1781:Measles epidemic in the Faroe Islands No measles for 65 years 1846: Measles epidemic (Peter Panum, Danish physiologist) Those individuals, who were older than 65 years and were infected in 1781 did not become sick, but some elderly people got the infection – resistance to virus 1.Life-long protection can be induced against some viruses 2.Presence of the virus is not needed for the maintenance of immunological memory 3.Immunological memory is harnessed by vaccination Immunological memory Inhabitants: Area: 1400 km 2

THE TWO ARMS OF THE IMMUNE SYSTEM Differentiation between harmless and harmful impacts DETECTION OF STRESS AND DANGER SIGNALS INNATE IMMUNITY Differentiation between self and non-self structures Antigen-specific recognition ADAPTIVE IMMUNITY Neutralization and elimination of foreign and harmful structures EXECUTIVE FUNCTIONS COORDINATED AND REGULATED ACTIONS INNATE IMMUNITY - immediate reaction - not antigen-specific - no memory ADAPTIVE IMMUNITY - developes in several days - specific - has memory communication Specificity is a prerequisit of memory

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

Retention of vaccina-specific antibodies and T cells after vaccination against smallpox virus.

Comparison of primary and memory B cell response

Movement of lymphocytes in the GC B cell zone: CXCL13(secreted by follicular dendritic cells) binds to the CXCR5 chemokine receptor on recirculating naive B cells and attracts these cells into the follicles. T cell zone: CCR7—CCL19, CCL21 S1PR1 Entry and egress from GC

Antigen entry to the GC  Soluble antigens, generally smaller than 70 kD, may reach the B cell zone through conduits that extend between the subcapsular sinus and the follicle and interact directly with specific B cells. Antigen > 70 kDa Antigen, mainly immunkomplexes can be transproted by: Subcapsular sinus macrophages, in the medullary region by resident dendritic cells marginal zone B cells, Naive B cells Blood-borne pathogens may be captured by plasmacytoid dendritic cells Capture of immunkomplexes is mediated by complement (and Fc) receptors

B cell Antigen and lymphocyte entry to the GC GC Soluble antigen No direct access of high molecular weight or particulate Ag to the follicles Sinuses Conduits Cognate recognition of Ag by rare naive B and T lymphocytes Membrane tethered Ag facilitates the activation of low-affinity B cells Intact antigen or Dendritic cell Intracellular undegraded Ag Recirculation to the cell surface HEV B cell

B B Memory B cell B apoptosis T CD40 CD40L Follicular dendritic cell (FDC) FcR CD21 Ag FcR No Ag DEVELOPMENT OF B CELL MEMORY IN THE FOLLICLES The role of follicular dendritic cells CD21--- CR2

B cell SELECTION OF HIGH AFFINITY B CELLS UPON INTERACTION WITH FOLLICULAR DENDRITIC CELLS VLA-4 LFA-1 VCAM-1 ICAM-1 Signaling through adhesion molecules inhibits apoptosis and supports B-cell survival Tight junction BCR Follicular dendritic cell CD21 C3d Complement Complement positively regulates B cell activation, augmenting signals delivered through the BCR complex

B cell antigen presentation !

extra follicular B cell activation I.Decision point: Extrafollicular plasma cell Or Intitiation of GC reaction

B cell activation in GCs short-lived plasma cell II. Decision point: Short-lived plasma cell Or proliferation in dark zone

Competition I.for antigen The higher affinity B cells the bigger chance to engage the antigen, and to acquire it, to present it for T cells II. for T cell help T cell help, and not direct competition for antigen, is the limiting factor in GC selection

B cell activation in GCs short-lived plasma cell III. Decision point: long-lived plasma cell Or memory B cell or start a new cycle

Phases of humoral immune responses. Naive B lymphocytes recognize antigens, and under the influence of helper T cells and other stimuli (not shown), the B cells are activated to proliferate, giving rise to clonal expansion, and to differentiate into antibody-secreting plasma cells. Some of the activated B cells undergo heavy-chain isotype switching and affinity maturation, and some become long-lived memory cells. Activation and differentiation of B lymphocytes

Memory B cell activation in GCs M M I.The memory B cell outcompete naive B cells II.Higher affinty immuncomplexes III.Earlier appearance of immunkomplexes (long term plasma cell, memory B cells) short-lived plasma cell

Memory B cells proliferation and differentiation to plasma cell upon re-activation or entry to the GC reaction again and Long-lived plasma cells Plasma cells generated during GC reaction migrate to bone marrow and survive for years, producing antibody. Immediate protection. Much of circulating IgG,IgA is produced by long-lived plasma cells, provides initial protection

IMMUNOLOGICAL MEMORY – B CELLS SUMMARY 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 by pre-existing neutralizing Abs to pathogens and/or toxins Germinal Center reaction B cell proliferation Somatic hypermutation Affinity maturation B T B B BB BB B B B B B B B FDC FDC T B B plasma cell B – T cell collaboration

Presence of specific antibodies during primary and secondary immune responses protects against repeated infections Innate immunity could not stop infection Innate immunity could not stop infection The successful primary immune response eliminated the pathogen and resulted in long-lasting immunological memory The successful primary immune response eliminated the pathogen and resulted in long-lasting immunological memory Antibodies produced during the primary immune response protects against re- infection by neutralization and opsonization. Antibodies produced during the primary immune response protects against re- infection by neutralization and opsonization.

Immediate protection by long-lived plasma cells

PRODUCTION OF IMMUNOGLOBULINS Fetus/newborn are not protected against new pathogens by B cells!

In the course of adaptive immune responses the amount and quality of antigen-specific antibodies is increasing Strong secondary immune response is mediated by long-lived pathogen-specific B cells and effector T cells Short-lived plasma cells generated during primary immune responses live for several weeks and the amount of pathogen-specific antibodies declines (1 year) T cell help is needed to ensure affinity maturation and isotype switch SECONDARY IMMUNE RESPONSE Higher speed and stronger response Predominantly IgG type high affinity antibodies in tissues and mucosal surfaces

Repeated antigen-specific B cell stimulation results in B cell activation and plasma cell differentiation How long the 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.

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 B-CELLS The adult immune system relies more and more on memory B cells memory

a a a CD24 CD38 17 year 28 year 59 year memory DEVELOPMENT OF THE ADAPTIVE IMMUNE SYSTEM B-CELLS

B cell memory: Quicker response Increase in the number of specific B cells The amount of antibody is increased Higher affinity antibodies (‘more specific’) Isotype switch In case of T dependent B cell activation Summary :

Memory B cells proliferation and differentiation to plasma cell upon re-activation or entry to the GC reaction again and Long-lived plasma cells Plasma cells generated during GC reaction migrate to bone marrow and survive for years, producing antibody. Immediate protection. Much of circulating IgG,IgA is produced by long-lived plasma cells, provides initial protection

T-CELL MEMORY Central memory cells Effector memory cells

T cell memory: Quicker response Increase in the number of responding cells

DEVELOPMENT OF CELLULAR MEMORY Negative regulation of the immune system Naive lymphocytes Az antigen-specific cell number Primary effector cells Secondary effector T cells Memory DIFFERENTIATION AICD EXPANSION AICD MEMORY Days Activation Induced Cell Death

Effector T Citokines/Cytotoxicity AICD Naive T Central memory T Effector T Citokines/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 INFECTION

I. Memory B cells proliferation and differentiation to plasma cell upon re-activation or entry to the GC reaction again and II. Long-lived plasma cells Plasma cells generated during GC reaction migrate to bone marrow and survive for years, producing antibody. Immediate protection. Much of circulating IgG,IgA is produced by long-lived plasma cells, provides initial protection I. Central memory T cells: In the lymph node (DC-mediated presentation), requires proliferation and II. Effector memory T cells: Periferial activation, limited proliferation Quick response (not immediate requires antigen presentation) Analogy with B cells :

Comparison of primary and memory T cell response

NON LYMPHOID TISSUESPERIPHERAL LYMPHOID TISSUES CIRCULATION Naive T cells EFFECTOR CELLS MIGRATE TO THE SITE OF INFECTIONS Effector/memory T cells DC + T NYIROK KERINGÉS RESTING DENDRITIC CELLS TISSUE ANTIGENS ACTIVATED DC INFLAMMATION

Primary T cell activation I Activation of Naiv lymphocytes

Primary T cell activation II Activation of Naiv lymphocytes

Primary T cell activation III Activation of Naiv lymphocytes

Quicker response I.Elevated number of specific cells II.TEM cells localized in the tissue III.No, partially requirements of costimulation

GENERAL ENTRY SITES LIMITED ENTRY SITES Brain Alveoli Peritoneum Lamina propria Skin Lung parenchyma Lymph node Spleen Liver Bone marrow ACCESS OF MEMORY T CELLS TO VARIOUS COMPARTMENTS General : CD43 LFA-1 P-selectin VLA-4 Tissue Specific: αVβ7integrin----Gut αVβ7integrin---Lung CD62L -Lymph node

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 2X10 7 2X10 5

Proliferation Cytotoxicity cytotoxicity Functional differences between lymphoid tcm cells and tissue-resident T EM cells Woodland DL & Kohlmeier JR 2009 Nat Rev 9:153

ANTIGEN DEPENDENCE OF 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 the number of antigen-specific T cells at peripheral sites steadily decreases in the months after pathogen clearance. TEM→ CEM

Secondary antigen-specific T cells develop 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 develop from central memory (T CM ) cells Woodland DL & Kohlmeier JR 2009 Nat Rev 9:153 Dynamics of the memory T-cell recall response in peripheral tissues.

HIV CTL Th ART HIV Interrupted treatment Herpes simplex virus BCG vakcina strain HIV-2 Mycobacterium leprae Chronic HBV Malaria Memory in persistant infections – INFECTIVE IMMUNITY Controlled infections maintain the production of antigen-specific effector T cells and ensure the continous production of antibodies Characteristic for poorly cytopathic persistant infections No antigen-independent memory cells Theory:

ORIGINAL ANTIGENIC SIN ABBAS MIT 2013 Pécs

AGE THYMUSPERIPHERY NAIVENAIVE IMMUNOLOGICAL EXPERIENCE MEMORYMEMORY

Active and passive immunization

Active: generates memory response The hosts immune system will eventually create antibodies and other defenses against the microbe Passive: ensure the protection by premade antibodies (the adaptive immune system of the person is not activated) pre-synthesized elements of the immune system are transferred to a person

Active and passive immunization activepassive protection slowimmediate (2 weeks) Time-spanlong short (years) time active passive injection protection ! !

Anti-viral immune response Defense: Innate Immunity:– type I interferons(INFα, β) – NK cells Adaptive immunity T cells --- cytotoxic T cells, cytokines B cells– antibody-mediated neutralization is the AIM of vaccination!!! !

Immunization ActivePassive Host itself produce preformed antibodies antibodies and cells are imported to the host biotic, naturally artificial