Adaptive Immunity Flashcards
Define adaptive immunity.
specific lymphocyte response to foreign antigen, which includes the development of immunological memory
What are the humoral and cellular mediators?
- humoral: antibodies
- cellular: lymphocytes
Define clonal selection.
process by which lymphocytes are activated and expanded by encounter with antigen that is specifically recognized by the TCR/BCR
What do CD4+ T cells do?
- helper T cells
- direct and facilitate adaptive and innate immune responses
- “director” of the adaptive immune response
What do CD8+ T cells do?
- cytotoxic T cells
- kill cells infected with intracellular pathogens
What do B cells do?
- produce antibodies
What are the steps for naive CD4+ T cell activation to effector T cell?
- APC presents MHC+peptide which is recognized by TCR
- co-stimulation by CD28-B7 interaction
- transcription factors are made, IL-2 is produced
- IL-2 acts on the secreting cell, initates T cell proliferation and effector functions
Describe the signaling cascade of naive CD4+ T cell activation.
- antigen peptide + MHC is recognized by TCR
- tyrosine phosphorylation of ITAMs on CD3 and zeta-chains
- ZAP-70 binds to zeta chains
- results in 3 cascades leading to transcription factors, all required for IL-2 production
- **NFAT **
- NF-kB
- AP-1
What happens when TCR signaling is blocked?
- IL-2 generation & T cell response inactivated
- CD4+ T cells will not provide T cell help
- CD8+ T cells will not kill intracellular pathogens
What do cyclosporin A (CsA) and FK-506 (tacrolimus) do?
- Immunosupressive Drugs: inhibit the activity of calcineurin
- direct: blocks activation of NFAT
- consequence: blocks synthesis of IL-2
What does Rapamycin (sirolimus) do?
- Immunosuppresive drug: inhibits signaling from IL-2 receptor
- Direct: blocks p70S6 kinase involved downstream of IL-2 signaling
- Consequence: blocks T cell proliferation and acquisition of effector functions
What is ZAP-70 deficiency? What is its molecular basis? Symptoms?
- autosomal recessive immunodeficiency disease, SCID
- lack of ZAP-70 results in complete lack of CD8+ T cells and CD4+ T cells are non functional
- Symptoms: frequent infections, failure to thrive
What is a mitogen? Examples?
substance that stimulates proliferation of T and B cells
ex. bacterial superantigens, mitogenic lectins, pharmacological activators
How do bacterial superantigens (sAG) work? What’s their clinical relevance?
- act as glue between TCR Vß region and non-polymorphic region of MHC protein
- TCR: specific Vß but any antigen specificity allowed
- MHC: Class II, any peptide allowed
- activate up to 1/5 of T cells in body, results in massive release of cytokines and moderate to severe illness
What are some examples of sAg? Symptoms?
- Toxic Shock Syndrome
- pathogen: Staphylococcus aureus superantigen (TSST-1)
- symptoms: hypotension, organ failure, fever
- S. aureus food poisoning
- pathogen: S. aureus enterotoxins (SEA, SEB, SEC, SED, SEE)
- symptoms: food poisoning effects
How do mitogenic lectins work? Examples? Usefulness?
- plant-derived carbohydrate-binding proteins that crosslink T cell surface receptors, mimicking antigen stimulation; does not require APCs
- examples:
- T Cells:
- concanavalin A (ConA)
- phytohemagglutinin (PHA)
- T & B Cells:
- pokeweed mitogen (PWM)
- T Cells:
- useful for in vitro T cell activation (funcitonal assays)
How do pharmacological stimulators work? Example? Usefulness?
- bypass TCR & APCs for T cell activation; activates transcription factors for IL-2 production
- phorbol myristate acetate (PMA) with ionomycin
- PMA: activates NF-kB and AP-1
- ionomycin: activates NFAT
- useful for in vitro T cell activation (funtional assays)
OVERVIEW:
How do antigen-specific CD4+ T cells find APCs presenting the appropriate stimulatory peptide+MHC & become activated?
- antigen is captured in lymphatic system via LNs or spleen
- naive T cells circulate between LNs and spleen searching for the antigen presented by APCs
- Signal 1: APC presenting correct MHC-II + peptide bind to CD4/TCR on the T helper cell
- Signal 2: Co-stimulation occurs via CD28 on T cell and **B7 **on APC
- signaling cascade results in IL-2 production
- T cells proliferate and become effector or memory cells in the periphery
- T cells look for their antigen presented in vascular endothelial cells via MHC-II and bind to those cells via **VFA-1 : VCAM-1 **interaction
- T cells move into periphery to site of inflammation
How do naive T cells gain entry into LNs/ spleen?
- naive T cell enter HEVs in LN, attach to endothelial cells & undergo diapedesis
- surface molecules
- naive T cells: L-selectin, LFA-1
- endothelial cells: GlyCAM-1/CD34,ICAM-1, (& cytokines on ECM)
How do activated effector/memory T cells gain entry to periphery?
- activated T cells exit LN in efferent lymph and collect in thoracic duct
- surface molecules: change so T cells can ciruclate between blood and sites of peripheral inflammation
- effector T cells: LFA-1,** VLA-4**, (Low L-selectin)
- vascular endothelial cell: ICAM-1, VCAM-1
What is the expression pattern of peripheral tissue endothelial adhesion molecules during an immune response?
- immediately: E-selectin, recruits neutrophils
- 24 hrs: ICAM-1, recruits monocytes
- 24-48 hrs: VCAM-1, recruits activated effector T cells
Compare naive (CD4+ and CD8+) T cells vs. activated T cells.
- naive T cells:
- migrate from blood to LNs
- High L-selectin : Glycam-1/CD34
- **LFA-1 **: ICAM-1
- activated T cells:
- migrate from blood to inflammed peripheral tissues
- High VFA-4 : VCAM-1
- **LFA-1 **: ICAM-1
What are the characteristics of a memory T cell?
- does not require co-stimulation for activation
- can turn into effector T cell in hours (must faster than primary response in naive T cells)
- long-lived
- gradually lost with age (i.e. shingles- varicella zoster virus)
What are two subsets of CD4+ TH cells?
- TH1
- TH2
What do TH1 cells do?
- provide help to macrophages & CD8+ T cells
- produce IFN-gamma and upregulate surface CD40L
- stimulates macrophages to kill intracellular bacteria
- stimulates CD8+ T cell activation via Pathway 3
What does IL-12 do? What induces its production?
- drives differentiation of naive CD4+ T cell to TH1 subtype along with IFN-gamma produced by NK cells
- produced by DCs and macs in response to viruses and some bacteria
What do TH2 cells do?
- provides help to B Cells
- produces IL-4, IL-5, IL-6 and upregulates surface CD40L
- stimulates B cell proliferation and differentiation to antibody-secreting plasma cells
- critical for immune response to certain parasites (i.e. worms) and responsible for immunpathologies such as allergies and asthma thru **Ig class switching **
How do TH1 and TH2 cells regulate each other?
- TH2 cells secrete TGF-ß and IL-10 which inhibit TH1 cells
- TH1 cells secrete IFN-gamma which inhibits proliferation of TH2 cells
How does T helper cell subtyping affect leprosy lesions?
- TH1 response: tuberculoid leprosy
- TH2 response: lepromatous leprosy
What are the possible steps for naive CD8+ T cell activation to effector TCTL?
- Pathway 1: directly stimulated by DCs in high inflammatory environment
- activated DCs have lots of B7, migrate to LNs
- DCs directly activate CD8+ T cell via MHC-I: TCR and B7: CD28
- Pathway 2: stimulated by DCs activated by CD4+ T cells
- activated DCs migrate to LN and activate CD4+ T cells via MHC-II: TCR and CD40: CD40L
- DCs become more activated and produce more B7 to activate CD8+ T cell
- Pathway 3: stimulated by IL-2 from CD4+ T cells activated by DCs
- CD4+ T cell is activated by DC to produce IL-2
- IL-2 binds to IL-2R on CD8+ T cell to activate it
What surface molecules do activated TCTLneed to kill infected target cells?
- ONLY CD8/TCR, no costimulation required
What are the ways activated TCTL kill target cells?
- release cytolytic granules into immunological synapse which leads to target cell apoptosis
- Fas-L on TCTL interacts with Fas on target cell to induce apoptosis
What is a T-dependent (TD) antigen?
any antigen with a protein component that can be presented by class II MHC
What are the steps for B cell activation by TD antigens (both initially and later with TH2 help)?
- B cells enter LNs or spleen and bind to native antigens via BCR (not processed peptides)
- BCR crosslinking by multivalent antigen (repeated epitopes)
signaling cascade –> transcription factors are made
B cell proliferation, autocrine cytokine secretion, and IgM secretion - BCR binds to antigen and internalizes it
- —continues w/ TH2 help—
- B cell presents antigen peptide via MHC-II and B7 co-stimulator to TH2 cell
- CD40L upregulation is induced in TH2 from specific antigen recognition, binds to CD40 on B cell
- cytokines IL-4, IL-5, IL-6 produced by TH2
- B cell differentiation:
- Ig class switching (non-IgM)
- affinity maturation (somatic hypermutation)
Describe the B cell co-receptor.
- structure: CD21 (CR2), CD19, CD81 (TAPA-1)
- binds to C3d opsonin on antigen
- functionally similar to CD4/CD8
- augments signals from BCR
Describe the signaling cascade of naive B cell activation.
- BCR crosslinking by multivalent antigen
- ITAMS on Ig-alpha and Ig-beta BCR are phosphorylated
- Syk kinase binds to Ig-alpha and Ig-beta
- results in 3 cascades leading to transcription factors, all required for B cell proliferation, autocrine cytokine secretion, and IgM secretion
- NFAT
- NF-kB
- AP-1
How is antibody isotype switching carried out?
- occurs in mature B cells in secondary lymphoid tissues w/ TH2 help
- specific isotypes stimulated by specific cytokines
- ex. IgA stimulated by IL-5
How is affinity maturation carried out?
- occurs in germinal centers in secondary lymphoid tissues
- B cells interact with TH2 cells, mature, and proliferate and undergo somatic hypermutation
- variable regions in Ig undergo random mutations
- mutated BCRs interact with follicular DCs bound to antigen
- high affinity B cells become antibody-secreting plasma and memory B cells
- low affinity B cells undergo apoptosis
What are the differences in primary and secondary antibody response to antigen?
- primary: no pre-formed antigen-specific B cells made
- significant lag time
- modest antibody titer
- secondary: memory B cells already made
- shorter response time
- higher antibody titer (particularly IgG)
What is an T-independent (TI) antigen?
- carbohydrate antigens that provoke an antibody response independent of CD4+ T cells
- cannot be presented by class II MHC, so T cells cannot respond to pure carbohydrate antigen
- ex. polysaccharide encapsulated bacteria
What are the steps for B cell activation by TI antigens?
- carried out by B-1 cells early in development
- express CD5
- BCR crosslinking by multivalent antigen (highly repetitive carbohydrate epitopes)
- strong signaling cascade –> transcription factors are made
- B cell proliferation, autocrine cytokine secretion, and IgM secretion
- NO T CELL HELP
- No Ig class switching (only IgM)
- No affinity maturation (low affinity Ab)
- No secondary response (no memory B cells)
What is the clinical relevance of TI B cell response?
- helpful for making vaccines to encapsulated bacteria
- conjugate TI carbohydrate Ag to TD “carrier” proteins which can be presented by MHC-II
- artificially adds T cell help to the response to provoke high-affinity, long-lasting IgG Ab response
- ex. *H. influenzae *vaccine
- splenectomized patients w/ B cell immunodeficiency are particularly vulnerable to TI pathogens
What is the distribution of antibody isotypes throughout the body?
- IgM: only in blood
- IgG & monomeric IgA: in blood and EC spaces
- dimeric IgA: mucosal spaces
- IgE: epithelial surfaces
How is IgA transported into mucosal spaces?
- IgA is transported across epithelial surfaces by **poly-Ig receptor **
- dimeric IgA taken from basolateral face of epithelial cell (mucosal side) thru poly-Ig receptor and transported accross the cell to apical face (lumen side)
- at apical face, receptor is cleaved and IgA is bound to mucus thru **secretory piece **
How is IgG transported and into what tissues?
- FcRB receptor
- across the **placenta **
- across endothelium into the extracellular spaces
What are the antibody effector functions?
- Ab bind to surface receptors on pathogens, prevent it from interacting with host cells
- Constant region of Ab bound to pathogen binds to Fc receptors on host cells, which induces phagocytosis of opsonized pathogen
- Fc-gamma, Fc-epsilon
What do Fc-gamma receptors do?
- bind to IgG constant regions
- found on macs
- promote phagocytosis and creation of phagolysosome
- found on NK cells
- promote release of lytic granules and cause apoptosis
What do Fc-epsilon receptors do?
- bind to IgE constant regions
- found on Mast cells
- triggers release of histamine
- causes asthma and allergy
- found on eosinophils
- triggers release of granules
- combats parasites
