immunology ch 8 part two

T-cell activation/priming

naive T cell divides, proliferates, and differentiates into effector T cell following encounter with antigen

first stage of primary adaptive immune response

T-cell activation/priming

activated CD4 T cells

secrete cytokines, 5 subtypes

activated CD8 T cells

cytotoxic

antigen processing by DCs

1. receptor-mediated endocytosis of bacteria

2. macropinocytosis of bacteria or viruses

3. viral infection

4. cross-presentation of exogenous viral antigens

5. transfer of viral antigens from infected dendritic cell to resident dendritic cells

myeloid DCs take up antigens

at site of infection and travel to secondary lymphoid tissue

infections of the skin & other peripheral tissues

T cell response in draining lymph node

infections of blood

T cell response in spleen

infections of mucosal tissue

T cell response in mucosal secondary lymphoid tissues

immature DCs

in the skin and peripheral tissues

DCs change

as they transport antigens

TLRs signal

to change gene expression patterns by morphology, cell surface molecules, function

mature/activated DCs

those that have changed as described above and now found in secondary lymphoid tissue

HEV

high endothelial venule

T cell entry into lymph node

blood, through HEV and move to T cell area/zone

from afferent lymph vessel

directly to T cell area

T cells that encounter their specific antigen

activated to proliferate and differentiate, takes a few days

T cells that don't encounter antigen leave

via efferent lymph vessel

T cell homing guided by

CCL19 and CCL21 (similar to what's seen with neutrophils)

CCL19/21

secreted by stomal cells and DCs, bound to surface of endothelial cells

afferent lymph vessel

vessel that brings lymph into the lymph node

efferent lymph vessel

vessel by which lymph & lymphocytes leave a lymph node enroute to blood

T cell into lymph node pathway

1. circulating T cell enters the high endothelial venule in the lymph node

2. binding of L-selectin to GlyCam-1 and CD34 allows rolling interaction (slowing down of T cell)

3. LFA-1 is activated by chemokine bound to extracellular matrix

4. activated LFA-1 binds tightly to ICAM-1

5. Diapedesis - lymphocyte leaves blood and enters lymph node

T cells bind to DCs

as they move through lymph node

LFA-1 on T cell

to ICAM-1 on DC

ICAM-3 on T cell

to DC-Sign on DC, unique to activated DCs

T cell joining DC pathway

1. T cell initially binds dendritic cell through low-affinity LFA-1:ICAM-1 interactions

2. Subsequent binding of T-cell receptors sends signal to LFA-1

3. Conformational change in LFA-1 increases affinity and prolongs cell to cell contact

unactivated T cells & effector T cells leave lymph node

through efferent lymph vessel, follow sphingosine-1-phosphate gradient

sphingosine-1-phosphate

- lipid made by all cells

- concentration lowest in T cell areas, higher towards medulla and efferent vessel

Signal 1

TCR & co-receptor bind to peptide:MHC complex, necessary but not sufficient enough for activation

co-stimulatory signal

co-stimulatory receptor CD28 on T cell bound to co-stimulatory B7 molecule on DC

co-stimulatory signal known as

signal 2, required for T cell activation

B7 expressed

by professional APCs, only during infection

CTLA4

similar to CD28, binds B7 more strongly which inhibits T cell activation and proliferation, expressed once T cells are activated

T cells synapse

localized areas of receptor/ligand binding between T cell and DC

c-SMAC

central supramolecular activation complex, includes TCR, CD2, CD4, CD8, CD28, PKC-0

p-SMAC

peripheral supramolecular activation complex, forms tight seal around c-SMAC, includes LFA-1, ICAM-1, talin

CD2

T cell marker

PKC-0

central for T cell activation

Talin

cytoskeletal molecule

signals from TCR and co-receptor activate

T cell

LCK phosphorylates

Immunoreceptor tyrosine-based activation motifs (ITAMs) of CD3 complex and zayda chain, plus ZAP-70

ZAP-70

protein kinase produced only by T cells, initiates pathways of T cell signaling, results in activation of transcription factors, end result: cell division, proliferation and differentiation

expression of IL-2 induced

- results in proliferation and differentiation

- autocrine action

- Co-stimulatory signal (B7 and CD28) - increases production of IL-2 by increasing its transcription factors

negative selection occurs in

thymus

many self-antigens

not expressed in thymus

self-antigens presented by

a cell not expressing B7

a T cell recognizing these self-antigens

becomes anergia, doesn't make IL-2, stays that way no matter what

adjuvants

enhances adaptive immune response to antigens, induces co-stimulatory activity in DCs

differentiation into different T cells depends on

- tissue of origin of DCs

- nature of pathogen

- innate immune response

TH1 cells

activate macrophages

TH17 cells

enhance neutrophil response

TH2 cells

activate cellular and antibody response to parasites

TFH cells

activate B cells, maturation of antibody response

Treg cells

suppress other effector T cells

master regulator

transcription factor that determines the differentiation pathway

polarized T-cell response

positive feedback results in further differentiation of same type of T cell, enhances cytokine production

Polarized TH1: cell-mediated immunity

a response dominated by the effector cells of the immune system

Polarized TH2: humoral immunity

response dominated by antibodies

CD8 T cell interact with wider range of cells

due to CD8 binding to MHC class I which is expressed by almost every cell

CD8 T cell activation requires stronger co-stimulatory activation

due to CD8 being cytotoxic, to not kill self-cells

IL-2 necessary for

CD8 T-cell proliferation and differentiation

CD8, TH1, TH2, TH17 cells travel

to infected tissue

differentiation into effector T cells involves

changes in cell surface molecules

co-stimulatory signal required for

activation of naive T cells

no co-stimulatory signal for

activation of effector functions

cytokines

alter behavior of cells- made by all effector T cells AFTER forming a conjugate pair with target cell (not stored)

cytotoxins

kill target cells- made by CD8 effector T cells and stored in lytic granules before encounter with target cell

cytokines produced by effector T cells

change gene expression patterns in target cells

janus kinases

JAKS, inactive forms of protein kinases

Signal Transducers & Activators of Transcription (STATs)

phosphorylated by JAKs, transcription actors

STATs and JAKs pathway

1. cytokine receptor subunits and JAKS are all separate

2. cytokine receptor subunits bind JAKs

3. cytokine binding assembles the receptor, which is then phosphorylated

4. STATS bind to phosphorylated receptor and are then phosphorylated

5. phosphorylated STAT dimers go to the nucleus and initiate gene expression

stopping of STAT and JAK pathway

phosphotases & SOCs

phosphotases

remove phosphate from JAKs, STATs, and cytokine receptors

suppression of cytokine signaling

SOCs, bind to phosphorylated residues

CD8 T cells

cytotoxic, kill infected cells while sparing surrounding, healthy cells, antigen-specific - only detect infected cells

after antigen activation & differentiation

synthesizing cytotoxins - packed into lytic granules and travel to site of infection

infected cells die by

apoptosis

IFN-Y

inhibits viral replication & activates macros

CD8 T cell and viral infected cells

1. Cytotoxic CD8 T cell recognizes virus-infected cell

2. CD8 T cell programs first target cell to die

3. CD8 T cell moves on to the second target cell

4. First target cells, second is dying and the third is being attacked

TH1 CD4 T cells

help macrophages at site of infection uptake and kill pathogens, increased synthesis of microbial agents

phagosomes with captured pathogens

fuse better with lysosomes

macrophage activation

enhanced macro function by effector T cells

only cytokine receptors on macros interacting with T cells

are loaded with cytokine to ensure activation is antigen specific

2 signals for macro activation

both provided by TH1 cells

TFH CD4 T cells

help activate B cells, remain in secondary lymphoid tissues, moving from T-cell area to B-cell area

B cell receptor

binds specific antigen and internalizes via receptor-mediated endocytosis --> antigenic proteins degraded to peptides --> MHC II presentation

linked recognition

B & TFH cells recognize different epitopes of same antigen

regulatory CD4 T cells (Tregs)

Produce immunosuppressive and anti-inflammatory cytokines to shut down the immune response when pathogen is eliminated

Tregs dampen effector T cell response by

- preventing DCs from interacting with and activating additional T cells

- direct contact with effector T cells

absence of Tregs