MCDB 436 (9): T-cell Mediated Immunity

co-stimulatory molecules

- T-cell: CD28 - APCs: CD80/86 binding of CD28:80/86 = REQUIRED for activation of naive T cells

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

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

TNFa

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

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

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

pSMAC vs cSMAC

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

activated T cell

stimulates differentiation pathway of T cells

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

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

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

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

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

CCR7

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

CXCR5

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

trapping of naive T cells in lymphoid tissue

bind to DCs, activated through TcRs

sailyl-Lewis X with T- and B-lymphocytes

- at rest: lack expression - upon activation: strongly express s-LeX. bind to L-selectin

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)

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

CD69

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

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

Id2

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

group 2 ILCs

helminths -> epithelial cells -> TSLP + IL-33 + IL-25 -> ILC2 -> IL-13, IL-4, IL-5 for TH2

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

false