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: Area: 1400 km 2

a a a CD24 CD38 New born 1 year 5 year Transient B cells (T1/T2)  mature B cell  memory B cell DEVELOPMENT OF THE ADAPTIVE IMMUNE SYSTEM memory

a a a CD24 CD38 17 year 28 year 59 year 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 response Dominance 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 cells Provides serological memory: pre-existing neutralizing Abs to pathogens and/or toxins Germinal Centre reaction B cell proliferation Somatic hypermutation Affinity maturation B T B B BB BB B B B B B B B FDC T B B plasma cell

Marginal zone Arteriola Germinal centre T cell area – PALS paracortex CELLULAR INTERACTIONS IN PERIPHERAL LYMPHOID TISSUES T B DC – T cell contact DC Proliferating B centroblasts B – T cell interactions Somatic hypermutation Further gene rearrangement (editing – L-chain) Isotype switch Differentiation to plasma cells Antibody production Memory B cell

B B B apoptosis T CD40 CD40L Follicular dendritic cell (FDC) FcR CD21 Ag FcR 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 Soluble antigen No direct access of high molecular weight or particulate Ag to the follicles Sinuses Conduits 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 cell Intracellular undegraded Ag Recirculation to the cell surface HEV

DC T cell B cell CELLULAR INTERACTIONS IN THE SUB-CORTICAL AREA CD40 CD40L B7 CD28 MHC TCR Recognition of antigen by B and T lymphocytes

Ag-FITC Actin-Alexa Red merged Phalloidin-Alexa red DAPIcontrol 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 antigens TLR ligands Cytokines... 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 MEMORY Negative regulation of the immune system 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 TEffector T C y tokines/cytotoxicity AICD Central memory T Effector T C y tokines/cytotoxicity PERIPHERAL LYMPHOID ORGANS PERIPHERAL TISSUES Skin 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 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

NON LYMPHOID TISSUESPERIPHERAL LYMPHOID TISSUES BLODD Naive T cells Activated DC INFLAMMATION EFFECTOR CELLS MIGRATE TO THE SITE OF INFECTIONS Effector/memory T cells DC + T LYMPH DENDRITIC CELLS TISSUE ANTIGENS

GENERAL ENTRY SITESLIMITED 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 cellsLymphoid central memory T cells PRODUCTION OF EFFECTOR MOLECULES CYTOTOXIC MEMORY T LYMPHOCYTES Proliferation Cytotoxicity

DEPENDENCE OF ANTIGEN IN THE MAINTENANCE OF MEMORY T LYMPHOCYTES IN AIRWAYS MONTHS AFTER INFECTION 136 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 (T EM ) cells LYMPH NODE Memory T cells Antigen-specific Non antigen-specific 24 – 72 hrs Secondary antigen-specific effector T cells developing from central memory (T CM ) cells Woodland DL & Kohlmeier JR 2009 Nat Rev 9:153

AGE THYMUSPERIPHERY NAIVENAIVE IMMUNOLOGICAL EXPERIENCE MEMORYMEMORY