MCDB 436 (9): T-cell Mediated Immunity

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co-stimulatory molecules

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1

co-stimulatory molecules

  • T-cell: CD28

  • APCs: CD80/86

binding of CD28:80/86 = REQUIRED for activation of naive T cells

<ul><li><p>T-cell: CD28</p></li><li><p>APCs: CD80/86</p></li></ul><p>binding of CD28:80/86 = REQUIRED for activation of naive T cells</p>
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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

<ul><li><p>MHCII:TCR + co-stimulator = activated T cell</p></li><li><p>MHCII:TCR without co-stim = anergic</p></li><li><p>co-stim without MHCII:TCR = no effect</p></li></ul>
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peripheral tolerance

T cell interacts with APC with only MHCII, no co-stim molecules

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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

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____ and ____ activate vascular endothelium

IL-1b :: TNFa

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_____ stimulates dendritic cell migration to lymph nodes and maturation

TNFa

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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

<p>produce abundant type I IFNs, may act as helper cells for Ag presentation by conventional dendritic cells</p><ul><li><p>express TLR7&amp;9, RLR, type I IFNs</p></li><li><p>not thought to be involved in ag-specific activation of naive T cells but rather early viral infection sentinels</p></li></ul>
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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

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TLR signaling effect on conventional DCs

  • induce CCR7 (chemokine receptor)

  • increase processing of Ags taken up into phagosomes

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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)

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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

<p>between T cells and APCs (CD4/MHCII and CD8/MHCI)</p><ul><li><p>LFA-1 on T cell, ICAM-1 on APC</p></li><li><p>ensures the T cell doesn&apos;t bind too strongly</p></li></ul>
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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

<p>area of contact b/t T cell and APC; aka supramolecular activation complex (SMAC)</p><ul><li><p>outer (pSCMAC) + inner (cSMAC)</p></li></ul><p>provides structure for directed secretion of T cell cytokines</p>
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pSMAC vs cSMAC

pSMAC - enriched for LFA-1 and talin (cytoskeletal protein) cSMAC - higher levels of TcR, CD4/CD8, CD28, CD2, PKC-e

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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

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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

<p>induces expression of IL-2 and IL-2R</p><ul><li><p>activated T cell has alpha chain, whereas naive T cell just has beta and gamma</p></li><li><p>IL-2 comes from T cells themselves; therefore, autocrine process</p></li></ul>
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activated T cell

stimulates differentiation pathway of T cells

<p>stimulates differentiation pathway of T cells</p>
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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

<p>progenitor -&gt; large # of lymphoctes -&gt; removal of self-reactive immature lymphocytes by clonal deletion (thymus for T, bone marrow for B) -&gt; pool of mature naive lymphocytes -&gt; proliferation + differentiation of activated specific lymphocytes form a clone of effector cells</p>
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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

true

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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

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CTLA-4

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

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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

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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

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23

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

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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

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25

CCR7

binds CCL21/19; on B, T, and DCs

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CXCR5

binds CXCL13 (from FDC); on B cells

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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

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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

<ul><li><p>T cells lose their ability to exit from the node and become activated to proliferate and differentiate into effector T cells</p></li><li><p>after several days: regain expression of receptors to exit node</p></li></ul>
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trapping of naive T cells in lymphoid tissue

bind to DCs, activated through TcRs

<p>bind to DCs, activated through TcRs</p>
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30

sailyl-Lewis X with T- and B-lymphocytes

  • at rest: lack expression

  • upon activation: strongly express s-LeX. bind to L-selectin

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L-selectin

expressed on naive T cells; binds to sulfated s-LeX moieties on vascular addressins

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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

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33

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)

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34

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)

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35

S1PR1

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

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CD69

T cell activation marker

  • inc CD69 = dec S1PR1 (activating)

  • dec CD69 = inc S1PR1 (effector or naive)

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37

polarizing mileu

effect of external factors on naive CD4+ T cell differentiation

  • environment, infection, hygiene, nutrition, epigenetics, genetics, etc.

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38

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

<ul><li><p>fate-specifying cytokines: IFN-gamma, IL-12, and receive from ILC1</p></li><li><p>produce: IFN-gamma</p></li><li><p>regulate: TFH cell pathway</p></li></ul><p>effect: macrophage activation, inflammation, opsonizing IgG isotypes effect onto: macrophages -&gt; kill dead intracellular bacteria</p>
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39

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

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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

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TFH cells

  • fate-specifying cytokines: IL-6

  • produce: IL-21

effect: germinal centre help effect onto: B cell -> isotype switching, affinity maturation

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42

induced Treg cells

  • fate-specifying cytokines: TGF-beta, IL-2

  • produce: TGF-beta, IL-10

effect: regulation, suppression of inflammatory responses

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43

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

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44

Id2

transcription factor in the common lymphocyte progenitor (CLP) required for the development of all ILCs

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45

group 1 ILCs

intracellular bacteria + viruses -> IL-12 -> ILC1 + NK -> IFN-gamma

for TH1

<p>intracellular bacteria + viruses -&gt; IL-12 -&gt; ILC1 + NK -&gt; IFN-gamma</p><p>for TH1</p>
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group 2 ILCs

helminths -> epithelial cells -> TSLP + IL-33 + IL-25 -> ILC2 -> IL-13, IL-4, IL-5

for TH2

<p>helminths -&gt; epithelial cells -&gt; TSLP + IL-33 + IL-25 -&gt; ILC2 -&gt; IL-13, IL-4, IL-5</p><p>for TH2</p>
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group 3 ILCs

intracellular bacteria -> IL-23 -> ILC3 -> IL17, IL-22

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48

ILC-cytokine inducing responses

  • MAMPs by different types of microorganisms (direct/indirect)

  • DAMPS

  • cytokine signals from other cells

  • environmental signals (pollutants, etc)

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49

CD4 effector T cell help

enhance effector functions - innate, isotype switching, etc

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thymic stromal lymphopoietin (TSLP)

produced in response to helminths; alarmins

  • cytokines primarily produced by epithelial cells that sense molecular patterns of helminths (chitin)

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51

T/F: ILCs require priming and differentiation to acquire effector functions

false

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