Excellent review article : Ley et al., Nature Immunology Reviews, 7:678, 2007 Video Acknowledgments to Dr. Tim Springer, Harvard University Homing of naïve/effector/memory cells Recruitment of phagocytic cells Leukocyte/Lymphocyte Trafficking Functions in Immune Response: Adhesion Molecules

Leukocyte Recirculation

IMMUNOSURVEILLANCE Critical for Effective Immune Responses Constant Process – required for rapidly controlling infections Leukocyte adhesion deficiencies – highlight the role of certain adhesion molecules in this process

The Big Picture Endothelial Cells Blood Flow --> PMN Rolling Activation Firm Adhesion Diapedesis

ADHESION MOLECULE FAMILIES (and related proteins) Selectins - Family of C-type Lectins Integrins - Family of Heterodimeric Receptors  2-integrins Cell Adhesion Molecules (CAMs) - Composed of Ig Domains Signaling Molecules (Receptors/Ligands) - Chemoattractant and Chemokine Receptors

Physical Factors Influencing Lymphocyte/Leukocyte Migration Blood Flow Physical Barriers Ability to Detect Infection

Step 1: Rolling

Selectins & CHO Ligands Step 1: Rolling * * * EndotheliumEndothelium LeukocyteLeukocyte P-Selectin E-Selectin L-Selectin Sialyl Lewis X and others

Intravital Microscopy. The mouse mesentery preparation. The following in vivo microscopy is of postcapillary venules from a different type of preparation, hamster cheek pouch Timothy A. Springer, Harvard Medical School

IMMUNOSURVEILLANCE Incomplete glycosylation of sLew x : no binding to selectins LAD II - Leukocyte Adhesion Deficiency Type 2

Step 2: Activation

Chemotactic Receptors & Ligands Step 2: Activation FMLP IL-1 C5a TNF-  Infection 1. Activates both cell types – endothelial and leukocyte 2. Causes “inside-out signaling 3. Gradient-dependent migration of leukocytes

 2 -integrins and Inflammatory Activators NH 2 COOH FMLP PAF IL-8 C5a  G protein Complex

Inside-Out Signaling

Cell Adhesion Molecules - CAMS Endothelium S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S ICAM-1 ICAM-2 VCAM PECAM

Step 3: Firm Adhesion

Infection Inflammatory Mediators

Inflammatory Mediators

LAD I - Leukocyte Adhesion Deficiency Type 1 Missing functional CD18 : no expression of CD11a-d

PECAM:PECAM Integrin:ICAM JAM-1:Integrin JAM-1:JAM-1 Step 4: Diapedesis

Endothelial Cells Blood Flow Leukocyte Rolling Selectin-mediated 1 Activation Cytokine-mediated 2 Firm Adhesion Migration Integrin-mediated 3 4

Naïve Lymphocyte Homing in Lymph Nodes L-Selectin S S S S S S S S S S LFA-1 ICAM-1 PNAd CCR7 CCL19 Rolling Activation Firm Adhesion