MIGRATION OF IMMUNE CELLS

LYMPHOCYTE HOMING AND RECIRCULATION

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

LYMPHOCYTE RECIRCULATION

1. Homing – most lymphocytes reside in lymphoid organs, few in circulation2. 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. MigrationAmong tissues, organsLymph node - Lymph node, Lymph node - TissuesBLOOD CIRCULATION - LYMPHATICS

4. Adhesion molecules HOMING RECEPTORS Antigen independent appearance (dependent on activation state of

lymphocyte SelectinsIntegrinsIg supergene family molecules

LIGANDS FOR VASCULAR ENDOTHELIAL CELL RECEPTORS Adressin ligands

INTERACTION WITH THE EXTRAVASCULAR CONNECTIVE TISSUEBinding, 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 (25x109)/lymph nodes/day

BB TBONE MARROW THYMUS

MALTSALTBALT

HEV

BLOOD

Thoracic ductLymphatics

TISSUES

SPLEEN

LYMPH NODES

MIGRATION OF LYMPHOCYTES IN CENTRAL AND PERIPHERAL LYMPHOID ORGANS

CIRCULATIONCIRCULATION

HEVHEV

LYMPHLYMPH

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 insecondary lymphoid tissue

Need to allow egress ofNeed to allow egress ofnaïve cells from the circulationnaïve cells from the circulation

Post-capillary venules

Present in non-lymphoid tissues

Molecules expressed by endothelial cells regulate traffickingand 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 arteryPost capillary venules in the paracortex have cuboidal endothelial cellsHIGH ENDOTHELIAL VENULES - specialised properties to allow lymphocytes and

nothing else into the lymph node

NAIVE LYMPHOCYTESHoming to lymphoid tissues Homing receptor on naive lymphocyteL-selectin – carbohydrate binding

Ligand on HEV - mucin-like adressin CD34+ and GlyCAM-1 sulphated sialyl-Lewisx

Lymph node - PNAd – retention (peripheral node addressin)

HIGH ENDOTHELIAL VENULESHEV

Lymphocytes slow down and bind to HEVLFA-1 integrin – ICAM-1/2 Ig family

CCL21 chemokine and CCR7 chemokine receptor

MIGRATION OF LYMPHOCYTES

HEV

CD34

L-selectin

Naive lymphocyteNaive lymphocyte

Naive B lymphocytes migrate to lymph node Naive B lymphocytes migrate to lymph node through HEVthrough HEV

Naive B cells are recruited to HEV by CCL21 Naive B cells are recruited to HEV by CCL21 kemokin produced by stromal cellskemokin produced by stromal cells

CCL21 and CCL19 chemokines produced by CCL21 and CCL19 chemokines produced by dendritic cells target B lynphocytes to lymph dendritic cells target B lynphocytes to lymph

nodesnodes

HOMING OF B LYMPHOCYTES TO HOMING OF B LYMPHOCYTES TO LYMPH NODESLYMPH NODES

Limfocyte Homing I

NAIVE LYMPHOCYTESHoming to lymphoid tissues Homing receptor on naive lymphocyteL-selectin – carbohydrate binding

Ligand on HEV – mucin-like adressin CD34+ and GlyCAM-1 sulphated sialyl-Lewisx PSGL-1Lymph node – PNAd - retention

Limfocita Homing IIExtravasation

HIGH ENDOTHELIAL VENULESHEV

Lymphocytes slow down and bind to HEVLFA-1 integrin – ICAM-1/2 Ig family

CCL21 chemokine and CCR7 chemokine receptor

Initial lymphocyte adhesion to antigen presenting cells in LN

Homingto

lymphnode

L-se

lect

in

VLA

-4

Homingto inflamed

vascularendothelium

CD

45R

A

CD

45R

O

Differentialsplicing of

CD45 mRNAin naïve & armed

T cells

CD

2

LFA

-1

CD

44

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 LYMPHOCYTESReturn to the site of stimulation (antigen)

Mucosal surface- MADCAM-1Retention in spleen, lymph node

LFA-1 – ICAM-1/2integrin – cell and extracellular matrix

Migration through activated endothelial cells of inflammed tissues

Lamina propria in gutMucosal epitheliumDermis 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 toAdhesion molecules and chemokines controlling T- cell homing tolamina proprialamina 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 cellNaive T cell

Activated T cellActivated 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 patchM sejt

Kripta

Villus

Epithelium

A BÉLFALHOZ KAPCSOLÓDÓ SZERVEZETT LIMFOID SZÖVET ÉS A BÉLFALHOZ KAPCSOLÓDÓ SZERVEZETT LIMFOID SZÖVET ÉS IZOLÁLT LIMFOID FOLLICULUSIZOLÁLT 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 (25x109)/lymph nodes/day

BB TBONE MARROW THYMUS

MALTSALTBALT

HEV

BLOOD

Thoracic ductLymphatics

TISSUES

SPLEEN

LYMPH NODES

MIGRATION OF LYMPHOCYTES IN CENTRAL AND PERIPHERAL LYMPHOID ORGANS