MCDB 436 (9): T-cell Mediated Immunity

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co-stimulatory molecules
- T-cell: CD28 - APCs: CD80/86 binding of CD28:80/86 = REQUIRED for activation of naive T cells
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effects of co-stimulation/lack of on T cell
- MHCII:TCR + co-stimulator = activated T cell - MHCII:TCR without co-stim = anergic - co-stim without MHCII:TCR = no effect
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peripheral tolerance
T cell interacts with APC with only MHCII, no co-stim molecules
immature DCs
- round, smooth surface - more phagocytic - lower levels of CD80/86 - lower levels of MHC II - lower levels of cytokine secretion - IL-12, IL-10, TNFa
____ and ____ activate vascular endothelium
IL-1b :: TNFa
_____ stimulates dendritic cell migration to lymph nodes and maturation
plasmacytoid DCs
produce abundant type I IFNs, may act as helper cells for Ag presentation by conventional dendritic cells - express TLR7&9, RLR, type I IFNs - not thought to be involved in ag-specific activation of naive T cells but rather early viral infection sentinels
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conventional DCs
activated by MAMPs in peripheral tissues, where they encounter pathogens -> TLR signaling induces CCR7 expression AND enhances processing of pathogen-derived Ags resident: highly phagocytic, macropinocytic; do not express co-stimulatory molecules
TLR signaling effect on conventional DCs
- induce CCR7 (chemokine receptor) - increase processing of Ags taken up into phagosomes
CCR7 signaling
respond to CCL19 and CCL21, directing them to the draining lymphoid tissue -> CCL19 + 21 provide further maturation -> co-stimulatory CD80/86 + MHC -> conventional DCs activate naive T cells, no longer phagocytic -> express CD80 + 86, MHCI/II, adhesion molecules (LFA/ICAM)
transient adhesive interactions
between T cells and APCs (CD4/MHCII and CD8/MHCI) - LFA-1 on T cell, ICAM-1 on APC - ensures the T cell doesn't bind too strongly
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immunological synapse
area of contact b/t T cell and APC; aka supramolecular activation complex (SMAC) - outer (pSCMAC) + inner (cSMAC) provides structure for directed secretion of T cell cytokines
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pSMAC - enriched for LFA-1 and talin (cytoskeletal protein) cSMAC - higher levels of TcR, CD4/CD8, CD28, CD2, PKC-e
APC signals to naive T cells
deliver signals for clonal expansion and differentiation - for both CD4 and CD8 - differentiation results in generation of effector T cells (diff from naive T) - provide cytokines that induce naive CD4 into distinct subsets also
CD28-dependent co-stimulation of activated T cells
induces expression of IL-2 and IL-2R - activated T cell has alpha chain, whereas naive T cell just has beta and gamma - IL-2 comes from T cells themselves; therefore, autocrine process
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activated T cell
stimulates differentiation pathway of T cells
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lymphocyte clonal expansion
progenitor -> large # of lymphoctes -> removal of self-reactive immature lymphocytes by clonal deletion (thymus for T, bone marrow for B) -> pool of mature naive lymphocytes -> proliferation + differentiation of activated specific lymphocytes form a clone of effector cells
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T/F: once a T cell becomes an effector cell, encounter with its specific Ag results in immune effector functions without need for co-stim
APC cytokine secretion
APCs secrete cytokines that drive the differentiation of T cells into different subsets and effector functions - include APCs and innate immune cells - by environmental conditions - PRR-MAMP/DAMP binding
inhibitory co-receptor signal expressed after T-cell activation - structurally similar to CD28 but not the "gas pedal" - CTLA-4 binds to CD80/86 for inhibition - MUCH higher affinity than CD28
CTLA-4 effects
- decreases production of T-cell derived IL-2 - results in limiting proliferative response of activated T cell - shuts down activation of T cell
effector T cell
respond to target cells without costimulation naive T recognizes Ag on APC -> secretes and responds to IL-2 -> clonal expansion -> differentiation -> effector function for both CD4 and CD8
high endothelial venules (HEV)
specialized post-capillary venous swellings; cuboidal endothelial cells - enable lymphocytes circulating in blood to directly enter lymph node/secondary lymphoid tissues - found in all secondary lymphoid organs (except spleen) - tonsils, PIs, pharynx, etc - express receptors to interact with leukocytes; enable naive lymphocytes to move in and out of the lymph nodes from the circulatory system
recruitment of leukocytes in the development of secondary lymphoid organs
1) stromal cells + HEVs secrete CCL21 2) DCs have CCR7 to bind CCL21, migrate into developing lymph node 3) DCs secrete CCL19, attracting T cells with CCR7 to developing lymph node 4) B cells initially attracted by CCL19 also with CCR7 5) B cells induce differentiation of follicular dendritic cells (FDCs), secreting CXCL13 for attracting more B cells on CXCR5
binds CCL21/19; on B, T, and DCs
binds CXCL13 (from FDC); on B cells
if a T cell DOESN'T encounter its specific Ag in the lymph node...
they leave the lymph node through efferent lymphatics to return to the circulation to enter another secondary lymphoid organ
if a T cell DOES encounter its specific Ag in the lymph node...
- T cells lose their ability to exit from the node and become activated to proliferate and differentiate into effector T cells - after several days: regain expression of receptors to exit node
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trapping of naive T cells in lymphoid tissue
bind to DCs, activated through TcRs
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sailyl-Lewis X with T- and B-lymphocytes
- at rest: lack expression - upon activation: strongly express s-LeX. bind to L-selectin
expressed on naive T cells; binds to sulfated s-LeX moieties on vascular addressins
vascular addressins
CD34 - on HEV cells GlyCAM-1 - on HEVs MAdCAM-1 - on mucosal endothelium, guides lymphocytes to MALT use vascular addressins to get into HEV or mucosal endothelium
lymphocyte entering lymphoid tissue - process
1) circulating lymphocyte enters HEV 2) L-selectin to GlyCAM-1 + CD34 + sLeX, allowing rolling interaction 3) LFA-1 activated by CCR7 signaling in response to CCL21 bound 4) activated LFA-1 binds to ICAM-1 5) extravasation (encouraged by intracellular chemokine gradient)
sphingosine 1-phosphate (S1P)
bioactive lipid; establishes a gradient between lymphoid organ and circulatory fluids. allows exit of lymphocytes from lymphoid tissue - major source = hematopoietic cells, mostly erythrocytes - establish gradient through S1P degradation (erythrocytes die, no degrading enzyme) - lymphatic sys: source = lymph endothelial cells - LPP1 and LPP3 degrade; localized enzymes to plasma membrane, function as ecto-enzymes (degrade extracellularly)
expressed on naive T cells, responsive to S1P gradient - no Ag recog: S1PR1 promotes movement to efferent flow - Ag recog: decrease S1PR1 expression, retained in T-cell zone - effector T cells: re-express S1PR1
T cell activation marker - inc CD69 = dec S1PR1 (activating) - dec CD69 = inc S1PR1 (effector or naive)
polarizing mileu
effect of external factors on naive CD4+ T cell differentiation - environment, infection, hygiene, nutrition, epigenetics, genetics, etc.
TH1 cells
- fate-specifying cytokines: IFN-gamma, IL-12, and receive from ILC1 - produce: IFN-gamma - regulate: TFH cell pathway effect: macrophage activation, inflammation, opsonizing IgG isotypes effect onto: macrophages -> kill dead intracellular bacteria
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TH2 cells
- fate-specifying cytokines: IL-4, and receive from ILC2 (and IgE) - produce: IL-4, IL-5, IL-13 - regulate: TFH cell pathway effect: allergic and helminth responses effect onto: bone marrow -> eosinophil (IL-5), mast cell, basophil + (IL-13) goblet cell -> mucus
TH17 cells
- fate-specifying cytokines: TGF-beta, IL-6, IL-23, and receive from ILC3 - produce: IL-17, IL-22 effect: inflammation effect onto: - stromal cells -> G-CSF, chemokines -> neutrophils - epithelial cells -> AMPs -> neutrophils IL17 = proinflammatory cytokine; cascade effect IL-22 = acts on epithelial to produce AMPs
TFH cells
- fate-specifying cytokines: IL-6 - produce: IL-21 effect: germinal centre help effect onto: B cell -> isotype switching, affinity maturation
induced Treg cells
- fate-specifying cytokines: TGF-beta, IL-2 - produce: TGF-beta, IL-10 effect: regulation, suppression of inflammatory responses
innate lymphoid cells (ILC)
cells of lymphoid lineage which lack specific Ag receptors (no TcR/Ig) and lack co-receptor complexes - migrate from bone marrow and populate lymphoid tissues + peripheral organs - fewer in # than B/T
transcription factor in the common lymphocyte progenitor (CLP) required for the development of all ILCs
group 1 ILCs
intracellular bacteria + viruses -> IL-12 -> ILC1 + NK -> IFN-gamma for TH1
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group 2 ILCs
helminths -> epithelial cells -> TSLP + IL-33 + IL-25 -> ILC2 -> IL-13, IL-4, IL-5 for TH2
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group 3 ILCs
intracellular bacteria -> IL-23 -> ILC3 -> IL17, IL-22
ILC-cytokine inducing responses
- MAMPs by different types of microorganisms (direct/indirect) - DAMPS - cytokine signals from other cells - environmental signals (pollutants, etc)
CD4 effector T cell help
enhance effector functions - innate, isotype switching, etc
thymic stromal lymphopoietin (TSLP)
produced in response to helminths; alarmins - cytokines primarily produced by epithelial cells that sense molecular patterns of helminths (chitin)
T/F: ILCs require priming and differentiation to acquire effector functions