1781: Measles epidemic in the Faroe Islands

No measles for 65 years

1846: Measles epidemic

Those individuals, who were older than 65 years and were infected in 1781 did not became sick, but some elderly people got the infection

1. Life-long protection can be induced against some viruses

2. Presence of the virus is not needed for the maintenance of immunological memeory

Immunological memory

Inhabitants: 46 000Area: 1400 km2

CD24CD24

CD38CD38

New bornNew born 1 1 yearyear 5 5 yearyear

TransienTransientt B B cellscells (T1/T2) (T1/T2) maturemature B B cellcell memmemory ory B B cellcell

DEVELOPMENT OF THE ADAPTIVE IMMUNE SYSTEM

memory memory memory

CD24CD24

CD38CD38

17 17 yearyear 28 28 yearyear 59 59 yearyear

memory memory memory

DEVELOPMENT OF THE ADAPTIVE IMMUNE SYSTEM

DEVELOPMENT OF PRIMARY – EFFECTOR – MEMORY T AND B LYMPHOCYTES IN THE COURSE OF ANTIGEN – SPECIFIC IMMUNE

RESPONSES

Presence of specific antibodies during primary and secondary immune responses protects against repeated infections

• A successful primary immune response eliminates the pathogen and results in long-lasting immunological memory• Antibodies produced during the primary immune response protect agaimst re-infection by neutralization and opsonization.

The amount and quality of antigen-specific antibodies is increasing in the

course of the adaptive immune responseDominance of IgG-type antibodies

B CELL MEMORY

Affinity maturation

Isotype switch

Th help is needed

IMMUNOLOGICAL MEMORY – B CELLS

Memory B cells• Perviously activated• Passed through affinity maturation• Present in the circulation• Rapid proliferation and differentiation to plasma cell upon re-activation or entry to the GC reaction again

Plasma cellsProvides serological memory: pre-existing neutralizing Abs to pathogens and/or toxins

Germinal Centre reaction• B cell proliferation• Somatic hypermutation• Affinity maturation

BT

BB

BBBB

BBB

B

BB

B

FDC

FDC T

B

B

plasmacell

Marginal zone

Arteriola

Germinal centre T cell area – PALS

paracortex

CELLULAR INTERACTIONS IN PERIPHERAL LYMPHOID TISSUES

T

B

DC – T cell contact

DC Proliferating Bcentroblasts

B – T cell interactionsSomatic hypermutation

Further gene rearrangement (editing – L-chain)

Isotype switchDifferentiation to plasma cells

Antibody production

Memory B cell

B

B

Memory B cell

Bapoptosis

T

CD40

CD40L

Follicular dendritic cell (FDC)

FcR

CD21

AgFcR

No Ag

DEVELOPMENT OF B CELL MEMORY IN THE FOLLICLES

Follicular dendritic cell

B cell

SELECTION OF HIGH AFFINITY B CELLS UPON INTERACTION WITH FOLLICULAR DENDRITIC CELLS

VLA-4

LFA-1

VCAM-1

ICAM-1

BCR

CD21 C3d

Inhibition of apoptosis

Tight junction

B cell

EXTRAFOLLICULAR ACTIVATION OF MARGINAL ZONE B CELLS BY DENDRITIC CELLS

GC

GC

Soluble antigenNo direct access of high molecular

weight or particulate Ag to the follicles

SinusesConduits

DENDRITIC CELLS PROVIDE A CELLULAR PLATFORM

Cognate recognition of Ag by rare naive B and T lymphocytes

Membrane tethered Ag facilitates the activation of low-affinity B cells

Dendritic cellIntracellular undegraded Ag

Recirculation to the cell surface

HEV

DC

T cell

B cell

CELLULAR INTERACTIONS IN THE SUB-CORTICAL AREA

CD40

CD40

CD40L

CD40LB7

B7

CD28

CD28

MHC

MHC

TCR

TCR

Recognition of antigen by B and T lymphocytes

Ag-FITC Actin-Alexa Red merged

Phalloidin-Alexa red DAPI control

Ag loaded dendritic cells interact with Ag-specific B cells

Ag and actin are reorganized to the contact site

ANTIGEN-LOADED DENDRITIC CELLS INTERACT AND ACTIVATE ANTIGEN-SPECIFIC B LYMPHOCYTES

Ag loaded dendritic cells interact with Ag-specific B cells

Ag and actin are reorganized to the contact site

Huang N-N. et al. J. Immunol. 175:7125, 2005

Repeated antigen-specific B cell stimulation results in B cell activation and plasma cell differentiation

• How long follicular dendritic cells can store antigen – months or years? • Polio virus: re-infection by Sabin drops • Subclinical infections (Diphteria in 10% of the population)• Cryptic antigens (measles may persist in neurons and may cause Subacute Sclerotizing Panencephalitis

Bystander help:Cross-reacting antigensTLR ligandsCytokines...

memory B cell plasma cell

How antigen-specific antibody production is maintained?

Memory B cells continuously differentiate to plasma cells

Long term memory cells in the bone marrow

MODEL 1. MODEL 2.

MODEL 3.

T-CELL MEMORY

Central

Effector

DEVELOPMENT OF CELLULAR MEMORYNegative regulation of the immune system

Days5 10 15 20 25 30

Naive lymphocytes

Az antigen-specific cell number

Primary effector cells

Secunder effector cells

Memory

DIFFERENTIATION

AICD

EXPANSION

AICD

MEMORY

Days

Activation Induced Cell Death

T-cells differentiate into central and effector memory cells

Naive T Effector T

Cytokines/cytotoxicity

AICD

Central memory T

Effector T

Cytokines/cytotoxicity

PERIPHERAL LYMPHOID ORGANS

PERIPHERAL TISSUESSkin dermis, gut lamina propria,

alveolar space

Tissue-specific migration

Effector memory T

Effector T

Cytokines/cytotoxicity

ANTIGEN/ SITE OF INFLAMMATION

IMMUNOLOGICAL MEMORY MEDIATED BY T LYMPHOCYTES

Naive T cell Effector T cell

cytokine productioncytotoxicity

Central Memory T cell Effector T cell

• Previously activated, partially differentiated cell type• Circulating CCR7+ cells in blood, lymphoid tissues• High proliferation rate induced by activation signals• Rapid differentiation to effector cells

EffectorMemory T cell

Effector T cell

• Previously activated, partially differentiated cell type• Closest to the effector state • Circulating CCR7- cells in blood and tissues• Slow proliferation, rapid effector functions

Maintained by cytokines:IL-7, IL-15

NON LYMPHOID TISSUES PERIPHERAL LYMPHOID TISSUES

BLODD

Naive T cells

Activated DCINFLAMMATION

EFFECTOR CELLS MIGRATE TO THE SITE OF INFECTIONSEFFECTOR CELLS MIGRATE TO THE SITE OF INFECTIONS

Effector/memoryT cells

DC + TDC + T

LYMPH

DENDRITIC CELLS

TISSUE ANTIGENS

GENERAL ENTRY SITES LIMITED ENTRY SITES

Brain

Alveoli

Peritoneum

Lamina propria

Skin

Lung parenchyma

Lymph node

Spleen

Liver

Bone marrow

WHERE MEMORY T CELLS HAVE ACCESS

Resting Activated Resting Activated

Tissue effector memory T cells Lymphoid central memory T cells

PRODUCTION OF EFFECTOR

MOLECULES

CYTOTOXIC MEMORY T LYMPHOCYTESCYTOTOXIC MEMORY T LYMPHOCYTES

Proliferation

Cytotoxicity

DEPENDENCE OF ANTIGEN IN THE MAINTENANCE OF MEMORY T LYMPHOCYTES IN AIRWAYS

MONTHS AFTER INFECTIONMONTHS AFTER INFECTION

11 33 66

After successful elimination of viral infections the number of antigen presenting DC and the newly activated memory T cells is decreased

Secondary antigen-specific effector T cells developing from effector memory (TEM ) cells

LYMPH NODE

Memory T cells

Antigen-specific

Non antigen-specific24 – 72 hrs

Secondary antigen-specific effector T cells developing from

central memory (TCM ) cells

Woodland DL & Kohlmeier JR 2009 Nat Rev 9:153

AGE

THYMUS PERIPHERY

N

A

I

V

E

IMMUNOLOGICAL EXPERIENCEIMMUNOLOGICAL EXPERIENCE

M

E

M

O

R

Y