Mature T cells circulate among secondary lympho

Blood circulation
Pathogen in
blood

Lymphocyte (B and T cells)

Pathogen in
Tissue fluid or
Mucous surface

WP
spleen

Blood circulation

Efferent lymph
Other secondary lymphoid tissues
(lymph node, Peyers patch, etc)

Less than 1 in 108 lymphocytes specific for a particular antigen.

Recirculation facilitates the encounter of lymphocyte with cognate antigen.

Lymphocytes ender secondary tissues through

High Endothelial Venules (HEVs).
Lymphocytes migrate into
Lymph node through the HEV.

Nave lymphocytes
In blood circulation
Lymphocytes exit through efferent lymph

Lymphocytes extravasation
Nave T cell

Chemokine signaling
CCL21
CCL19
HEV

CCR7
T cell

T cell area

B cell follicles

T and B cells are localized in distinct reg

in secondary lymphoid tissues.
Lymph node

White pulp of spleen

The survival of T cells (several months) depends on low-affinity TCR re

Of self-peptide/MHC interaction in the periphery.

How do antigens encounter T and B cells in

Secondary lymphoid tissues?
Antigens are presented to T cells by antigen presenting cells (Dendritic cells,
Dendritic cells are the most effective APC.
HSC
Neutrophil
CMP

CLP

B
M

Monocyte

Present in many tissues

(Secondary lymphoid tissues, skin,
Interstitial space)

Different subsets
(Myeloid dendritic cells,
Dendritic cellLymphoid dendritic cells, plasmacyto
dendritic cells, Langerhans cells,
Interstitial dendritic cells)

Dendritic cells take up antigen at the site of

and migrate to lymph nodes.
Dendritic cells can capature antigen by phagocytosis and macropinocytosis.
(Macropinocytosis: large volumes of surrounding fluid are engulfed.)

Before taking up antigen, the dendritic cells are called immature dendritic
These immature dentritic cells are effective in taking up antigens, but exp
Levels of MHC and T cell co-stimulation molecules (B7).

Mature DC loses the ability to take up ant

expresses high levels of MHC/antigen, T ce
co-stimulation molecules and migrate to th
lymph node.

Immature DC
Mature DC
Recognition of pathogen by PRRs
and inflammatory cytokines (IL-1, TNF-)
activate DCs.

Green: Class II MHC

Red: lysosomal protein

Activated DCs express high levels of:

MHC/peptide
T cell costimlatory
Molecule (B7)

Antigen presentation
Facilitate T cell
activation

Adhesion molecule

Stabilize interaction
With T cells

Chemokine (CCL18)

attracts T cells

Macrophages also present antigens to T cells

Resting macrophage expresses low levels of MHC class I

molecules and no B7.

Recognition of pathogens by PRRs and phagocytosis acti

macrohages to express MHC class II/peptide and B7.

Macrophage cannot migrate from sites of infection to l

node and unable to present antigen from peripheral tis

Macrophages in secondary lymphoid tissues phagocytose

pathogens and present antigens to surrounding T cells.

The phagocytosis by macrophage in secondary lymph nod

also prevents the pathogens from entering blood circu

B cell can present antigens that bind to BCR

B cells can internalize soluble antigens through antigen receptor.

(DCs can also internalize soluble antigens by macropinocytosis. However, m
cannot phagocytose soluble antigens)

BCR-antigen interaction activates the expression of B7 and increases the ex

of MHC.

B cells can only interact with antigens that enter into secondary lymphoid t
B cell can only present antigens that bind to antigen receptor.
(DCs and macrophages can present many kinds of antigens)

Pathogens enter mucous associated lymphoid

tissues through M (multifold) cells.

transcytosis

Antigen presentation in secondary lymphoid ti

Skin and other connective tissue
antigen

Dendritic cells

Afferent lymphatic vessel

Dendritic cells
Marophages
B cells

Mucous surface
antigen

M cell

Dendritic cells
Macrophages
B cells

T cells
MALT

T cells
Lymph node

Blood
antigen
Blood circulation

Dendritic cells
Marophages
B cells

T cells
spleen

T cells interact with APCs in secondary lymphoi

T cells interact with APCs through cell adhesio

Cell adhesion molecules initiate transient interac

CD2, CD58, ICAM-1,2,3: Ig superfamily members
LFA-1: integrin

Dendritic cells

The initial transient inter

Allows TCR to recognize
MHC-antigen.
TCR signaling stabilizes
the interaction.

T cell activation requires both TCR-antigen/

and co-stimulator interactions.

Ig superfamily
members

B7.1 (CD80), B7.2 (CD86) are expressed by activated DCs, Ms and B cel
The requirement for B7 explains why only APCs can activate T cells.

The requirement for co-stimulatory molecules is

measure to prevent T cell response to self-anti
pathogen

APC

Non-APC or unactivated APC

Activation through
PRRs-PAMPs interaction

Class I MHC-selfantigen

T cell with cognate antigen receptor

MHC-antigen
B7

T cell activation

T cell anergy

T cell activation is initiated by the clust

of antigen receptors.
APC
Antigen/MHC
Co-receptor

TCR

Immunological synapse

Lipid raft T cell

kinase

Lipid anchored kinases

Signal transduction

Antigen receptor clustering bring together many signaling molecules such as k

with their substrates.

Clustered antigen receptors tend to be associated with lipid rafts.

Lipid rafts are membrane regions enriched for saturated lipids and cholester
Many signaling molecules are associated with lipid raft through covalently a

Receptor clustering leads to the phosphorylatio

Complex by Lck.

ITAM: immunoreceptor tyrosin-based

Lck is a src-family tyrosine kinase.
activation motifs.
YXX[L/I]X6-9YXX[L/I]

Phosphorylated ITAM is binding site for SH2 dom

in ZAP-70 (tyrosin kinase).

Phosphorylated ZAP-70 activates many downstr

Signaling pathways.
ZAP-70

Phosphorylation
(kinases/phosphatases)
GEF

PLC-

Ras
PIP2
IP3

DAG
MAP kinase cascade

Ca2+

NFAT

PKC

NF-B

AP-1

transcription

Expression of genes involved in proliferation and T cell effector func

Abbreviations can be found on page 232.

Activated T cells produce IL-2 and IL-2R.

IL-2

IL-8
IL-1, TNF-

IL-1, IL-6
TNF-
IL-2R: CD25

Co-stimulators (B7-CD28) augment the production of IL-2 by stabilizing IL-2 m

upregulating transcription of IL-2 gene.
CTLA-4 is homologous to CD28, and is induced by T cell activation.
Co-stimulator functions and terminate T cell activaiton.

CTLA-4 in

Immunosuppressive drugs (cyclosporin A and FK506) inhibit IL-2 production.

Rapamycin inhibits signaling through IL-2R.

Activated T cells differentiate into effector

Nave CD4+ T cell

Uncommitted effector
T cell (TH0)

TH1

TH1 cytokines

TH2

TH2 cytokines

Activate macrophage Activate B cells

Nave CD8+ T cell

Cytotoxic T lymphocytes (CTL)

Kill cells infected cells

B cells encounter antigens in secondary lymphoi

Skin and other connective tissue
antigen

Dendritic cells

Afferent lymphatic vessel

Dendritic cells
Marophages
B cells

Mucous surface
antigen

M cell

Dendritic cells
Macrophages
B cells

T cells
MALT

T cells
Lymph node

Blood
antigen
Blood circulation

Dendritic cells
Marophages
B cells

T cells
spleen

Clustering of antigen receptor initiates B cell

pathogen
antigen
BCR
Lipid raft
Ig/
Membrane anchored kinases

Signal transduction

Antigen receptor clustering leads to a phospho

cascade.

Srk family kinases

Syk is activated by transphosphorylat

Phosphorylated Syk activates many downstream

Signaling pathways.
Phosphorylation
(kinases/phosphatases)

Syk

GEF

PLC-

Ras
PIP2
IP3

DAG
MAP kinase cascade

Ca2+

NFAT

PKC

NF-B

AP-1

transcription

Expression of genes involved in proliferation and B cell effector func

Abbreviations can be found on page 232.

B cell activation is enhanced by co-receptor

Co-receptor can stimulate B cell activation by 1000-10,000 fold.
CD19 knockout severely reduces B cell activation.
(cleavage product of C3b)

B cell activation

Why do the same transcription factors activat

expression of different genes in B and T cell

Transcriptional activation involves a combination of many transcription fa

of which are specific to B or T cells. (Combinatorial regulation of gene e

T1

NF-kB

T2

T cell specific gene

B cell specific gene

T cell

T cell specific gene

B1

NF-kB

B2

B cell
B cell specific gene

BCR also internalizes antigens for presentat

to T cells.
Ag

BCR

Ag
Receptor-mediated
endocytosis

Ag

endosome

MHC II
Clip
Degradation of Ag
MHC II

Golgi complex

Invariant chain

Ag-BCR interaction provides activation signal I,

Which induces the expression of MHC II and B7.
Internalization of Ag by BCR leads to antigenpresentation with MHC II.

Interaction with cognate CD4 T cell activates

The T cell to express CD40L (CD154, TNF family
member).

CD40L interacts with CD40 to stimulate B cell

proliferation.

TH cells secret IL-4, IL-5, which facilitate

B cell proliferation and differentiation.

Activated B cells undergo additional diversification

at the Ig loci and differentiate into plasma
cells or memory cells.

The secreted cytokines are confined to the

B-T contact region.

Relevant parts in book

T cell activation: page 229-235
B cell activation: page 254-261