5th SEMINAR THE ADAPTIVE IMMUNE RESPONSE: LYMPHOID ORGANS GENERATION OF MATURE NAIVE LYMPHOCYTES LYMPHOCYTE RECIRCULATION

RECOGNITION BY CELLS OF THE ADAPTIVE IMMUNE SYSTEM Antigen-specific receptors: B cell receptor (BCR) and T cell receptor (TCR) The basic structure (90%) of the receptors (BCR or TCR) is common Each cell expresses a receptor that is unique in specificity (the 10% difference means different specificity) These differences in antigen- specificity are achieved during maturation in the CENTRAL LYMPHOID ORGANS (bone marrow and thymus)

PRIMARY (CENTRAL) LYMPHOID ORGANS Places of the maturation (antigen-independent development) of lymphocytes: bone marrow: generation of lymphoid progenitors, maturation of B cells thymus: maturation of T cells (and NK cells)

GENERATION OF LYMPHOCYTES B cellT cell Maturation Starts in the bone marrow, continues in the bone marrow Starts in the bone marrow, continues in the thymus ActivationIn the peripheral lymphoid tissues Effector cellsPlasma cell T helper T cytotoxic

THE BONE MARROW Dendritic cells Stem cells Stromal cells BONE Central sinus Osteoblasts Osteoclasts ProgenitorsPrecursors Blood circulation Immature T cells (thymocytes) on their way to the thymus (20x10 6 /day) Mature B cells (3x10 6 /day) flat bones (sternum, ribs, scapulae, hip bone) epiphysis of long bones

BONE MARROW STROMAL CELLS NURTURE DEVELOPING B CELLS Types of cytokines and cell-cell contacts needed at each stage of differentiation are different (see next figure) 1.Specific cell-cell contacts between stromal cells and developing B cells 2.Secretion of cytokines by stromal cells Secreted factors - CYTOKINES B Stromal cell Cell-cell contact

GENERATION OF INDIVIDUAL ANTIGEN- SPECIFIC RECEPTOR (BCR)

Limphoid progenitors mature B H rearrangement Pre-BCR L rearrangement selection clonal deletion B B B B  Pro-B Pre-B c-kit/CD44 RAG-1/RAG-2 STEPS OF B CELL DEVELOPMENT IN THE BONE MARROW 1.rearrangement of the immunoglobulin heavy chain (somatic gene recombination – V-D-J genes) 2.production of heavy chains, expression of preBCR (μ chain + surrogate light chain) 3.allelic exclusion of heavy chain genes, IL-7-dependent proliferation of functional heavy chain expressing pre B cells 4.rearrangement of the immunoglobulin light chain (somatic recombination – V-J genes) 5.expression of functional BCRs, proliferation 6.negative selection: clonal deletion (by apoptosis or anergy) of self-reactive B cells 7.mature, selected B cells leave the bone marrow via the medullary sinuses immature B

Blood circulation Macrophage Hassall’s corpuscle Dendritic cell Thymocytes Epithelial cells Capsule Septum Mature naive T- lymphocytes STRUCTURE OF THE THYMUS

INVOLUTION OF THYMUS The functional amount of the thymus tissue is decreasing by age, leading to less and less newly produced mature T cells.

DEVELOPMENT OF T CELLS IN THE THYMUS 1.proliferation of lymphoid progenitors after their arrival to the thymus 2.rearrangement of the beta chain (somatic gene recombination – V-D-J genes) /or gamma and delta chains  γδ T cells/ 3.production of beta chains, expression of preTCR (β chain + preTα) 4.allelic exclusion of beta chain genes, IL-7- dependent proliferation of functional beta chain expressing pre T cells 5.rearrangement of the alpha chain (somatic recombination – V-J genes) /still some will become γδ T cells/ 6.expression of functional TCRs 7.positive selection: clonal ignorance for those cells which do not recognize self-MHC molecules 8.negative selection: clonal deletion (by AICD) of self- reactive B cells 9.mature, selected T cells leave the thymus via blood vessels

T CELL DEVELOPMENT NK  rearrangement Pre-T Pre-T  positive selection negative selection T T T mature T limphoid progenitors THYMUS  rearrangement c-kit/CD44 RAG-1/RAG-2 (B- CELL DEVELOPMENT) circulation Pro-T T mature B H rearrangement Pre-BCR L rearrangement negative selection clonal deletion B B B B  Pro-B Pre-B immature B immature T

AFTER LEAVING THE CENTRAL LIMPHOID ORGANS MATURE NAIVE LYMPHOCYTES TRAVEL TO THE SITES OF ACTIVATION: THE SECONDARY LYMPHOID ORGANS/TISSUES

SECONDARY LYMPHOID ORGANS/TISSUES LYMPH NODES SPLEEN TONSILS (Waldeyer’s ring) Diffuse lymphoid layers under the epithelial barriers: SALT (skin-associated lymphoid tissue) MALT (mucosa-associated lymphoid tissue) BALT (bronchus-associated lymphoid tissue) GALT (gut-associated lymphoid tissue) Sites of lymphocyte activation and terminal differentiation

LYMPH NODES

STRUCTURE OF LYMPH NODES

THE SPLEEN No connection to lymphatic vessels Filtrates blood-borne antigens Red pulp is the ‚cemetery’ of RBCs White pulp is similar to lymph nodes

Tonsilitis WALDEYER’S RING Most pathogens are acquired through the naso-oral cavity, hence there are accumulations of mucosa-associated lymphoid tissues (Can be referred to as NALT – nasal-associated lymphoid tissue, or organized MALT)

GALT Dome area Villi GC Kripta

GALT the intestines are full of symbiotic and pathogenic microbes continuous antigen uptake from the lumen by M (microfold) cells and DCs low dose antigen exposure enhances the fitness of the immune system regulator mechanisms are very important

THE LYMPHOCYTE RECIRCULATION Mature naive lymphocytes leave the central lymphoid organs to travel to the sites of activation: the secondary lymphoid organs/tissues (SLO) They enter the different SLOs randomly via the process called ‚HOMING’ They either GET ACTIVATED after recognizing an antigen and differentiate to effector cells or they LEAVE VIA THE EFFERENT LYMPHATIC VESSELS The lymph is collected by lymph nodes, the lymphocytes pass many of them, and in every node they may get activated Eventually all the lymph is flowing into the THORACIC DUCT and get back to the circulation, so the lymphocytes can reach another SLO They do their recirculation until they find an antigen or until the end of their lifespan

HOMING Similar to extravasation of neutrophil granulocytes during acute inflammation The endothelial cells of HEVs (high endothelial venules) express mucin-like adressin type adhesion molecules Mature naive lymphocytes express adhesion molecules (homing receptors) that can interact with the ones expressed by HEVs T and B cells find their areas in the SLOs by chemotaxis