Chapter 3, Part A (Pages 37-45): Leukocyte Migration into Tissues

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1 Allergy and Immunology Review Corner: Chapter 3, Part A (pages 37-45) of Cellular and Molecular Immunology (Seventh Edition), by Abul K. Abbas, Andrew H. Lichtman and Shiv Pillai. Chapter 3, Part A (Pages 37-45): Leukocyte Migration into Tissues Prepared by Cindy S. Bauer, MD, Medical College of Wisconsin; Teresa Pun, MD, University of Manitoba, and Paul Keiser, MD, Walter Reed Army Medical Center 1. Blood neutrophils, monocytes, and activated T lymphocytes use essentially the same mechanisms to migrate to sites of infection. This may include: A. Macrophages that have encountered microbes producing cytokines, such as INFgamma and IL-10. B. Integrins mediating weak tethering and rolling of leukocytes on the endothelium. C. Selectins on the endothelium mediating tight binding to leukocytes. D. Chemokines increasing the affinity of leukocyte adhesion and stimulate the migration of cells through the endothelium to sites of infection. 2. Which selectin can be found in secretory granules of endothelial cells? A. E-Selectin B. P-Selectin C. L-Selectin D. N-Selectin 3. Chemokines involved in inflammatory reactions are produced by leukocytes in response to external stimuli. Chemokine receptors: A. Are G-protein coupled receptors. B. Are never located on leukocytes. C. Exhibit distinct (non-overlapping) specificity for chemokines within each family. D. Are difficult and slow to down-regulate. 4. Chemokine functions are diverse and include which of the following? A. Chemokines are anti-angiogenic B. Chemokines direct cells of host defense away from sites of infection. C. Chemokines are involved in the development of lymphoid organs. D. Chemokine secretion can only be induced by TLR signaling. 5. Chemokines involved in neutrophil migration include which of the following? A. CXCL1 to 3 and CXCL5 to 8. B. CXCL13 C. CXCL9 to 11 D. CCL 24 and 26

2 6. What are the ligands on leukocytes that bind to E-selectin (CD62E) and P-selectin (CD62P) on endothelial cells? A. Sialylated carbohydrate groups related to the Lewis X or Lewis A family. B. ICAM-1 (CD54), ICAM-2 and ICAM-3 C. IL-1 and TNF D. Inactivated complement factor C3b (ic3b) and L-selectin 7. Which family of chemokines has the largest number of receptors? A. CXC (α chemokines) B. CC chemokines (β chemokines) C. CX 3 C chemokines D. C chemokines 8. Which of the following chemokine receptors act as co-receptors for the human immunodeficiency virus? A. CCR7 and CXCR5 B. CCL19 and CCL21 C. CXCL9 and CXCL10 D. CCR5 and CXCR4 9. Leukocyte adhesion deficiency type 1 results is characterized by defective leukocyte adhesion and migration with recurrent bacterial and fungal infections. It is caused by mutations in CD18, resulting in dysfunction of which of these molecules? A. LFA-1 and Mac-1 B. LFA-1 and VLA-4 C. ICAM-1, ICAM-2 and ICAM-3 D. VCAM-1 and MadCAM Leukocyte adhesion deficiency type 2 leads to failure of leukocyte migration into tisses and recurrent bacterial and fungal infections. It results from a mutation in a GDPfucose transporter that is required for the synthesis of the sialyl Lewis X components of ligands for which molecules? A. ICAM-1 B. E-selectin C. PSGL-1 D. PNAd Answers 1. D, page 44, legend to figure 3-3 Macrophages that have encountered microbes produce cytokines, such as TNF and IL-1. Selectins on the endothelium mediate weak tethering and rolling of leukocytes on the endothelium. Integrins mediate firm adhesion. Chemokines increase the affinity of neutrophil integrins and stimulate the migration of cells through the endothelium to sites of infection.

3 2. B, page 39 P-selectin (CD62P), so-called because it was first found in platelets, is stored in cytoplasmic granules of endothelial cells and is rapidly redistributed to the surface in response to microbial products, cytokines, histamine from mast ce;;s and thrombin generated during blood coagulation. These granules are called Weibel-Palade bodies (page 32, updated 6 th edition of Abbas). E-selectin is synthesized and expressed on the endothelial cell surface within 1 to 2 hours in response to the cytokines IL-1 and TNF and microbial products such as LPS. 3. A, pages The receptors for chemokines belong to the seven-transmembrane, GTP-binding (G) protein-coupled receptor (GPCR) superfamily. These receptors initiate intracellular responses through associated trimeric G proteins Chemokine receptors may be rapidly downregulated by exposure to the chemokine, and this is a likely mechanism for termination of responses Chemokine receptors are expressed on all leukocytes, with the greatest number and diversity seen on T cells. 4. C, page 43 Chemokines are essential for the recruitment of circulating leukocytes from blood vessels into extravascular sites Extravascular chemokines stimulate movement of leukocytes and their migration toward the chemical gradient of the secreted protein, a process called chemokinesis Chemokines are involved in the development of lymphoid organs, and they regulate the traffic of lymphocytes and other leukocytes through peripheral lymphoid tissues. Chemokines are required for the migration of dendritic cells from sites of infection into draining lymph nodes. 5. A, page 42, Table A, page 39 The ligands on leukocytes that bind to E-selectin and P-selectin on endothelial cells are complex sialylated carbohydrate groups related to the Lewis X or Lewis A family, present on various surface glycoproteins of granulocytes, monocytes, and some previously activated effector and memory T cells. The best defined of these is the tetrasaccharide sialyl Lewis X (slex). A leukocyte membrane glycoprotein called P- selectin glycoprotein ligand 1 (PSGL-1) is post-translationally modified to display the carbohydrate ligands for P-selectin. Several different molecules may display the carbohydrate ligands for E-selectin, including the glycoproteins PSGL-1 and E-selectin ligand 1 and some glycolipids. 7. B, page 43 There are 10 distinct receptors for CC chemokines (called CCR1 through CCR10), six for CXC chemokines (called CXCR1 through CXCR6), and one for CX3CL1 (called CX3CR1). 8. D, page 43 Certain chemokine receptors, notably CCR5 and CXCR4, act as co-receptors for the

4 human immunodeficiency virus (HIV) (see Chapter 20). Some activated T lymphocytes secrete chemokines that bind to CCR5 and block infection with HIV by competing with the virus. 9. A, page 40 CD18 refers to the β 2 -integrin, which is a component of LFA-1 (CD11aCD18) and Mac-1 (CD11bCD18). 10. B, page 39 The ligands on leukocytes that bind to E-selectin and P-selectin on endothelial cells are complex sialylated carbohydrate groups related to the Lewis X or Lewis A family, present on various surface glycoproteins of granulocytes, monocytes, and some previously activated effector and memory T cells. The best defined of these is the tetrasaccharide sialyl Lewis X (slex). A leukocyte membrane glycoprotein called P- selectin glycoprotein ligand 1 (PSGL-1) is post-translationally modified to display the carbohydrate ligands for P-selectin. Several different molecules may display the carbohydrate ligands for E-selectin, including the glycoproteins PSGL-1 and E-selectin ligand 1 and some glycolipids. Allergy and Immunology Review Corner: Chapter 3, Part A (pages 45-53) of Cellular and Molecular Immunology (Seventh Edition), by Abul K. Abbas, Andrew H. Lichtman and Shiv Pillai. Chapter 3, Part B (Pages 45-53): Leukocyte Migration into Tissues Prepared by Teresa Pun, MD, University of Manitoba, and Paul Keiser, MD, Walter Reed Army Medical Center 1. What is the role of sphingosine 1-phosphate (S1P) in T cell trafficking and homing? A. S1P is present in higher concentrations in tissues and lower concentrations in blood and lymph. B. Naive T cells move along a S1P concentration gradient and move into peripheral tissues after S1P binds to the S1PR1 receptor on T cells. C. Circulating naive T cells express high levels of S1PR1. D. S1PR1 expression is not required for cells to be able to leave the lymph node. 2. Which of the following changes in surface molecule expression on T cells is necessary for naive T cell homing into lymph nodes? A. Increased L-selectin and decreased CCR7 B. Decreased L-selectin and increased CCR7. C. Decreased L-selectin and decreased CCR7. D. Increased L-selectin and increased CCR7. 3. Which chemokine mediates the migration of naive B cells into follicles? A. CXCL13

5 B. CXCR5 C. E-selectin D. CCL25 4. Which adhesion molecules are expressed on monocytes? A. ICAM-1 and VCAM-1 B. LFA-1 and Mac-1 C. P-selectin, E-selectin and Mac-1 D. LFA-1, VLA-4 and L-selectin 5. Two populations of monocytes can be defined by chemokine receptor expression. Which chemokine receptor distinguishes inflammatory monocytes? A. CX 3 CR1 B. CCR2 C. CXCL8 D. CXCR1 6. What is the L-selectin ligand in Peyer s patches? A. GlyCAM-1 B. MadCAM-1 C. ICAM-1 D. CD34 7. Inflamed skin expresses CCL17 and CCL27. Skin-homing effector cells are attracted via expression of CCR4, CCR10 and what ligand for E-selectin? A. PSGL-1 B. PNAd C. CLA-1 D. LFA-1 8. Gut-homing effector T cells express an integrin that binds to MadCAM-1 and what receptor for CCL25? A. CCR4 B. CCR10 C. CCR7 D. CCR9 9. Central memory T cells, in contrast to effector memory T cells, home to secondary lymphoid organs by expressing which surface marker? A. CD45RA B. CD45RO C. L-selectin D. P-selectin 10. Bone marrow-homing IgG-secreting plasma cells express VLA-4 and CXCR4 which bind to which molecules on bone marrow sinusoidal endothelial cells?

6 A. ICAM-1 and CCL25 B. ICAM-1 and CCL17 C. VCAM-1 and CXCL12 D. VCAM-1 and CXCL13 Answers 1. B, page 49 The exit of naive T cells from lymph nodes is dependent on a lipid chemoattractant called sphingosine 1-phosphate (S1P), which binds to a signaling receptor on T cells called sphingosine 1-phosphate receptor 1 (S1PR1) (Fig. 3-7). S1P is present at relatively high concentrations in the blood and lymph compared with tissues... Signals generated by S1P binding to S1PR1 stimulate directed movement of the naive T cells along the S1P concentration gradient out of the lymph node parenchyma. Circulating naive T cells have very little surface S1PR1 because the high blood concentration of S1P causes internalization of the receptor. Once a naive T cell enters a lymph node, where S1P concentrations are low, it may take several hours for the surface S1P1R to be reexpressed. This allows time for a naive T cell to interact with antigen-presenting cells before it is directed down the S1P concentration gradient into the efferent lymphatic. S1P and the S1PR1 are also required for mature naive T cell egress from the thymus, migration of activated T cells out of lymph nodes, and migration of antibody-secreting B cells from secondary lymphoid organs. 2. D, pages 48-49, legend to figure 3-6 Naive T lymphocytes home to lymph nodes as a result of L-selectin binding to its ligand on high endothelial venules, which are present only in lymph nodes, and as a result of binding chemokines (CCL19 and CCL21) displayed on the surface of the high endothelial venule... Recall that both these chemokines bind to the chemokine receptor called CCR7, which is highly expressed on naive lymphocytes. This interaction of the chemokines with CCR7 ensures that naive T cells increase integrin avidity and are able to adhere firmly to HEVs. 3. A, page 52 Once naive B cells enter the stroma of secondary lymphoid organs, they migrate into follicles, the site where they may encounter antigen and become activated. This migration of naive B cells into follicles is mediated by CXCL13, which is produced in follicles and binds to the CXCR5 receptor on naive B cells. 4. D, page 45 Both monocytes and neutrophils express L-selectin and P- and E-selectin ligands and use all three selectins to mediate initial rolling interactions with cytokine-activated endothelial cells. Neutrophils express the integrins LFA-1 and Mac-1, which, on activation, bind to endothelial ICAM-1 and mediate stable arrest of the cells on the vessel wall. Monocytes express the integrins LFA-1 and VLA-4, which bind to endothelial ICAM-1 and VCAM-1, causing stable arrest of these leukocytes. 5. B, page 45

7 There are at least two populations of monocytes in the blood, and in both humans and mice, the populations are defined, in part, by chemokine receptor expression. Inflammatory monocytes, which are the main type recruited to inflammatory sites, express CCR2 in both mice and humans. This receptor binds several chemokines, but the most important one for monocyte recruitment is CCL2 (MCP-1). Thus, monocyte recruitment occurs when resident tissue cells express CCL2 in response to infection. The other population of monocytes, sometimes called nonclassical, lacks CCR2 but expresses CX3CR1. The ligand for this receptor, CX3CL1, is expressed both in soluble form and as a membrane-bound molecule that can support adhesion of monocytes to endothelium. 6. B, pages The PNAd carbohydrate groups that bind L-selectin may be attached to different sialomucins on the HEV in different tissues. For example, on lymph node HEVs, the PNAd is displayed by two sialomucins, called GlyCAM-1 (glycan-bearing cell adhesion molecule 1) and CD34. In Peyer's patches in the intestinal wall, the L-selectin ligand is a molecule called MadCAM-1 (mucosal addressin cell adhesion molecule 1). 7. C, page 51 Skin-homing effector T cells express a carbohydrate ligand for E-selectin called CLA-1 (cutaneous lymphocyte antigen 1) and the CCR4 and CCR10 chemokine receptors, which bind CCL17 and CCL27, chemokines that are commonly expressed in inflamed skin. 8. D, page Gut-homing effector T cells express the α4β7 integrin, which binds to MadCAM-1 on gut endothelial cells, and CCR9, which binds to CCL25, a chemokine expressed in inflamed bowel. 9. C, page 51 Two subsets of memory T cells, namely, central memory and effector memory T cells, were initially identified on the basis of differences in CCR7 and L-selectin expression. Central memory T cells were defined as human CD45RO+ blood T cells that express high levels of CCR7 and L-selectin; effector memory T cells were defined as CD45RO+ blood T cells that express low levels of CCR7 and L-selectin but express other chemokine receptors that bind inflammatory chemokines. These phenotypes suggest that central memory T cells home to secondary lymphoid organs, whereas effector memory T cells home to peripheral tissues. 10. C, page 52 The mechanisms by which different B cell populations migrate to different tissues are, not surprisingly, similar to the mechanisms we described for tissue-specific migration of effector T cells and depend on expression of distinct combinations of adhesion molecules and chemokine receptors on each B cell subset. For example, bone marrow-homing IgGsecreting plasma cells express VLA-4 and CXCR4, which bind respectively to VCAM-1 and CXCL12 expressed on bone marrow sinusoidal endothelial cells.