T-cell activation, costimulation, adhesion & polarization

draining lymph node

antigen taken up in tissue (skin for Langerhans cells) —> enter the lymphatic system

mature DC enters lymph node from infected tissue & transfers antigen to resident DC —> B7-positive DC stimulates naive T-cells

blood DC go to spleen

mucosa DC to mucosa associated lymphoid tissue

acquisition of cytokine receptors to travel to lymph node

stop antigen uptake ( no MHC recycling)

increase B7

in the lymph nodes

after initial activation for some days & then emigration of antigen-specific T-cells from the draining lymph node

• migration of naive T-cell to lymph node mediated by S1P (sphingosine-1-phosphate) binding to S1PR1 on naive T-cells

• in lymph node recognition of DC /self-antigen: MHC) leads to activation signal —> increase in CD69 expression inhibits S1PR1 (one of the earliest changes)

• leads to trapping during initial activation

• CD69 transiently expressed —>disappears after some days allowing the emigration of T-cells

CD69 is a target for auto-immune diseases to change migration activity

need tight interaction between T-cell & APC

LFA-1 interacts with ICAM-1 0r ICAM-2 on APC

CD2 interacts with CD58

1. signal 1 Activation —> given by TCR for initial activation (with coreceptor CD4/CD8)

2. Signal 2 Survival —> costimulation CD28/B7 (CD80 or CD86) from same APC

3. Signal 3 Differentiation —> by cytokines produced by the APC

signal 1+2 sufficient for proliferation

signal 1 alone leads to activation-induced cell death

contact zone T-cell & DC

SMAC = supramolecular adhesion complex (central cSMAC & peripheral pSMAC)

pSMAC: LFA1-1:ICAM-1

cSMAC: TCR, CD4, CD28, peptide:MHC, CD8 (all signaling molecules)

T-cell initially binds APC through low-affinity LFA1:ICAM-1 interaction

subsequent binding of TCR signals LFA-1

conformational changes in LFA-1 increases affinity & prolongs cell-cell contact

—>inside/outside signaling

induced by IL-2/IL-2R

naive T-cell: IL-2R with γß chain (moderate activity)

activated T-cell: IL-2R with γß & α (CD25) chain —> high affinity

early induction of CD69 & α chain of IL-2R to allow high interaction

—>activation of 1 clone not enough to fight pathogens

massive T-cell proliferation due to the production of GF IL-2

APC stimulates effector CD4 T-cel to induce expression of CD40L & IL-2

—>cross-talk professional APC & CD4+ T-cell

partially mature T-cell terminates maturation of DC by interaction CD40 & CD40L

fully activated APC increases expression of co-stimulatory factors B7 & 4-1BBL

(costimulatory receptor/ligand pair not always in Ig-superfamily —>here TNF superfamily)

other molecules participate in signal 2

—>most CD8 T-cell responses require CD4 T-cells

also production of IL-2 driving CD8 T-cell proliferation

not limited to CD28/B7 interaction (CD28 superfamily part of Ig-superfamily)

CD28 constitutive at cell surface & in competition with inhibitory receptor CTLA-4 (same ligand)

receptor costimulatory or inhibitory (ITIM domain)

inhibitory receptors expressed after activation —> competition —> immune response needs to be shut off after some time to avoid unlimited T-cell proliferation

—> T-cell alive but less able to mediate effector functions

CTLA-4 & PD-1 key targets for tumor-immunotherapy (persistent tumor) —> can cure solid tumors (immune checkpoint blockade)

inhibitory ligands expressed by some tumor cells to escape immune system

TNF superfamily numbered or initial names

trimers at the cell surface, some processed to be secreted

costimulatory pairs:

CD70-CD27

4-1BLL - 4-1BB

OX40L - OX40

GITRL - GITR

BAFF - BCMA / BAFFR

other important TNF-receptors: TRAIL-receptor & Fas (proapoptotic death domain), CD40

L-selectin (adhesion molecule) for extravasation of blood cells to SLO on inactivated but not active (should go to infected tissue)

increase of adhesion molecules on T-cell for tight binding to APC: VLA4, LFA-1, CD2, CD44

no changes in expression of TCR & coreceptor CD4

CD45 changes from CD45RA (rested) to CD45RO (active) —>RO associates with TCR & CD4 (splicing variant)

break in T-cell activation (ITIM motif in cytoplasmic tail)

stops proliferation

higher affinity of CTLA-4 for B7 than CD28 —>delivery of inhibitory signals

CTL recognizes & binds virus-infected cell —>programs target for death (DNA fragmentation) —>migrates to new target & target cell dies of apoptosis

—> serial killer

protected from its killing machinery (perforin forms pores & granzyme starts apoptotic pathway)

—>expression of GZ inhibitor serpin —> allows killing of many target cells by 1 T-cell

granzyme & perforin in granules & released into immunological synapse

polarized secretion towards target cell

targets mitochondria & nucleus

engagement of TCR by peptide: MHC complex causes directed release of perforin & granzyme complexed with serglycin

serglycin maintains their inactive form, due to pH changes released from serglycin —> active outside the cell

granzyme B delivered into the cytosol of infected cells via pores formed by perforin —> targets BID & procaspase 3 —>cleavage

truncated BID disrupts mitochondrial outer membrane —> release of cytochrome C into cytoplasm & activation of apoptosis

active caspase 3 cleaved ICAD releasing caspase —> activated DNase CAD induces DNA fragmentation (DNA ladder in gel visible)

secreted proteins acting at distance with pleiotropic functions (1 cytokine has many functions)

homodimer: receptors for erythropoietin & growth hormone (hematopoietic factor)

heterodimer with common chain: common ß-chain (receptors for IL-3,-5 & GM-CSF)

common γ-chain (receptors for Il-2,-4,-7,-9,-15,-12)

heterodimer without common chain: Ig superfamily, IL-1 family receptors & IFN receptors & IL-13

TNF-receptor family: trimeric for CD40, FAS, CD30, CD27 (ligand also trimeric)

chemokine receptor family: monomer for CCR1-10, CXCR1-5, CX3CR1

cytokine receptor with at least tow chains —> cytoplasmic domains bind Janus kinases JAKs

cytokine binding dimerizes the receptor & brings together cytoplasmic JAK —> activate each other (auto-phosphorylation) & phosphorylation receptor

STAT (signal transducer & activators of transcription) bind phosphorylated receptors with SH2 domain (binds phosphorylated tyrosine)

STAT gets phosphorylated & forms dimers that translocate into the nucleus & initiate gene transcription

four JAK: JAK1-4

7 STAT: specificity via SH” domain for phosphorylated JAK ( don’t interact with all JAK)

IFNγ-STAT1 specific for IFNγ signaling

IL-4 STAT6

also STAT heterodimers induced

suppressor of cytokine signaling SOCS (contains SH2 & competes with STAT —> degradation of the receptor)

phosphatase CD45, SHP (also in NK-cell activation) removed phosphorylation from JAK

Th1 cells

secretes IFNγ

Th2

secretes IL-4, IL-5 & IL-13

Th17

secretes IL-17 & IL-22

Tfh

secretes IL-21

iTreg

secretes TGFß & IL-10

regulatory immunosupressive effect

high denisty of microbial organisms (microbiota) in intestine—> important metabolic functions but also potential threats (some opportunistic pathogens)

adaptive to restrain untoward inflammation directed against microbiota while retaining capacity to mount a host-protective immune response should barrier breach occurs

balance between Th17 & iTreg determined by production of vitamine A metabolite all-trans reinoic acid & production of the pro-inflammatory IL-6

homeostasis: antigens from microbiota presented by a specialized subset of DC producing at-RA but not IL-6

when antigens recognized in context of TLR-stimulating signals, at-RA production decreased & increase IL-6 —> Th17

T-bet

GATA-3

RORγT

Bcl-6

FoxP3

against intracellular pathogens in phagocytes

activates macrophages

against large pathogens that cannot be internalized

eosinophil, mast cell, basophil

against extracellular bacteria

neutrophils

differentiation of B-cells into plasma cells (isotype switching & affinity maturation)

suppress immune response (lack of T-cell activation)

germinal center response

produced by Th1, Tfh, CTL & NK

inhibits Th2 & Th17 cell differentiation

activation of macrophages —> increase of MHCI & II (also on DC)

produced by naive T cells, Th1, some CD8 T-cells

T-cell growth & differentiation

stimulates NK cell growth

produced by Th2 & Tfh

activates B-cells, growth & IgE /IgG

produced by Th2

increased eosinophil growth & differentiation

produced by Th2

increased production of mucus (goblet cells)

produced by Th17

indirect stimulation of neutrophil recruitment

stimulates fibroblasts & epithelial cells to secrete chemokines

produced by Th17

stimulates mucosal epithelium & skin to produce antimicrobial peptides

produced by Th17

Th17 & iTreg differentiation

inhibits Th1 & Th2

produced by Treg & Th2

increased MHCII on B-cells

inhibits inflammatory cytokine release from macrophages

BALB/c mice infected with Leishmania major —> with or w/o treatment of Ab blocking IL-4

untreated mice develop Th2 response & fail to cure infection —> die

mice treated with anti-IL4-AB develop Th1 response & eliminate the parasite

BALB/c prone for Th2 polarization & C57BI/6 for Th1

->Th2 response not helpful against the intracellular pathogen (requires Th1 response)

-> development of CD4 T-cell subsets can be manipulated by altering the cytokine acting during the early stages of infection