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Chemokines Reveal Important Roles In Lymphocyte and Dendritic Cell Trafficking

by Andrew D. Luster, M.D., Ph.D.


Chemokines play an important role in recruiting inflammatory cells into tissues in response to infection and inflammation. The identification of several new chemokines has revealed that chemokines also play an important role coordinating the movement of T cells, B cells and dendritic cells necessary to generate an immune response.

T cells routinely patrol the body in search of foreign antigens and recirculate through the blood, tissue and lymphatics making over 20 round trips each day. Several recently identified chemokines seem to participate in guiding T cells in their journey. One such chemokine independently identified by several groups and given the various and sundry names of SLC(1), Exodus-2(2), 6Ckine(3), and TCA-4(4) appears to play an important role in directing T cells into peripheral lymph nodes. SLC is constitutively expressed in high endothelial venules, stromal cells of the spleen in T cell rich areas and endothelium of  lymphatics(5). SLC is a potent chemotactic factor for naive T cells and induces T cell arrest on ICAM-1(6). SLC is a ligand for CCR7 which is expressed on T cells and activated dendritic cells (7-9). A role for SLC in the trafficking of T cells into lymph nodes has been suggested from studies that have examined the mutant mouse strain DDD. This mutant mouse strain has a  paucity of lymph node T cells due to a defect in the lymph node stroma (10). It has recently been shown that lymph nodes from the DDD mouse do not express the SLC chemokine. Furthermore, genetic analysis has revealed that the mutant allele maps to  mouse chromosome 4, the same chromosome SLC resides on. Another new chemokine likely to play a role in guiding T cells to and within organs of the immune system is ELC, which has also been identified a MIP-3B(11) and CK-B11(12). ELC is also a ligand for CCR7(13) and expressed constitutively in dendritic cells within lymphoid organs and is strongly chemotactic for naive T cells and activated but not resting B cells(14).

Much the same way T cells recirculate, B cells also traffick through the body, and this process is also controlled by chemokines. The B cell specific CXC chemokine independently identified as BCA-1(15) and BLC(16) is an important participant in this process. BCA is a potent chemotactic factor for B cells  and is expressed in the follicles of Peyer's patches, the spleen and lymph nodes. BCA is a ligand for CXCR5 (BLR1),which is highly expressed on peripheral blood B cells. A role for BCA and CXCR5 in B cell trafficking was revealed by the generation of a mouse strain deficient in CXCR5(17). These mice have an impairment in the trafficking of peripheral blood B cells into lymph nodes.

Chemokine Receptor
SLC/Exodus-2/6Ckine/TCA-4 CCR7
ELC/MIP-3B/CKB-11 CCR7
MIP-3a/LARC/Exodus CCR6
BCA-1/BLC CXCR5
DCCK1/PARC/MIP-4 ?
TECK ?

Dendritic cells are thought to play a pivotal role in generating an immune response by capturing and presenting antigen to lymphocytes in a process that leads to the activation of T and B  cells. Dendritic cells in the tissue are thought to pick up  antigen and bring the antigen back to the lymph nodes where the antigen loaded dendritic cells then interacts with lymphocytes to generate an immune response. Several recent studies have suggested that chemokines may guide the dendritic cells in their journey (18,19). Immature dendritic cells reside in the tissue where thay are very efficient at engulfing antigen but are not very efficient at activating lymphocytes.

Immature dendritic cells respond to a number of chemokines, including the recently identified CC chemokine called MIP-3a (11), LARC(20) or Exodus-1(21). MIP-3a is a ligand for CCR6, which is highly expressed on immature dendritic cells(22-25). MIP-3a is expressed in tonsils by inflamed epithelium, a  site known to be infiltrated by immature debdrutuc cells(18). Moreover, MIP-3a is induced by inflammatory stimuli such as lipopolysaccharide (LPS) or TNFa. It has been hypothesized  that a stimulus such as LPS induces the local tissue production of MIP-3a, which attracts immature dendritic cells into the tissue(18,19). Once in the vicinity of the inflammatory stimulus, immature dendritic cells differentiate into cells more capable of activating lymphocytes. During  this maturation process, dendritic cells downmodulate the expression of CCR6 and hence responsiveness to MIP-3a. At the same time, they upregulate their expression of CCR7  and hence responsiveness to SLC and ELC. This switch in  chemokine receptor expression and chemokine responsiveness results in the mature dendritic cells leaving the tissue and being drawn into the lymphatics, and ultimately, into the T cell rich regions of lymph nodes. While the molecular details still remain to be elucidated, it is likely that the expression of chemokines by lymph  node stroma and dendritic cells coordinate the juxtaposition of antigen loaded dendritic cells with recirculating  T and B cells. A chemokine that may play a role in this is process is DCCK1(26), which was also identified as PARC(27) ,AMC-1(28) and MIP-4. DCCK1 is expressed by activated  mature debdrutuc cells and recruits naive T cells. Another chemokine that may also participate in this process is  TECK(29). TECK is expressed in thymic dendritic cells and is a active on macrophages, dendritic cells and thymocytes.The receptors for DCCK1 and TECK have not yet been identified.

In sum, although initially identified as cytokines profoundly induced by pro-inflammatory stimuli that control the recruitment of leukocytes into inflammatory foci, the chemokines are emerging as important regulators of cellular trafficking in development and homeostasis. In addition, the chemokines also seem to be critical for the coordinated movement of dendritic cells and lymphocytes necessary to generate long lasting antigen specific immunity.


Cell Type Receptor Chemokine
Neutrophil CXCR1

CXCR2

IL-8, GCP-2

IL-8,GCP-2;GRO-a,GRO-b,GRO-g

ENA-78, NAP-2, LIX

Eosinophil CCR3

CCR1

MCP-3,MCP-4;Eotaxin-1,Eotaxin-2,Rantes

MCP-3,MCP-4;MIP-1a,Rantes,HCC-1

Basophil CCR2

CCR3

MCP-1,MCP-2,MCP-3,MCP-4,MCP-5

MCP-3,MCP-4;Eotaxin-1,Eotaxin-2,Eotaxin-2,Rantes

Monocyte CCR1

CCR2

CCR4

CCR5

CCR8

CX3CR1

CXCR4

?

MCP-2,MCP-4;MIP-1a,Rantes,HCC-1

MCP-1,MCP-2,MCP-3,MCP-4,MCP-5

MDC, Tarc

MIP-1A, MIP-1B, Rantes

I-309

Fractalkine

SDF-1

TECK

Resting T Cell CCR7

XCR1

CXCR4

?

MIP-3B (ELC), SLC (6Ckine,exodus-2)

Lymphotactin

SDF-1

Parc, DC-Ck1

Activated T cell TH1-CCR5

TH1- CXCR3

      CCR1

      CCR2

       CCR7

        ?

      CX3CR1

TH2-CCR3

 TH2-CR4

MIP-1a, MIP-1B, Rantes

IP-10, MIG, I-Tac

MCP-3, MCP-4, MIP-1a,Rantes

MCP-1, MCP-2, MCP-3, MCP-4; MCP-5

MIP-3B(ELC),SLC(6Ckine,Exodus-2)

PARC

Fractalkine

MCP-3,MCP-4; Eotaxin-1, Eotaxin-2, Rantes

TARC, MDC

Natural Killer cell CCR2

CCR5

CX3CR1

CXCR3

MCP-1, MCP-2, MCP-3, MCP-4, MCP-5

MIP-1a, MIP-1B; Rantes

Fractalkine

IP-10, MIG, I-Tac

Dendritic Cell Immature-CCR1

                CCR3

                 CCR4

                CCR5

                CCR6

                CCR2

                ?

Mature-CXCR4

              CCR7

MCP-3, MCP-4; MIP-1a; Rantes

MCP-3, MCP-4; Eotaxin-1, Eotaxin-2, Rantes

TARC, MDC

MIP-1a, MIP-1b, Rantes

MIP-3a, (LARC,Exodus-1)

MCP-1, MCP-2, MCP-3, MCP-4, MCP-5

TECK

SDF-1

MIP-3b(ELC), SLC(6Ckine,Exodus-2)

B Cell CXCR5

CXCR4

BCA-1 (BLC)

SDF-1


References:

1. Nagira,M., et.al. 1997. Molecular cloning of a novel human CC chemokine secondary lymphoid-tissue chemokine that is a potent chemoattractant for lymphocytes and  mapped to chromosome 9p12.J. Biol. chem.272:19518-19524.

2. Hromas,R., et.al. 1997. Isolation and characterization of Exodus-2, a novel C-C chemokine with a unique 37-amino acis carboxyl-terminal extension.J.Immunol.159:2554-2558.

3. Hedrick,J.A., and A.Zlotnik.1997. Identification and characterization of a novel B chemokine containing six conserved cysteines.J.Immunol.159:1589-1593.

4. Tanabe,s.,et.al.1997. Identification of a new mouse B-chemokine, thymus-derived chemotactic agent 4, with activity on T lymphocytes and mesangial cells.J. Immunol. 159:5671-5679.

5. Gunn,M.D.,et.al. 1998. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and  chemotaxis of naive T lymphocytes. Proc. Natl. Acad. Sci. USA 95:258-263.

6. Campbell,J.J., et.,al. 1998. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279: 381-384.

7. Yoshida,R., etl.al. 1998. Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7. J.Biol.chem. 273:7118-22.

8. Campbell, J.J.,etl.al.1998. 6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonist for the MIP-3B receptor CCR7. J Cell Biol 141:1053-9.

9. Willimann,K.,et.al. 1998. The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts T cells via CCR7. Eur J Immunol 28:2025-34.

10.Nakano,H.,et.al. 1998. A novel mutant gene involved in T-lymphocyte-specific homing into peripheral lymphoid  organs on mouse dhromosome 4. Blood 91:2886-2895.

11. Rossi,d.L.,et.al.1997. Identification through bioinformatics of two new macrophage proinflammatory human chemokines MIP-3a and MIP-3B1,2.J. Immunol. 158:1033-1936.

12. Kim,C.H., et al. 1998. CKB-11/macrophage inflammatory protein-3B/EB11-ligand chemokine is an efficacious chemo-attractant for T and B cells.J. Immunol. 160:2418-2424.

13.Yoshida,R., et.al. 1997. Molecular cloning of a novel human CC chemokine EFI1-ligand chemokine that is a specific functional ligand for EBI1,CCr7, J.Biol. Chem. 272:12803-9.

14. Ngo, v.N., et.al. 1998. epstein-barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissue and strongly attracts naive T cell and activated B cells. J Exp Med 188:181-191.

15. Legler,D.F., et.al. 1988. B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR/CXCR5. J.Exp. Med. 187:655-660.

16. Gunn, M.D., et.al.1998. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature 391:799-803.

17. Forster,R.,et.al.1996. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell87: 1037-1047.

18. Dieu, M.C., et.al. 1998. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites.J.Exp. Med. 188:373-383.

19. Sozzani, S., et.al. 1998. Differential regulation of  chemokine receptors during dendritic cell maturation: a model for their trafficking properties. J. Immunol. 161: 1083-1086.

20. Hieshima,K., et.al. 1997. Molecular cloning of a novel human CC chemokine liver and activation-regulated chemokine  (LARC) expressed in liver. chemotactic activity for lymphocytes and gene localization on chromosome 2. J. Biol.Chem. 271:5846-5853.

21. Hromas,R., et.al. 1997. Cloning and Characterization of Exodus, a Novel B-chemokine. Blood 89:3315-3322.

22. Greaves,D.R., et.al. 1997. CCR6, a CC chemokine receptor that interacts with macrophage inflammatory protein 3a and is higly expressed in human dendritic cells. J Exp.Med. 186:837-844.

23. Baba,M., et.al. 1997. Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC. J. Biol Chem 272:14893-8.

24. Liao,F., et.al. 1997. STRL22 is a receptor for the CC chemokine MIP-3a. Biochem Ciophys Res Commun 36:212-7.

25. Power, C.A., et.al. 1997. Cloning and characterization of a specific receptor for novel CC chemokine MIP-3a from lung dendritic cells. J. Exp. Med. 186:825-835.

26. Adema, G.J.,et.al. 1997. A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells.  Nature 387:713-717.

27. Hieshima, K.,et.al. 1997. A novel human CC chemokine PARC that is most homologous to  macrophage-inflammatory protein-1a/LD78a and chemotactic for T lymphocytes, but  not for monocytes 1,2. J. Immunol. 159:1140-1149.

28. Kodelja, B., et.al. 1998. alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1a with a Th2-associated expression pattern1. J. Immunol. 1601: 1411-1418.

29. Vicari, A.P., et.al. 1997. TECK: A novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development. Immunity 7:291-301.

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