Transcript B CELLS Memory B cells

Immunological memory
Inhabitants: 46 000
Area: 1400 km2
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
DEVELOPMENT OF THE ADAPTIVE IMMUNE SYSTEM
Transient B cells (T1/T2) mature B cell  memory B cell
CD24 New born
memory
1 year
memory
CD38
5 year
memory
DEVELOPMENT OF THE ADAPTIVE IMMUNE SYSTEM
17 year
28 year
59 year
CD24
memory
memory
CD38
memory
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 reinfection by neutralization and opsonization.
The amount and quality of antigenspecific antibodies is increasing in the
course of the adaptive immune response
Dominance of IgG-type antibodies
B CELL MEMORY
Affinity maturation
Isotype switch
Th help is needed
IMMUNOLOGICAL MEMORY – B CELLS
Germinal Centre reaction
• B cell proliferation
• Somatic hypermutation
• Affinity maturation
B
B
FDC
B
FDC
B
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
T
B
B
B BB B
BB B B B
T
B
plasma
cell
Plasma cells
Provides serological memory:
pre-existing neutralizing Abs to
pathogens and/or toxins
CELLULAR INTERACTIONS IN PERIPHERAL LYMPHOID
TISSUES
T cell area – PALS
paracortex
Germinal centre
DC
DC – T cell
contact
T
B – T cell interactions
Somatic hypermutation
Further gene rearrangement
(editing – L-chain)
Isotype switch
Differentiation to plasma cells
Antibody production
B
Marginal zone
Arteriola
Proliferating B
centroblasts
Memory B cell
DEVELOPMENT OF B CELL MEMORY IN THE
FOLLICLES
T
B
Follicular dendritic
cell (FDC)
CD40L
CD40
CD21
FcR
B
Ag
Memory B cell
FcR
No Ag
B
apoptosis
SELECTION OF HIGH AFFINITY B CELLS UPON INTERACTION WITH
FOLLICULAR DENDRITIC CELLS
Tight junction
B cell
VLA-4 VCAM-1
LFA-1
ICAM-1
BCR
CD21 C3d
Follicular dendritic cell
Inhibition of apoptosis
EXTRAFOLLICULAR ACTIVATION OF MARGINAL ZONE B CELLS BY
DENDRITIC CELLS
HEV
Dendritic cell
Intracellular undegraded Ag
Recirculation to the cell surface
GC
B cell
Sinuses
Conduits
GC
Soluble antigen
No direct access of high molecular
weight or particulate Ag to the follicles
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
CELLULAR INTERACTIONS IN THE SUB-CORTICAL AREA
CD40
CD40L
DC
Recognition of antigen by
B and T lymphocytes
MHC TCR
T cell
B7 CD28
CD28
TCR
CD40L
CD40
MHC
B7
B cell
ANTIGEN-LOADED DENDRITIC CELLS INTERACT AND ACTIVATE
ANTIGEN-SPECIFIC B LYMPHOCYTES
Phalloidin-Alexa red
Ag-FITC
Ag loaded dendritic cells interact with
Ag-specific B cells
Huang N-N. et al. J. Immunol. 175:7125, 2005
DAPI
Actin-Alexa Red
control
merged
Ag and actin are reorganized to the
contact site
How antigen-specific antibody production is maintained?
MODEL 2.
MODEL 1.
memory
B cell
plasma cell
Bystander help:
Cross-reacting antigens
TLR ligands
Cytokines...
Memory B cells continuously
differentiate to plasma cells
Long term memory cells in
the bone marrow
MODEL 3.
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
T-CELL MEMORY
Central
Effector
DEVELOPMENT OF CELLULAR MEMORY
Negative regulation of the immune system
AICD
DIFFERENTIATION
Naive
lymphocytes
Az antigen-specific cell
number
Activation Induced Cell Death
Memory
Secunder
effector cells
Primary effector
cells
EXPANSION
AICD
MEMORY
5
10
15
20
25
30
Days
Days
T-cells differentiate into central and effector memory cells
Naive T
Effector T
AICD
Cytokines/cytotoxicity
Central memory T
Effector memory T
PERIPHERAL TISSUES
Skin dermis, gut lamina propria,
alveolar space
PERIPHERAL
LYMPHOID ORGANS
Tissue-specific migration
Effector T
Effector T
Cytokines/cytotoxicity
ANTIGEN/ SITE OF INFLAMMATION
Cytokines/cytotoxicity
IMMUNOLOGICAL MEMORY MEDIATED BY T LYMPHOCYTES
Naive T cell
Effector T cell
cytokine production
cytotoxicity
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
Effector
Memory 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
EFFECTOR CELLS MIGRATE TO THE SITE OF INFECTIONS
NON LYMPHOID TISSUES
PERIPHERAL LYMPHOID TISSUES
Effector/memory
T cells
INFLAMMATION
Activated DC
TISSUE ANTIGENS
DC + T
Naive T cells
DENDRITIC CELLS
LYMPH
BLODD
GENERAL ENTRY SITES
LIMITED ENTRY SITES
Brain
Lung parenchyma
Alveoli
Lymph node
Spleen
Liver
Peritoneum
Lamina propria
Bone marrow
Skin
WHERE MEMORY T CELLS HAVE ACCESS
CYTOTOXIC MEMORY T LYMPHOCYTES
PRODUCTION OF
EFFECTOR
MOLECULES
Tissue effector memory T cells
Resting
Activated
Lymphoid central memory T cells
Resting
Activated
Proliferation
Cytotoxicity
DEPENDENCE OF ANTIGEN IN THE MAINTENANCE OF MEMORY T
LYMPHOCYTES IN AIRWAYS
MONTHS AFTER INFECTION
1
3
6
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
Memory T cells
LYMPH NODE
24 – 72 hrs
Non antigen-specific
Secondary antigen-specific
effector T cells developing from
central memory (TCM ) cells
Antigen-specific
Woodland DL & Kohlmeier JR 2009 Nat Rev 9:153
AGE
THYMUS
PERIPHERY
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IMMUNOLOGICAL EXPERIENCE