cell killing mediated via?
NK cell killing is mediated via perforin, granzymes, serglycine, and Fas.
What do EBV-infected cells express to activate NK cells? What receptor does this bind on the NK cell?
EBV-infected cell expresses CD48 -> binds 2B4 receptor on NK cell
What do stressed cells express that activate NK cells? What do they bind on NK cells?
Stressed cell expresses MICA/B, ULBP -> binds NKG2D on NK cell
What do viral hemagglutinin bind to on NK cells? Does this activate or inhibit NK cells?
Viral hemagglutinin on target cell -> binds NKp44/46 on NK cell
What does HLA-E bind to to activate NK cells? What does it bind to to inhibit NK cells?
Activation: HLA-E -> binds NKG2C on NK cell
Inhibition: HLA-E -> binds NKG2A/B
What do IgG-bound target cells bind to on NK cells? Does this activate or inhibit them?
IgG-bound target cell -> binds FcyRIIIA on NK cell (ADCC)
Activates killing
Which cytokines induce development of Th17 cells?
IL-6, TGFβ, IL-1, IL-21, and IL-23
How are B and T cells segregrated in the lymph? WHat do they bind to cause this segregration?
Anatomic segregation of B and T cells:
- T-cell zone (parafollicular zone) -> T cell expresses CCR7, which binds CCL19/21 in the T cell/parafollicular zone (as the concentration/gradient of CCL19/21 is highest there).
- B-cell zone (follicles) -> B cell expresses CXCR5, which binds CXCL13 in the B-cell zone/follicles (as the concentration/gradient of CXCL13 is highest there).
What cytokine is present in high levels during early maturation of B and T lymphocytes? What is deficiency of this cytokine associated with?
Maturation of B and T lymphocytes is characterized early on by high levels of IL7 (lack of this cytokine can lead to X-Linked severe combined immunodeficiency disease [SCID])
What does positive selection insure during maturation of T cells?
That an individual’s T cells can respond to peptides bound to his/her own MHC molecules.
What sequences do VDJ recombinase recognize? Where are these sequences located?
It recognizes DNA sequences called recombination signal sequences (RSS); recombination occurs between two gene segments (immunoglobulin or TCR) only if one of the segments is flanked by one 12-nucleotide spacer and by one 23-nucleotide spacer -> 12/23 rule.
In what cells is RAG1/RAG2 expressed? What does it do?
Expressed in immature lymphocytes (i.e., when antigen receptors are being assembled); cleaves double-stranded DNA between the coding segment and its recombination signal sequence.
What does Ku do?
Binds DNA ends (hairpin in the case of the coding segment)
What do DNA-PK (DNA-dependent protein kinase complex) and Artemis do?
Open DNA hairpin at a random site
What does terminal deoxynucleotidyl transferase (TdT) do?
Adds nucleotides for junctional diversity (creates the greatest variability for diversity)
What does endonuclease do?
Removes nucleotides for junctional diversity.
What does DNA ligase IV:XRCC4 do?
Ligates DNA
What markers are present in the pro B cell stage? What rearrangement occurs during this stage?
CD 19+, CD20+; Heavychain D-J then V-DJ rearrange ment
What is produced in the pre B cell stage? What signalling and rearrangement occur?
Cytoplasmic µ chain produced here; signaling through pre-B–cell receptor and then light-chain V-J rearrangement.
What occurs in the immature naive B cell stage?
Light-chain product (κ or λ) binds μ heavy chain to make IgM; receptor editing occurs
What chains are expressed in the mature naive B cell? Via what process? What is expressed on the cell surface?
Express δ heavy chain (as well as μ) via alternative splicing so that IgM and IgD are expressed on the cell surface
What occurs during the memory B cell and plasma cell stages? What type of mutations?
Memory cell: Isotype switch and somatic hypermutation occurs
Plasma cell: Alternative splicing yields membrane and secreted Ig
Flash
At which stage does signaling through the pre-B–cell receptor occur?
Pre B Cell
What does alternative splicing yield?
membrane versus secretory Ig
What does differential splicing produce?
Differential splicing produces different immunoglobulin isotypes. IgD is the only Ig without a switch region; so, class switching will never apply to it
What molecules, if absent, will not allow class switching? What disease occurs?
o AID, UNG, CD40, CD40L -> if lacking, cannot class switch -> Ig gets ‘stuck’ at IgM -> Hyper IgM phenotype ensues.
What transcription factors are associated with commitment to the B cell?
Transcription Factors associated with commitment to the B cell include: PU.1, IKAROS, E2A, EBF, PAX5, and IRF8.
What signals does B cell survival in the periphery depend on?
B-cell survival in the periphery depends on survival signals such as BLYSS, BAFF, and APRIL.
What are the receptors on B cell for BLYSS, BAFF, and APRIL? Absence of which one is a risk factor for what disease?
BR3 and TACI (early on) and BCMA (later on). No TACI -> CVID risk factor
What are the 3 types of mature B cells?
B1 cells, Marginal zone B cells, and B2 cells (conventional B cells or follicular B cells).
What immune system are B1 cells categorized in? How much diversity is there? What cells are they analagous to? What percent of total B lymphocytes do they make up? What do they produce? What do they respond to? Where are they found? Are they T cell dependent?
Innate; limited diversity; analogous to γδ cells; make up 5–10% of total B lymphocytes; self-renewing; produce natural antibodies (low-affinity polyreactive immunoglobulins) that respond to microbes and lipids; found in peritoneal cavity and fetus; T-cell-independent.
When are marginal zone B cells developed by? How quickly do they respond to antigens? Are they T cell dependent?
Developed by 2 years of age (which explains why infants have poor polysaccharide responses); first responders (especially to polysaccharide antigens); T–cell-independent.
What cell types are included in B2 cells? What category of the immune system to they fall into? What do they respond to? Are they T cell dependent?
B2 cells (conventional B cells or follicular B cells): includes memory B cells and plasma cells; adaptive; respond to protein antigens; T–cell-dependent.
Where are immature T cells located? What do they express? Where do they go when they undergo positive selection? Where do they go when they undergo negative selection?
When T cells are immature (DN; CD4–/CD8–), they are located in the subcapsular cortex. As they undergo positive selection, they move to the cortex. As they undergo negative selection, they move to the medulla.
How do T cells leave lymphoid organs? What do they do next? What types of cells do they form?
T cells leave lymphoid organs by expressing sphingosine-1-phosphate (S1P) receptors. They undergo activation, expansion, and differentiation. Then memory or effector T cells form central memory T cells or effector memory T cells.
What are the markers on central memory T cells and effector memory T cells.
Central memory T cells: CD45RA–, CD27+, CCR7+, CD62L+ (Lselectin).
Effector memory T cells: CD45RA–, CD27–, CCR7–, CD62L– (Lselectin)
Expression of what molecule commits T cells to develop?
Notch
Do double negative T cells express the TCR? What are the stages of DN T cell? What happens at each stage, and what B cell stage is it analagous to?
Does not express T-cell receptor; stages: DN1, DN2 (β chain D-J then V-DJ rearranges; analogous to pro B cell), DN3 (signaling through pre-T–cell receptor; analogous to pre B cell), and DN4 (proliferation)
What happens during the double positive stage of T cell maturation?
CD4+/CD8+; positive and negative selection occurs; α chain V-J rearranges
What do single-positive thymocytes undergo? And what do they become?
Cells undergo selection to become CD4+ or CD8+
Where does negative selection occur for T cells?
The medulla, which is also where the AIRE protein functions
What are the two types of lymphocyte apoptosis?
Passive/intrinsic and active/extrinsic.
What occurs in passive/intrinsic lymphocyte apoptosis? What pathways does it occur via? What is it mediated by?
Programmed death by neglect; mitochondrial pathways; mediated by caspase 9; bcl-2 and bcl-XL (antiapoptotic); bid/bim (proapoptotic).
What are the steps of the active/extrinsic pathway of lymphocyte apoptosis? What is it mediated by?
Repeated lymphocyte activation causes increased Fas (CD95)/FasL(CD178) expression, which causes increased Fas-associated protein with Death Domain (FADD); mediated by caspase 8.
What do both types of lymphocyte pathways converge on?
caspase 3
What are the most common mutations seen in autoimmune lymphoproliferative syndrome (ALPS)? What does this result in?
Mutations in Fas(CD95) are the most common defect seen in autoimmune lymphoproliferative syndrome (ALPS), which results in defective lymphocyte apoptosis.
