M3

• A unique property of the immune system is the constant and highly regulated movement of its major cellular components through the blood, into tissues, and often back into the blood again
• The previous modules discussed the basic components and mechanisms of the different types of the immune system
• The real challenge in understanding the immune system comes from the interaction of its components for different types of infections
• Learning Objectives: 1. Distinguish the mechanism involved in cellular migration and inflammation. 2. Compare acute from chronic inflammation
• Cellular Migration

  Delivery of leukocytes of myeloid lineage (mainly neutrophils and monocytes) from the circulation into tissue sites of infection or injury. 2. Delivery of lymphocytes from their sites of maturation to peripheral lymphoid organs. 3. Delivery of effector lymphocytes from secondary lymphoid organs to sites of infection in any tissue
• Leukocyte Migration

  Leukocyte homing and recruitment to different tissues are governed by general principles. Naïve lymphocytes migrate mainly into secondary lymphoid organs, whereas activated lymphocytes and myeloid leukocytes preferentially home into infected or injured tissues. Memory lymphocytes migrate into various tissues. Leukocyte homing and recruitment require adhesion to the endothelial lining of postcapillary venules
• Effector lymphocytes and myeloid leukocytes


  Preferentially home into tissues where there is infection or tissue injury
• Memory lymphocytes

  Migrate into lymphoid organs, mucosal tissues, skin, and other tissues
• Leukocyte homing and recruitment

  Require the adhesion of leukocytes to the endothelial lining of postcapillary venules, involving molecules on the surfaces of both leukocytes (adhesion molecules and chemokine receptors) and endothelial cells (adhesion molecules and chemokines)
• Endothelial cells activation at sites of infection and tissue injury


  Activated by cytokines secreted by sentinel cells in the tissues, resulting in increased expression of adhesion molecules and chemokines, leading to increased adhesiveness for circulating myeloid leukocytes and previously activated lymphocytes
• Microbes and necrotic tissues induce the expression of molecules that mediate leukocyte-endothelial adhesion

  Effector leukocytes migrate through endothelium mainly when and where they are needed
• Adhesion molecules

  • Mediate the adhesion of circulating leukocytes to vascular endothelial cells, including selectins and integrins
• Selectins


  • Plasma membrane carbohydrate-binding adhesion molecules mediating low-affinity adhesion of circulating leukocytes to endothelial cells lining post capillary venules, including P-selectin (CD62P) and E-selectin (CD62E)
• 1. selectin


  • Stored in cytoplasmic granules of endothelial cells, redistributed to the luminal surface in response to histamine and thrombin
• 1. selectin


  • Synthesized and expressed on the endothelial cell surface in response to cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF), as well as microbial products like lipopolysaccharide (LPS)
• 1. selectin


  • Expressed on leukocytes, promotes adhesion of neutrophils to activated endothelial cells, required for naïve T and B lymphocytes to home into lymph nodes through high endothelial venules (HEVs)
• Integrins

  • Cell surface proteins mediating adhesion of cells to other cells or extracellular matrix through specific binding interactions with various ligands, rapidly increasing their affinity for ligands in response to intracellular signals
• Integrins are induced in all leukocytes by chemokine binding to chemokine receptors and in T cells by antigen binding to antigen receptors
• Major Leukocyte-Endothelial Adhesion Molecules

  • Family: Selectins; Molecule: P-selectin, E-selectin, L-selectin; Distribution: Varies among different types of leukocytes and in blood vessels at different locations; Ligand: Varies
• Major Leukocyte-Endothelial Adhesion Molecules

  • Selectin
  • Integrin
• Selectin Molecules


  • P-selectin (CD62P)
  • E-selectin (CD62E)
  • L-selectin (CD62L)
• Integrin Molecules

  • LFA-1 (CD11aCD18)
  • Mac-1 (CD11bCD18)
  • VLA-4 (CD49aCD29)
  • α4β7 (CD49dCD29)
• Endothelium activated by histamine or thrombin


  1. selectin (CD62P) ligand is Sialyl Lewis X on PSGL-1 and other glycoproteins; neutrophils, monocytes, T cells (effector, memory)
• Endothelium activated by cytokines (TNF, IL-1)


  1. selectin (CD62E) ligand is Sialyl Lewis X (e.g., CLA-1) on glycoproteins; neutrophils, monocytes, T cells (effector, memory)
• Neutrophils, monocytes, T cells (naive and central memory), B cells (naive)


  1. selectin (CD62L) ligand is Sialyl Lewis X/PNAd on GlyCAM-1, CD34, MadCAM-1, others; endothelium (HEV)
• Neutrophils, monocytes, T cells (naive, effector, memory), B cells (naive)

  LFA-1 (CD11aCD18) ligand is ICAM-1 (CD54), ICAM-2 (CD102); endothelium (upregulated when cytokine activated)
• Neutrophils, monocytes, dendritic cells


  Mac-1 (CD11bCD18) ligand is ICAM-1 (CD54), ICAM-2 (CD102); endothelium (upregulated when cytokine activated)
• Monocytes, T cells (naive, effector, memory)

  VLA-4 (CD49aCD29) ligand is VCAM-1 (CD106); endothelium (upregulated when cytokine activated)
• Monocytes, T cells (gut homing, naive, effector, memory), B cells (gut homing)


  α4β7 (CD49dCD29) ligand is VCAM-1 (CD106), MadCAM-1; endothelium in gut and gut-associated lymphoid tissues
• Chemokines and their receptors

  • CC Chemokines
  • CCL2 (MCP-1) - CCR2
  • CCL3 (MIP-1α) - CCR1, CCR5
  • CCL4 (MIP-1β) - CCR5
  • CCL5 (RANTES) - CCR1, CCR3, CCR5
  • CCL11 (Eotaxin) - CCR3
  • CCL17 (TARC) - CCR4
  • CCL19 (MIP-3β/ELC) - CCR7
  • CCL21 (SLC) - CCR7
  • CCL22 (MDC) - CCR4
  • CCL25 (TECK) - CCR9
  • CCL27 (CTACK) - CCR10
  • CXC Chemokines
• Chemokines stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues
• Chemokines

  • CXCL8 (IL-8)
  • CXCL9 (Mig)
  • CXCL10 (IP-10)
  • CXCL12 (SDF1)
  • CXCL13 (BCA-1)
  • XCL1 (Lymphotactin)
  • CX3CL1 (Fractalkine)
• Chemokine Receptors

  • CXCR1, CXCR-2
  • CXCR3
  • CXCR4
  • CXCR5
  • XCR1
  • CX3CR1
• Major Functions of Chemokines

  • Neutrophil recruitment
  • Effector T cell recruitment
  • B cell migration into lymph nodes; plasma cell migration into bone marrow
  • B cell migration into lymph nodes and into follicles; T follicular helper cell migration into follicles
  • T cell and NK cell recruitment
  • T cell, NK cell, and monocyte recruitment
• Some chemokines are produced by cells in response to external stimuli and are involved in inflammatory reactions. Other chemokines are produced constitutively in tissues and maintain the distribution of cells in these tissues, such as localization of T and B cells in lymphoid organs
• In inflammatory reactions, chemokines serve to recruit circulating leukocytes from blood vessels into extravascular sites. Chemokines play two roles in inflammation: Increased adhesion of leukocytes to endothelium and Migration of leukocytes through blood vessels and toward the site of infection or tissue damage
• Chemokines are involved in the development of lymphoid organs, and they regulate the traffic of lymphocytes and other leukocytes through different regions of secondary lymphoid organs
• Chemokines are required for the migration of DCs from sites of infection into draining lymph nodes
• Leukocyte recruitment from the blood into tissues requires adhesion of the leukocytes to the endothelial lining of postcapillary venules and then movement through the endothelium and vessel wall into the extravascular tissue
• Steps in leukocyte recruitment into tissues

  1. Selectin-mediated rolling of leukocytes on endothelium

  2. Chemokine-mediated increase in affinity of integrins

  3. Stable integrin-mediated arrest of leukocytes on endothelium

  4. Transmigration of leukocytes through the endothelium