Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we investigate whether dendritic cells (DC), known to interact directly with T and B cells, might also contribute to the recruitment of B cells through the production of chemotactic factors. We found that B cells responded to several chemokines (CXCL12, CCL19, CCL20, and CCL21), which can be produced by DC upon activation. In addition, supernatant from DC (SNDC) potently and selectively attracted naive and memory B cells but not germinal center (GC) B cells or other lymphocytes (CD4(+), CD8(+) T cells or NK cells). Production of this activity was restricted to DC and was not increased following DC activation by LPS or CD40 ligand. Surprisingly, the B-cell chemotactic response to SNDC was insensitive to pertussis toxin treatment. In addition, the chemotactic factor(s) appeared resistant to protease digestion and highly sensitive to heat. This suggested that the DC chemotactic factor(s) is different from classical chemoattractants and does not involve G(alpha(i)) proteins on the responding B lymphocytes. It is interesting that SNDC was able to synergize with several chemokines to induce massive migration of B lymphocytes. These observations show that DC spontaneously produce factors that, alone or in cooperation with chemokines, specifically regulate B-cell migration, suggesting a key role of DC in the recruitment or localization of B lymphocytes within secondary lymphoid organs.
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PMID:Selective attraction of naive and memory B cells by dendritic cells. 1159 Feb 1

Cognate interaction of chemokine receptor CCR7 on lymphocytes with its ligands CCL19 and CCL21 expressed on high endothelial venules (HEVs) is essential for effective migration of T and B cells across HEVs into secondary lymphoid organs. Plt mice, which lack expression of CCL19 and CCL21-ser, both ligands for CCR7 on HEVs, as well as CCR7-deficient mice, have a defective cell migration and reduced homing of lymphocytes. FTY720, a novel immunosuppressant, causes a reduction of lymphocytes in peripheral blood and tissues and their sequestration into lymphoid tissues. In this study we demonstrate that FTY720 rescues the homing defect in both CCR7(-/-) mice and plt mice. After FTY720 treatment, the number of CD4(+) and CD8(+) T cells as well as B cells in peripheral blood is reduced while pertussis toxin-sensitive homing into peripheral lymph nodes, mesenteric lymph node, and Peyer's patches is increased. Immunohistology demonstrates that FTY720 enables these cells to enter lymphoid tissue through HEVs. Thus, our data suggest an alternative G-alpha(i)-dependent, CCR7-CCL19/CCL21-independent mechanism for lymphocyte homing through HEVs which is strongly augmented in the presence of FTY720.
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PMID:CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720. 1174 87

In this study we examined the role of chemokines in regulating T lymphocyte transmigration across the lining high endothelial cells (HEC) of high endothelial venules (HEV). The roles played by CCL21 (SLC), CCL19 (MIP-3 beta, ELC) and CXCL12 (SDF-1) were assessed using an in vitro transendothelial migration culture system, which constitutively supports high levels of lymphocyte transmigration. We determined that transmigration of T lymphocytes across HEC is inhibitable by treatment of the T lymphocytes with pertussis toxin (PTX) (80% inhibition). This was attributed to blockade of Gi-protein coupled receptors of T lymphocytes, since a non-ADP-ribosylating form of PTX had no significant effect on transendothelial migration. Inhibition of Gi-protein-coupled receptors on the endothelium had no effect on T cell transmigration. Treatment of T lymphocytes with a desensitizing concentration of CXCL12 caused a 60% reduction in T lymphocyte migration across HEC, and the CXCR4 antagonist SDF-1P2G reduced transmigration by 40%. Desensitizing concentrations of CCL21 and CCL19 had no significant effects on T lymphocyte transendothelial migration. Homologous desensitization of T lymphocytes to each chemokine was confirmed in a transwell migration assay. An approximately 3-kb mRNA corresponding to rat SDF-1 beta was constitutively expressed in HEC and cell surface CXCL12 was detectable by enzyme-linked immunosorbent assay. Together, these findings support a pivotal role for HEC-expressed CXCL12 and its receptor on T cells in the regulation of T lymphocyte homing to lymph nodes.
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PMID:Activation of pertussis toxin-sensitive CXCL12 (SDF-1) receptors mediates transendothelial migration of T lymphocytes across lymph node high endothelial cells. 1187 Jun 28

Migration of autoaggressive T cells across the blood-brain barrier (BBB) is critically involved in the initiation of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. The direct involvement of chemokines in this process was suggested by our recent observation that G-protein-mediated signaling is required to promote adhesion strengthening of encephalitogenic T cells on BBB endothelium in vivo. To search for chemokines present at the BBB, we performed in situ hybridizations and immunohistochemistry and found expression of the lymphoid chemokines CCL19/ELC and CCL21/SLC in venules surrounded by inflammatory cells. Their expression was paralleled by the presence of their common receptor CCR7 in inflammatory cells in brain and spinal cord sections of mice afflicted with EAE. Encephalitogenic T cells showed surface expression of CCR7 and the alternative receptor for CCL21, CXCR3. They specifically chemotaxed towards both CCL19 or CCL21 in a concentration dependent and pertussis toxin-sensitive manner comparable to naive lymphocytes in vitro. Binding assays on frozen sections of EAE brains demonstrated a functional involvement of CCL19 and CCL21 in adhesion strengthening of encephalitogenic T lymphocytes to inflamed venules in the brain. Taken together our data suggest that the lymphoid chemokines CCL19 and CCL21 besides regulating lymphocyte homing to secondary lymphoid tissue are involved in T lymphocyte migration into the immunoprivileged central nervous system during immunosurveillance and chronic inflammation.
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PMID:Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis. 1220 25

The marginal zone (MZ) of the spleen is an important site for the capture of blood-borne pathogens and a gateway for lymphocytes entering the white pulp. We have recently reported that Leishmania donovani infection results in a remarkably selective loss of MZ macrophages (MZM) from the MZ. To understand the basis of this observation, we have investigated how MZM maintain their anatomical distribution in the steady state in uninfected mice. We now report that plt/plt mice, which lack functional CCL19 and CCL21, have significantly reduced numbers of MZM compared with normal C57BL/6 (B6) mice. Similarly, in B6.CD45.1-->plt/plt chimeras, donor-derived MZM were rare compared with the number observed in reciprocal plt/plt-->B6.CD45.1 chimeras. Moreover, we show that administration of pertussis toxin, an inhibitor of chemokine receptor signaling, to B6 mice results in exit of MZM from the MZ, that MZM can migrate in response to CCL19 and CCL21 in vitro, and that MZM colocalize with CD31+CCL21+ endothelial cells. Collectively, these data indicate that CCL21 and, to a lesser extent, CCL19 play significant roles in the distinctive localization of MZM within the splenic MZ. Deficiency of CCL19 and CCL21, as also previously observed in mice infected with L. donovani, may thus account for the selective loss of MZM seen during this infection.
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PMID:Localization of marginal zone macrophages is regulated by C-C chemokine ligands 21/19. 1547 21

The nervous systems affect immune functions by releasing neurohormones and neurotransmitters. A neurotransmitter dopamine signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. The secondary lymphoid tissues are highly innervated by sympathetic nerve fibers that store dopamine at high contents. Lymphocytes also produce dopamine. In this study, we examined expression and function of dopamine receptors in lymphocytes. We found that D3 was the predominant subtype of dopamine receptors in the secondary lymphoid tissues and selectively expressed by naive CD8+ T cells of both humans and mice. Dopamine induced calcium flux and chemotaxis in mouse L1.2 cells stably expressing human D3. These responses were almost completely inhibited by pertussis toxin, indicating that D3 was coupled with the Galphai class of G proteins. Consistently, dopamine selectively induced chemotactic responses in naive CD8+ T cells of both humans and mice in a manner sensitive to pertussis toxin and D3 antagonists. Dopamine was highly synergistic with CCL19, CCL21, and CXCL12 in induction of chemotaxis in naive CD8+ T cells. Dopamine selectively induced adhesion of naive CD8+ T cells to fibronectin and ICAM-1 through activation of integrins. Intraperitoneal injection of mice with dopamine selectively attracted naive CD8+ T cells into the peritoneal cavity. Treatment of mice with a D3 antagonist U-99194A selectively reduced homing of naive CD8+ T cells into lymph nodes. Collectively, naive CD8+ T cells selectively express D3 in both humans and mice, and dopamine plays a significant role in migration and homing of naive CD8+ T cells via D3.
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PMID:Dopamine selectively induces migration and homing of naive CD8+ T cells via dopamine receptor D3. 1639 68

The encounter between APC and T cells is crucial for initiating immune responses to infectious microorganisms. In the spleen, interaction between dendritic cells (DC) and T cells occurs in the periarteriolar lymphoid sheath (PALS) into which DC and T cells migrate from the marginal zone (MZ) along chemokine gradients. However, the importance of DC migration from the MZ into the PALS for immune responses and host resistance to microbial infection has not yet been elucidated. In this study, we report that following Leishmania donovani infection of mice, the migration of splenic DC is regulated by the CCR7 ligands CCL19/CCL21. DC in plt/plt mutant mice that lack these chemokines are less activated and produce less IL-12, compared with those in wild-type mice. Similar findings are seen when mice are treated with pertussis toxin, which blocks chemokine signaling in vivo. plt/plt mice had increased susceptibility to L. donovani infection compared with wild-type mice, as determined by spleen and liver parasite burden. Analysis of splenic cytokine profiles at day 14 postinfection demonstrated that IFN-gamma and IL-4 mRNA accumulation was comparable in wild-type and plt/plt mice. In contrast, accumulation of mRNA for IL-10 was elevated in plt/plt mice. In addition, plt/plt mice mounted a delayed hepatic granulomatous response and fewer effector T cells migrated into the liver. Taken together, we conclude that DC migration from the MZ to the PALS is necessary for full activation of DC and the optimal induction of protective immunity against L. donovani.
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PMID:Loss of dendritic cell migration and impaired resistance to Leishmania donovani infection in mice deficient in CCL19 and CCL21. 1662 17

CCL19 and CCL21 are thought to be critical for experimental autoimmune encephalomyelitis (EAE) induction, but their precise role is unknown. We examined the role of these chemokines in inducing EAE. C57BL/6 mice lacking expression of these chemokines (plt/plt mice) or their receptor CCR7 were resistant to EAE induced with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55)) and pertussis toxin. However, passive transfer of pathogenic T cells from wild-type mice induced EAE in plt/plt mice, suggesting a defect independent of the role of CCR7 ligands in the migration of immune cells. Examination of draining lymph node (DLN) cells from MOG(35-55)-immunized plt/plt mice found decreased IL-23 and IL-12 production by plt/plt dendritic cells (DCs) and a concomitant defect in Th17 cell and Th1 cell generation. In contrast, production of the Th17 lineage commitment factors IL-6 and TGF-beta were unaffected by loss of CCR7 ligands. The adoptive transfer of in vitro-generated Th17 cells from DLN cells of MOG(35-55)-immunized plt/plt mice developed EAE in wild-type recipient mice, whereas that of Th1 cells did not. Pathogenic Th17 cell generation was restored in plt/plt DLNs with the addition of exogenous IL-23 or CCL19/CCL21 and could be reversed by inclusion of anti-IL-23 mAb in cultures. Exogenous CCL19/CCL21 induced IL-23p19 expression and IL-23 production by plt/plt or wild-type DCs. Therefore, CCR7 ligands have a novel function in stimulating DCs to produce IL-23 and are important in the IL-23-dependent generation of pathogenic Th17 cells in EAE induction.
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PMID:CCR7 ligands are required for development of experimental autoimmune encephalomyelitis through generating IL-23-dependent Th17 cells. 1962 43

It is unclear where within tissues subsets of effector and memory CD8 T cells persist during viral infection and whether their localization affects function and long-term survival. Following lymphocytic choriomeningitis virus infection, we found most killer cell lectin-like receptor G1 (KLRG1)(lo)IL-7R(hi) effector and memory cells, which are long-lived and high proliferative capacity, in the T cell zone of the spleen. In contrast, KLRG1(hi)IL-7R(lo) cells, which appear terminally differentiated and have shorter life spans, were exclusively localized to the red pulp. KLRG1(lo)IL-7R(hi) T cells homed to the T cell zone using pertussis toxin-sensitive chemokine receptors and appeared to contact gp38(+) stromal cells, which produce the chemokines CCL19 and CCL21 and the T cell survival cytokine IL-7. The transcription factors T-bet and B lymphocyte-induced maturation protein-1 controlled effector CD8 T cell splenic migration. Effector CD8 T cells overexpressing T-bet homed to the red pulp, whereas those lacking B lymphocyte-induced maturation protein-1 homed to the T cell zone. Upon memory formation, CD62L(+) memory T cells were predominantly found in the T cell zone, whereas CD62L(-) cells were found in the red pulp. Thus, effector and memory CD8 T cell subset localization within tissues is linked to their differentiation states, and this may identify anatomical niches that regulate their longevity and homeostasis.
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PMID:Differential localization of effector and memory CD8 T cell subsets in lymphoid organs during acute viral infection. 2092 25

Dendritic cells (DCs) respond to chemotactic signals to migrate from sites of infection to secondary lymphoid organs where they initiate the adaptive immune response. The key chemokines directing their migration are CCL19, CCL21, and CXCL12, but how signals from these chemokines are integrated by migrating cells is poorly understood. Using a microfluidic device, we presented single and competing chemokine gradients to murine bone-marrow derived DCs in a controlled, time-invariant microenvironment. Experiments performed with counter-gradients revealed that CCL19 is 10-100-fold more potent than CCL21 or CXCL12. Interestingly, when the chemoattractive potencies of opposing gradients are matched, cells home to a central region in which the signals from multiple chemokines are balanced; in this region, cells are motile but display no net displacement. Actin and myosin inhibitors affected the speed of crawling but not directed motion, whereas pertussis toxin inhibited directed motion but not speed. These results provide fundamental insight into the processes that DCs use to migrate toward and position themselves within secondary lymphoid organs.
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PMID:Dendritic cells distinguish individual chemokine signals through CCR7 and CXCR4. 2110 54


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