MICR2221 Dendritic cells and initiation of adaptive immunity

role of dendritic (DC) cells

capture and present antigens to activate naive T cells

what immune response are DC and T cells part of

adaptive

where are immature DC cells found

mostly in periphery (e.g. skin and mucosa)

(in all tissues but conc where infections first start)

ability of immature vs mature DC cells

efficient antigen capture/uptake vs ineff

ineff presentation and costimulation vs eff

where do mature DC cells migrate to

secondary lymphoid organs

3 methods DCs sample a wide array of material in environment

macropinocytosis

phagocytosis

receptor mediated endocytosis

what is macropinocytosis

formation of large vesicles from plasma memb, req formation of ruffles on cell surface

what environmental sampling method of DCs is nonspecific

macropinocytosis

in what DC cell is macropinocytosis constitutive/always occur

immature DC cells

types of receptors on DC surface

(used for phagocytosis and recep med endocytosis)

C-type lectins

Fc receptors

Scavenger receptors

Receptors for Hsp

what are the C-type lectin receptors and what do they recognise

mannose receptor and DEC205

recognit glycosylated proteins

what are the Fc receptors on DCs and what do they recognise

FC gamma R1 and Fc epsilon R1

bind Fc of IgG and IgE

what scavenger receptor is on DCs

CD36

binds apoptotic bodies

what binds Hsp receptor on DC cell surface

Hsp70 and gp96

from tumour or infected cells

what is phagocytosis

receptor mediated uptake of large particulate species (bact, yeast, fungi, apoptotic bodies, necrotic bodies)

what are danger singnals and what do they trigger

maturation signals that trigger DC maturation

two types of danger signals that trigger DC maturation

direct

indirect

what are direct danger signals and what receptors recognit them

mols assoc with infection e.g. cell wall components, lipoproteins, dsRNA, flagellin

recognit by toll-like receptors (TLRs)

what are indirect signals and what do they trigger

pathogens or responses to tissue damage (e.g. tumour necrosis factor alpha, interleukin 1 beta, prostaglandin E2)

trigger molecule secretion

what does toll-like receptor (TLR) simulation cause

immediate, transient increase in macropinocytosis for 1 hr

why is the increase in macropinocytosis due to TLR stim only transient

DC stops sampling as it switches/matures to antigen presentation mode

where are inactive T-cells concentrated

secondary lymphoid tissues e.g. lymph nodes

migratory route of DC cells to the secondary lymphoid structures e.g. lymph nodes

epidermis to dermis to afferent lymphatic vessels to lymph nodes where interact with T-cells

what simulates DC migration from the epidermis to lymph nodes (secondary lymphoid tissue)

danger signal stimulation

what are langerhans cells

type of dendritic cell

what do immature langerhans cells interact with in epidermis layer and how

keratinocytes via E-cadherin (anchoring mol)

what is E-cadherin

an anchoring mol that langerhans cells use to hold on to keratinocytes

what does maturation of langerhans cells cause

decreased exp of E-cadherin

increased exp of chemokine receptor 7 (CCR7) enabling homing to lymph nodes

what does decreased expression of E-cadherin in langerhans cells cause

detachment from keratinocytes

what does increased expression of chemokine receptor 7 enable

homing of langerhans cells to lymph nodes

how is the migration of langerhans cells directed towards the lymph nodes

follow conc grad of chemokine receptor 7 ligands (CCL21 and CCL19)

what are CCL21 and CCL19

chemokine receptor 7 ligands

what cells exp CCL21

endothelial cells of lymphatic vessels

what cells exp CCL19

stromal cells in the T cell zone of lymph nodes

where does CCL21 and 19 binding to chemokine receptor 7 direct langerhans cell migration

to lymphatic vessels and then to lymph nodes

two types of t cell

cytotoxic t cell (CD8) and Helper T cell (CD4)

what are the only cells that can activate naive T cells

dendritic cells

what MHC class proteins do CD8 t cells bind

MHC class I

what MHC class do CD4 t cells recognise

MHC class II

what is MIIC

MHC class II compartment (specialised endosome)

MHC class II antigen presentation pathway

antigen capture/endocytosis into MIIC where proteolysis

MHC class II delivered to MIIC via ER and Golgi, where invariant chain degredation to enable it to bind antigen fragment, deliver and pres on cell surface

MHC class II regulation state that switches off antigen presentation in immature DCs

low activity vacuolar proton pump (high lyso/endo pH)

high levels of cystatin C prevs cleavage of Invariable chain by cathepsin S

Cell surface MHC class II rapidly endocytosed

all result in low protease activity for antigen and I chain proteolysis

MHC class II regulation state that switches on antigen presentation in mature DCs

high activity vacuolar proton pump (low lyso/endo pH)

low levels of cystatin C so cleavage of Invariable chain by cathepsin S

limited MHC class II endocytosis

all result in high protease activity for antigen and I chain proteolysis

what is the MHC class II pathway for

recognising and presenting antigens from outside of the cell/extracellular fluid

what is the MHC class I pathway for

recognising and presenting antigens from inside the cell

explain MHC class I pathway

antigens processed by 26s proteasome in cyto and transloc into ER via TAP (transporter assoc with antigen processing)

In ER get transl, fold, bind antigen frag, transloc to golgi, to p memb where present

How does the activity of the MHC class I pathway in DCs differ from MHC class II in immature DCs

Class II has little activity in immature, but moderate class I pathway activity

why is moderate MHC class I activity needed in immature DCs

would be very suseptible to infection if no adaptive defence

but still want to mature to increase ability (mature have increased exp of MHC class I and II)

what is cross presentation

DCs pres extracellular antigens on MHC class I to T cells

unique to DCs

important for initiation of adaptive immunity espec against virus

some virus dont enter DCs but do other cells, so if dont enter then there would be no way to init mature of DCs and some presentation

what do mature DCs have increased ability to do other than present antigens

release co-stimulatory mols B7.1 and B7.2

(co-stimulation)

what are co stimulatory mols needed for

t cell activation, cant activate naive T cells with only antigen recognit