MIGRATION OF IMMUNE CELLS LYMPHOCYTE HOMING AND RECIRCULATION

NEUTROPHIL GRANULOCYTES ARE RECRUITED FROM THE BONE MARROW RESERVOIRE TO INFECTED TISSUES

LYMPHOCYTE RECIRCULATION 1. Homing – most lymphocytes reside in lymphoid organs, few in circulation 2. Recruitment – chemokines and chemokine receptors, chemotaxis Few antigen-specific lymphocytes should be recruited to the site of antigen entry – ANTIGEN RECOGNITION (lymph node) The appropriate effector lymphocytes shoud migrate to the site of antigen EFFECTOR/MEMORY CELLS (tissue, lymphoid tissue) 3. Migration Among tissues, organs Lymph node - Lymph node, Lymph node - Tissues BLOOD CIRCULATION - LYMPHATICS 4. Adhesion molecules HOMING RECEPTORS Antigen independent appearance (dependent on activation state of lymphocyteSelectins Integrins Ig supergene family molecules LIGANDS FOR VASCULAR ENDOTHELIAL CELL RECEPTORS Adressin ligands INTERACTION WITH THE EXTRAVASCULAR CONNECTIVE TISSUE Binding, detachement

1.The central lymphoid organs are not connected to lymphatics – Isolated from the environment 2.The spleen has no lymph circulation – immune response to blood borne antigens 3.HEV – high endothelial venules – special entry sites of blood circulating lymphocytes to peripheral lymphoid organs 4.1 lymph node circle/hour, 25 billion lymphocytes (25x10 9 )/lymph nodes/day BONE MARROWTHYMUS MALT SALT BALT HEV BLOOD Thoracic duct Lymphatics TISSUES SPLEEN LYMPH NODES MIGRATION OF LYMPHOCYTES IN CENTRAL AND PERIPHERAL LYMPHOID ORGANS

CIRCULATIONHEV LYMPH

Role of endothelial cells in trafficking and recirculation Endothelial cells are involved in: Vasomotor tone, vascular permeability, regulation of coagulation, immune modulation and lymphocyte extravasation High endothelial venules Constitutively present in secondary lymphoid tissue Need to allow egress of naïve cells from the circulation Post-capillary venules Present in non-lymphoid tissues Molecules expressed by endothelial cells regulate trafficking and recirculation through lymphoid and non-lymphoid tissues

Post capillary venules in 2º lymphoid tissue are called HIGH ENDOTHELIAL VENULES. Specialised to allow lymphocytes and nothing else into the lymph node HEV High endothelial venules Post capillary venules in other tissues are lined by simple squamous epithelium Blood enters lymph node via the artery Post capillary venules in the paracortex have cuboidal endothelial cells HIGH ENDOTHELIAL VENULES - specialised properties to allow lymphocytes and nothing else into the lymph node

NAIVE LYMPHOCYTES Homing to lymphoid tissues Homing receptor on naive lymphocyte L-selectin – carbohydrate binding Ligand on HEV- mucin-like adressin CD34+ and GlyCAM-1 sulphated sialyl-Lewis x Lymph node- PNAd – retention (peripheral node addressin) HIGH ENDOTHELIAL VENULES HEV Lymphocytes slow down and bind to HEV LFA-1 integrin – ICAM-1/2 Ig family CCL21 chemokine and CCR7 chemokine receptor MIGRATION OF LYMPHOCYTES HEV CD34 L-selectin Naive lymphocyte

Naive B lymphocytes migrate to lymph node through HEV Naive B cells are recruited to HEV by CCL21 kemokin produced by stromal cells CCL21 and CCL19 chemokines produced by dendritic cells target B lynphocytes to lymph nodes HOMING OF B LYMPHOCYTES TO LYMPH NODES

Limfocyte Homing I NAIVE LYMPHOCYTES Homing to lymphoid tissues Homing receptor on naive lymphocyte L-selectin – carbohydrate binding Ligand on HEV – mucin-like adressin CD34+ and GlyCAM-1 sulphated sialyl-Lewis x PSGL-1 Lymph node – PNAd - retention

Limfocita Homing II Extravasation HIGH ENDOTHELIAL VENULES HEV Lymphocytes slow down and bind to HEV LFA-1 integrin – ICAM-1/2 Ig family CCL21 chemokine and CCR7 chemokine receptor

Initial lymphocyte adhesion to antigen presenting cells in LN

Homing to lymph node L-selectin VLA-4 Homing to inflamed vascular endothelium CD45RA CD45RO Differential splicing of CD45 mRNA in naïve & armed T cells CD2LFA-1 CD44 Adhesion molecules Naïve Activated Different adhesion molecules of naive, armed and effector CD4 + T cells Associates with TcR and CD4 - phosphatase activity reduces threshold of T cell signalling

EFFECTOR/MEMORY LYMPHOCYTES Return to the site of stimulation (antigen) Mucosal surface- MADCAM-1 Retention in spleen, lymph node LFA-1 – ICAM-1/2 integrin – cell and extracellular matrix Migration through activated endothelial cells of inflammed tissues Lamina propria in gut Mucosal epithelium Dermis in skin Activated endothel LFA-1 VLA-4 VCAM-1ICAM-1 Activated/effector/memory lymphocyte ALTERED EXPRESSION OF CELL SURFACE ADHESION MOLECULES

Adhesion molecules and chemokines controlling T- cell homing to lamina propria T-cells activated in mucosal tissue associated lymphoid tissues return to MALT

T-cell activated in mucosal tissue associated lymphoid tissues return to MALT Naive T cell Activated T cell

Elephantiasis caused by blockage of lymphatic vessels with Wuchereria bancrofti microfilariae

INAPPROPRIATE DRAINAGE IN CHRONIC INFLAMMATION TOLERANT STATE

Bél lumen Nyirok Mesenteriális nyirokcsomó felé Izolált limfoid folliculus Peyer patch M sejt Kripta Villus Epithelium A BÉLFALHOZ KAPCSOLÓDÓ SZERVEZETT LIMFOID SZÖVET ÉS IZOLÁLT LIMFOID FOLLICULUS Lamina propria

1.The central lymphoid organs are not connected to lymphatics – Isolated from the environment 2.The spleen has no lymph circulation – immune response to blood borne antigens 3.HEV – high endothelial venules – special entry sites of blood circulating lymphocytes to peripheral lymphoid organs 4.1 lymph node circle/hour, 25 billion lymphocytes (25x10 9 )/lymph nodes/day BONE MARROWTHYMUS MALT SALT BALT HEV BLOOD Thoracic duct Lymphatics TISSUES SPLEEN LYMPH NODES MIGRATION OF LYMPHOCYTES IN CENTRAL AND PERIPHERAL LYMPHOID ORGANS