《免疫学》（英文版） Chapter 15 Leukocyte Migration and Inflammation

Leukocyte Migration and Inflammation CHAPTER 15 343 Basement across FIGURE 15-4(a)Schematic cross-sectional diagram of a lymph node postcapillary venule with high endothelium. Lymphocytes are shown in various stages of attachment to the HEV and in migration across the wall into the cortex of the node. (b)Scanning electron mi 学 crograph showing numerous lymphocytes bound to the surface of a high-endothelial venule (c)Micrograph of frozen sections of lym- phoid tissue. Some 85% of the lymphocytes(darkly stained)are 代个 bound to HEVs(in cross section), which comprise only 1%-2% of the total area of the tissue section. /Part(a) adapted from A O Anderson and N. D. Anderson, 1981, in Cellular Functions in Immi lity and Inflammation, J.. Oppenheim et al.(eds ) Elsevier, North Holland: part(b)from S. D. Rosen and L. M. Stoolman, 1987, Vertebrate Lectins, Van Nostrand Reinhold: part (c) from S. D. Rosen nations of adhesion molecules and chemokines; receptors lymph nodes, Peyer's patches, tonsils, and spleen) that direct the circulation of various populations of lympho- these microenvironments, dendritic cells capture cytes to particular lymphoid and inflammatory tissues are and present it to the naive lymphocyte, resulting in its activa called homing receptors. Researchers have identified a num- tion. Naive cells do not exhibit a preference for a particular ber of lymphocyte and endothelial cell-adhesion molecules type of secondary lymphoid tissue but instead circulate hat participate in the interaction of lymphocytes with HEVs indiscriminately to secondary lymphoid tissue throughout and with endothelium at tertiary sites or sites of inflamma- the body by recognizing adhesion molecules on HEVs tion(see Table 15-1). As is described later, in the section The initial attachment of naive lymphocytes to HEVs is chemokines, these molecules play a major role in determin generally mediated by the binding of the homing receptor ing the heterogeneity of lymphocyte circulation patterns L-selectin to adhesion molecules such as GlyCAM-1 and CD34 on HEVs(Figure 15-5a). The trafficking pattern of Naive Lymphocytes Recirculate naive cells is designed to keep these cells constantly recircu to Secondary Lymphoid Tissue lating through secondary lymphoid tissue, whose primary function is to trap blood-borne or tissue-borne antigen. A naive lymphocyte is not able to mount an immune re- Once naive lymphocytes encounter antigen trapped sponse until it has been activated to become an effector cell. secondary lymphoid tissue, they become activated and en- Activation of a naive cell occurs in specialized microenviron- large into lymphoblasts. Activation takes about 48 h, and ments within secondary lymphoid tissue(e.g, peripheral during this time the blast cells are retained in the paracortical

nations of adhesion molecules and chemokines; receptors that direct the circulation of various populations of lympho￾cytes to particular lymphoid and inflammatory tissues are called homing receptors.Researchers have identified a num￾ber of lymphocyte and endothelial cell-adhesion molecules that participate in the interaction of lymphocytes with HEVs and with endothelium at tertiary sites or sites of inflamma￾tion (see Table 15-1). As is described later, in the section on chemokines, these molecules play a major role in determin￾ing the heterogeneity of lymphocyte circulation patterns. Naive Lymphocytes Recirculate to Secondary Lymphoid Tissue A naive lymphocyte is not able to mount an immune re￾sponse until it has been activated to become an effector cell. Activation of a naive cell occurs in specialized microenviron￾ments within secondary lymphoid tissue (e.g., peripheral lymph nodes, Peyer’s patches, tonsils, and spleen). Within these microenvironments, dendritic cells capture antigen and present it to the naive lymphocyte, resulting in its activa￾tion. Naive cells do not exhibit a preference for a particular type of secondary lymphoid tissue but instead circulate indiscriminately to secondary lymphoid tissue throughout the body by recognizing adhesion molecules on HEVs. The initial attachment of naive lymphocytes to HEVs is generally mediated by the binding of the homing receptor L-selectin to adhesion molecules such as GlyCAM-1 and CD34 on HEVs (Figure 15-5a). The trafficking pattern of naive cells is designed to keep these cells constantly recircu￾lating through secondary lymphoid tissue, whose primary function is to trap blood-borne or tissue-borne antigen. Once naive lymphocytes encounter antigen trapped in a secondary lymphoid tissue, they become activated and en￾large into lymphoblasts. Activation takes about 48 h, and during this time the blast cells are retained in the paracortical Leukocyte Migration and Inflammation CHAPTER 15 343 Lymphocytes passing across the wall Basement membrane High endothelium (a) (b) (c) FIGURE 15-4 (a) Schematic cross-sectional diagram of a lymph￾node postcapillary venule with high endothelium. Lymphocytes are shown in various stages of attachment to the HEV and in migration across the wall into the cortex of the node. (b) Scanning electron mi￾crograph showing numerous lymphocytes bound to the surface of a high-endothelial venule. (c) Micrograph of frozen sections of lym￾phoid tissue. Some 85% of the lymphocytes (darkly stained) are bound to HEVs (in cross section), which comprise only 1%–2% of the total area of the tissue section. [Part (a) adapted from A. O. Anderson and N. D. Anderson, 1981, in Cellular Functions in Immu￾nity and Inflammation, J. J. Oppenheim et al. (eds.), Elsevier, North￾Holland; part (b) from S. D. Rosen and L. M. Stoolman, 1987, Vertebrate Lectins, Van Nostrand Reinhold; part (c) from S. D. Rosen, 1989, Curr. Opin. Cell Biol. 1:913.]

PART Immune Effector mechanisms Naive t cell Mucosal-homing Skin- homing effector t cell effector t cel CLA L-selectin L-selectin ICAM-1( CD34 GlyCAM-1 d LPAM-1 E-selectin ICAM-1 MAdCAM-1 Intestinal lamina propria Skin dermal venule endothelium Teri FIGURE Examples of homing receptors and vascular addres- pressed on HEV cells. (b, c)Various subsets of effector T cells express sins involved in selective trafficking of naive and effector T cells.(a)Naive high levels of particular homing receptors that allow them to home T cells tend to home to secondary lymphoid tissues through their HEv to endothelium in particular tertiary extralymphoid tissues. The initial regions. The initial interaction involves the homing receptor L-selectin interactions in homing of effector T cells to mucosal and skin sites are and mucin -like cell-adhesion molecules such as CD34 or GlyCAM-1 ex- illustrated. region of the secondary lymphoid tissue. During this phase, home to these sites. Inflamed endothelium expresses a num- called the shut-down phase, the antigen-specific lympho- ber of adhesion molecules, including E-and P-selectin and cytes cannot be detected in the circulation(Figure 15-6). the Ig-superfamily molecules VCAM-1 and ICAM-1, that Rapid proliferation and differentiation of naive cells occurs bind to the receptors expressed at high levels on memory and during the shut-down phase. The effector and memory cells effector cells that are generated by this process then leave the lymphoid tis- sue and begin to recirculate Effector and Memory Lymphocytes Adopt Different Trafficking Patterns hut-down phase The trafficking patterns of effector and memory lympho- 2 cytes differ from those of naive lymphocytes Effector cells g tend to home to regions of infection by recognizing inflamed fg vascular endothelium and chemoattractant molecules that o e are generated during the inflammatory response. Memory lymphocytes, on the other hand, home selectively to the type e of tissue in which they first encountered antigen. Presumably this ensures that a particular memory cell will return to the issue where it is most likely to reencounter a subsequent threat by the antigen it recognizes Effector and memory cells express increased levels of cer- Days following antigen exposure tain cell-adhesion molecules. such as lfa-1 that interact with ligands present on tertiary extralymphoid tissue(such FIGURE 15-6 T-cell activation in the paracortical region of a lymph as skin and mucosal epithelia)and at sites of inflammation, node results in the brief loss of lymphocyte recirculation. During this allowing effector and memory cells to enter these sites. Naive shut-down phase, antigen-specific T cells cannot be detected leaving cells lack corresponding cell-adhesion molecules and do not the node in the efferent lymph

region of the secondary lymphoid tissue. During this phase, called the shut-down phase, the antigen-specific lympho￾cytes cannot be detected in the circulation (Figure 15-6). Rapid proliferation and differentiation of naive cells occurs during the shut-down phase. The effector and memory cells that are generated by this process then leave the lymphoid tis￾sue and begin to recirculate. Effector and Memory Lymphocytes Adopt Different Trafficking Patterns The trafficking patterns of effector and memory lympho￾cytes differ from those of naive lymphocytes. Effector cells tend to home to regions of infection by recognizing inflamed vascular endothelium and chemoattractant molecules that are generated during the inflammatory response. Memory lymphocytes, on the other hand, home selectively to the type of tissue in which they first encountered antigen. Presumably this ensures that a particular memory cell will return to the tissue where it is most likely to reencounter a subsequent threat by the antigen it recognizes. Effector and memory cells express increased levels of cer￾tain cell-adhesion molecules, such as LFA-1, that interact with ligands present on tertiary extralymphoid tissue (such as skin and mucosal epithelia) and at sites of inflammation, allowing effector and memory cells to enter these sites. Naive cells lack corresponding cell-adhesion molecules and do not home to these sites. Inflamed endothelium expresses a num￾ber of adhesion molecules, including E- and P-selectin and the Ig-superfamily molecules VCAM-1 and ICAM-1, that bind to the receptors expressed at high levels on memory and effector cells. 344 PART III Immune Effector Mechanisms (a) Naive T cell L-selectin L-selectin CD34 GlyCAM-1 HEV Tertiary extralymphoid tissue LFA-1 LPAM-1 ICAM-1 E-selectin CLA (b) L-selectin LFA-1 ICAM-1 (c) Mucosal-homing effector T cell Skin-homing effector T cell Intestinal lamina propria endothelium Skin dermal venule endothelium MAdCAM-1 SS SS SS SS SS SS SS SS SS SS SS SS SS FIGURE 15-5 Examples of homing receptors and vascular addres￾sins involved in selective trafficking of naive and effector T cells. (a) Naive T cells tend to home to secondary lymphoid tissues through their HEV regions. The initial interaction involves the homing receptor L-selectin and mucin-like cell-adhesion molecules such as CD34 or GlyCAM-1 ex￾pressed on HEV cells. (b, c) Various subsets of effector T cells express high levels of particular homing receptors that allow them to home to endothelium in particular tertiary extralymphoid tissues. The initial interactions in homing of effector T cells to mucosal and skin sites are illustrated. 2468 Days following antigen exposure Shut-down phase Antigen-specific T cells in efferent lymph FIGURE 15- 6 T-cell activation in the paracortical region of a lymph node results in the brief loss of lymphocyte recirculation. During this shut-down phase, antigen-specific T cells cannot be detected leaving the node in the efferent lymph

Leukocyte Migration and Inflammation CHAPTER 15 345 Unlike naive lymphocytes, subsets of the memory and stream. Figure 15-7 depicts the typical interactions in ex- effector populations exhibit tissue-selective homing behavior. travasation of naive T cells across HEVs into lymph no Such tissue specificity is imparted not by a single adhesion The first step is usually a selectin-carbohydrate interaction receptor but by different combinations of adhesion molecules. similar to that seen with neutrophil adhesion Naive lympho- For example, a mucosal homing subset of memory/effector cytes initially bind to HEVs by l-selectin, which serves as a cells has high levels of the integrins LPAM-1( Ba4B7)and homing receptor that directs the lymphocytes to particular LFA-1(aLb2), which bind to MAdCAM and various ICAMs tissues expressing a corresponding mucin-like vascular ad- on intestinal lamina propria venules(see Figure 15-5b)How- dressin such as CD34 or GlyCAM-1 Lymphocyte rolling is ever, these cells avoid direction to secondary lymphoid tissues less pronounced than that of neutrophils. Although the ini because they have low levels of the L-selectin that would facil- tial selectin-carbohydrate interaction is quite weak, the slow itate their entry into secondary lymphoid tissue. A second sub- rate of blood flow in postcapillary venules, particularly in set of memory/effector cells displays preferential homing to regions of HEVs, reduces the likelihood that the shear force the skin. This subset also expresses low levels of L-selectin but of the flowing blood will dislodge the tethered lymphocyte displays high levels of cutaneous lymphocyte antigen(CLA) In the second step, an integrin-activating stimulus is medi and LFA-1, which bind to E-selectin and ICAMs on dermal ated by chemokines that are either localized on the endothelial venules of the skin(see Figure 15-5c). Although effector and surface or secreted locally. The thick glycocalyx covering of the memory cells that express reduced levels of L-selectin do not HEVs may function to retain these soluble chemoattractant tend to home through HEVs into peripheral lymph nodes, factors on the HEvs. If, as some have proposed, HEVs secrete they can enter peripheral lymph nodes through the afferent lymphocyte-specific chemoattractants, it would explain why lymphatic vessels. neutrophils do not extravasate into lymph nodes at the HEvs even though they express L-selectin Chemokine binding to Adhesion-Molecule Interactions play G-protein-coupled receptors on the lymphocyte leads to acti- ritical roles in Extravasation vation of integrin molecules on the membrane as occurs in neutrophil extravasation. Once activated, the integrin mole The extravasation of lymphocytes into secondary lymphoid cules interact with Ig-superfamily adhesion molecules(e.g tissue or regions of inflammation is a multistep process in- ICAM-1), so the lymphocyte adheres firmly to the endothe- volving a cascade of adhesion-molecule interactions similar lium. The molecular mechanisms involved in the final step, to those involved in neutrophil emigration from the blood- transendothelial migration, are poorly understood rolling Activation Arrest/adhesion T cell L-selectin IA1(④ Transendothelial migration Chemokine ICAM-1 CD34 FIGURE 15-7 Steps in extravasation of a naive T cell through a high- cell-adhesion molecules differ. Activation of the integrin LFA-1, induced endothelial venule into a lymph node Extravasation of lymphocytes in- by chemokine binding to the lymphocyte, leads to firm adhesion fol cludes the same basic steps as neutrophil extravasation but some of the lowed by migration between the endothelial cells into the tissue

Unlike naive lymphocytes, subsets of the memory and effector populations exhibit tissue-selective homing behavior. Such tissue specificity is imparted not by a single adhesion receptor but by different combinations of adhesion molecules. For example, a mucosal homing subset of memory/effector cells has high levels of the integrins LPAM-1 (47) and LFA-1 (Lb2), which bind to MAdCAM and various ICAMs on intestinal lamina propria venules (see Figure 15-5b). How￾ever, these cells avoid direction to secondary lymphoid tissues because they have low levels of the L-selectin that would facil￾itate their entry into secondary lymphoid tissue. A second sub￾set of memory/effector cells displays preferential homing to the skin. This subset also expresses low levels of L-selectin but displays high levels of cutaneous lymphocyte antigen (CLA) and LFA-1, which bind to E-selectin and ICAMs on dermal venules of the skin (see Figure 15-5c). Although effector and memory cells that express reduced levels of L-selectin do not tend to home through HEVs into peripheral lymph nodes, they can enter peripheral lymph nodes through the afferent lymphatic vessels. Adhesion-Molecule Interactions Play Critical Roles in Extravasation The extravasation of lymphocytes into secondary lymphoid tissue or regions of inflammation is a multistep process in￾volving a cascade of adhesion-molecule interactions similar to those involved in neutrophil emigration from the blood￾stream. Figure 15-7 depicts the typical interactions in ex￾travasation of naive T cells across HEVs into lymph nodes. The first step is usually a selectin-carbohydrate interaction similar to that seen with neutrophil adhesion. Naive lympho￾cytes initially bind to HEVs by L-selectin, which serves as a homing receptor that directs the lymphocytes to particular tissues expressing a corresponding mucin-like vascular ad￾dressin such as CD34 or GlyCAM-1. Lymphocyte rolling is less pronounced than that of neutrophils. Although the ini￾tial selectin-carbohydrate interaction is quite weak, the slow rate of blood flow in postcapillary venules, particularly in regions of HEVs, reduces the likelihood that the shear force of the flowing blood will dislodge the tethered lymphocyte. In the second step, an integrin-activating stimulus is medi￾ated by chemokines that are either localized on the endothelial surface or secreted locally. The thick glycocalyx covering of the HEVs may function to retain these soluble chemoattractant factors on the HEVs. If, as some have proposed, HEVs secrete lymphocyte-specific chemoattractants, it would explain why neutrophils do not extravasate into lymph nodes at the HEVs even though they express L-selectin. Chemokine binding to G-protein–coupled receptors on the lymphocyte leads to acti￾vation of integrin molecules on the membrane, as occurs in neutrophil extravasation. Once activated, the integrin mole￾cules interact with Ig-superfamily adhesion molecules (e.g., ICAM-1), so the lymphocyte adheres firmly to the endothe￾lium. The molecular mechanisms involved in the final step, transendothelial migration, are poorly understood. Leukocyte Migration and Inflammation CHAPTER 15 345 L-selectin Naive T cell Chemokine LFA-1 ICAM-1 CD34 HEV Rolling 1 Activation 2 Arrest/adhesion 3 Transendothelial migration 4 FIGURE 15-7 Steps in extravasation of a naive T cell through a high￾endothelial venule into a lymph node. Extravasation of lymphocytes in￾cludes the same basic steps as neutrophil extravasation but some of the cell-adhesion molecules differ. Activation of the integrin LFA-1, induced by chemokine binding to the lymphocyte, leads to firm adhesion fol￾lowed by migration between the endothelial cells into the tissue.