Leukotrienes, mast cells, and T cells
© BioMed Central Ltd 2003
Received: 26 September 2003
Accepted: 1 October 2003
Published: 15 October 2003
Unravelling the complex interactions that regulate the recruitment and subsequent cellular crosstalk between leukocyte subsets in inflamed synovium offers considerable therapeutic potential. In rheumatoid arthritis (RA), synovial membrane is characterised by T-cell infiltrates including both CD4 and CD8 subsets that occupy distinct domains within the tissue [1, 2]. The former have attracted the most attention, given their proposed central role in the development and maintenance of acquired immune responses in the synovium. Their functional importance, however, has been critically reviewed, particularly in light of equivocal or negative outcomes in clinical trials in which CD4 T cells have been specifically targeted [1, 3, 4]. Thus far, only CTLA4-Ig has shown any clinical promise . Although comprising up to 40% of the synovial T-cell compartment, CD8 T cells have received less attention. CD8 T cells are widely distributed throughout the synovial membrane and in synovial fluid, exhibit an activated phenotype and enhanced migratory activity, express proinflammatory cytokines, and contribute to formation of ectopic germinal centres in synovial tissues [1, 6, 7]. Recruitment of CD8 T cells to the synovial compartment has been considered a function of appropriate chemokine gradients, lymphocyte chemokine receptor expression, and activation of endothelial cells, expressing adhesion molecules.
Antigen-experienced CD8 T cells segregate into at least two populations in mice, namely central memory CD8 T cells (Tcm; CD62Lhi, CCR7hi), which traffic primarily to lymphoid tissues, and effector memory CD8 T cells (Teff; CD62lo, CCR7lo), which migrate to nonlymphoid tissues . Distinct populations can be generated in vitro using IL-15 and IL-2 to promote Tcm and Teff populations, respectively. Whereas CD62L and CCR7 have been attributed homing function for Tcm, the molecular basis for Teff recruitment to target tissues has not previously been understood. Ott and colleagues  now report an elegant series of experiments suggesting that mast-cell-dependent leukotriene B4 (LTB4) may subserve CD8 Teff recruitment to tissues. Mast-cell biology has assumed increasing prominence in theories of synovitis, providing a potential cellular link between humoral autoimmunity (B cells) and synovial inflammation . The present observations provide a novel molecular mechanism for interactions between mast cells and T cells .
Using a transwell migration assay, Ott and colleagues observed that murine CD8 Teff cells but not Tcm cells migrated in response to soluble factor(s) released by Fcε RI-activated, but not resting, bone-marrow-derived mast cells . Importantly, migration occurred within minutes of mast-cell coculture, suggesting release of a preformed or rapidly synthesised factor. In control experiments, both Tcm and Teff migrated to CCL5 (RANTES [regulated upon activation, normal T-cell expressed and secreted]), indicating that Tcm cells were motile in vitro. Subsequent gene-chip expression array analysis comparing Tcm and Teff revealed higher expression of BLT1, a receptor for LTB4, in Teff cells. Commensurate with a functional role for leukotrienes, the 5-lipoxygenase-activating enzyme inhibitor MK-886 inhibited mast-cell-induced Teff migration; and purified LTB4, but not LTC4, directly induced Teff directional migration in a bell-shaped dose–response curve typical of many chemokines. In contrast, centrally derived (lymph node) CD122hi Tcm cells were unable to migrate to LTB4 unless first activated via the T-cell receptor in the presence of IL-2 to promote a Teff phenotype. Using the inhibitor CP-105696, LTB4-induced Teff migration was shown to be dependent on BLT1 (high affinity) rather than BLT2 (low affinity). Finally, addition of pertussis toxin inhibited migration further, implicating BLT1 via activation of Gi-type G proteins. Together, these data strongly suggest that a novel function of tissue-activated mast cells could be to rapidly recruit Teff cells to tissues during the early phase of innate inflammatory responses.
Mast-cell presence and activation in synovium has been long described within inflammatory aggregates and adjacent to the cartilage pannus junction, where they may be associated with cytokine expression [11, 12]. Their potential effector function includes release of proinflammatory cytokines, chemokines, proteases, vasoactive amines (e.g. histamine) and arachidonate metabolites, including prostaglandins and leukotrienes. Mast cells could therefore promote downstream activation of mononuclear cells, chondrocytes, osteoclasts, and angiogenesis . Such functional import has recently been elegantly demonstrated in vivo. Administration of serum from K/B×N mice failed to induce arthritis in Sl/Sld or W/Wv murine strains, which exhibit functional mast-cell deficiency. Importantly, mast-cell engraftment into W/Wv recipients recovered the incidence of arthritis following serum transfer . Therefore, by virtue of FcγR and complement receptor expression, activated mast cells could provide a cellular mechanism whereby autoantibodies in the appropriate tissue context could promote host tissue inflammatory damage.
The data from Ott and colleagues  now suggest that mast cells could significantly modify T-cell function not only through chemokine release but also via LTB4. Indeed, since LTB4 is also a potent inducer of neutrophil migration, these effects may have broader functional importance in synovium. LTB4 antagonists are effective in reducing collagen- and cytokine-induced arthritis, and 5-LO-deficient mice exhibit reduced collagen-induced arthritis [13–15]. However, it is currently unclear whether LTB4 occupies a sufficiently critical hierarchical position in effector mediator pathways to provide a therapeutic target, given the multiplicity of other chemokines present in synovial tissues to which synovial T cells and indeed other leukocyte subsets are responsive. Thus, although LTB4 antagonism has proved to be of some clinical utility in pulmonary inflammation, it has yet to be properly tested in chronic human synovitis. Other important issues arise. It would be of interest to further define CD8 effector subpopulations in RA tissues and thereafter to determine which are LTB4 responsive. Comparison with migratory activity to other chemokines prominent in synovial tissues will also be essential. More difficult is the question of testing the central role for mast cells in RA in the clinical context. Whereas mast-cell-focused therapies have not yet been specifically attempted, cytokine effector pathways including tumour necrosis factor α (TNFα) have already proven amenable to target – mast cells, however, may represent only a proportion of the TNFα competent cell sources in synovium. More specific approaches targeting mast-cell stabilisation or deletion are awaited. As always, the issue of cellular priority in the chronic, feedback-rich environment of the rheumatoid synovium will await further deductive biologic investigation.
central memory T cells
effector T cells
tumour necrosis factor.
- Panayi GS, Corrigall VM, Pitzalis C: Pathogenesis of rheumatoid arthritis. The role of T cells and other beasts. Rheum Dis Clin North Am. 2001, 27: 317-334.View ArticlePubMedGoogle Scholar
- Bradfield PF, Amft N, Vernon-Wilson E, Exley AE, Parsonage G, Rainger GE, Nash GB, Thomas AM, Simmons DL, Salmon M, Buckley CD: Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis Rheum. 2003, 48: 2472-2482. 10.1002/art.11219.View ArticlePubMedGoogle Scholar
- Firestein GS, Zvaifler NJ: How important are T cells in chronic rheumatoid synovitis?: II. T cell-independent mechanisms from beginning to end. Arthritis Rheum. 2002, 46: 298-308. 10.1002/art.502.View ArticlePubMedGoogle Scholar
- Schulze-Koops H, Lipsky PE: Anti-CD4 monoclonal antibody therapy in human autoimmune diseases. Curr Dir Autoimmun. 2000, 2: 24-49.View ArticlePubMedGoogle Scholar
- Emery P: The therapeutic potential of costimulatory blockade with CTLA4Ig in rheumatoid arthritis. Expert Opin Investig Drugs. 2003, 12: 673-681. 10.1517/eoid.12.4.673.23757.View ArticlePubMedGoogle Scholar
- Kang YM, Zhang X, Wagner UG, Yang H, Beckenbaugh RD, Kurtin PJ, Goronzy JJ, Weyand CM: CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J Exp Med. 2002, 195: 1325-1336. 10.1084/jem.20011565.PubMed CentralView ArticlePubMedGoogle Scholar
- Ruth JH, Rottman JB, Katschke KJ, Qin S, Wu L, LaRosa G, Ponath P, Pope RM, Koch AE: Selective lymphocyte chemokine receptor expression in the rheumatoid joint. Arthritis Rheum. 2001, 44: 2750-2760. 10.1002/1529-0131(200112)44:12<2750::AID-ART462>3.0.CO;2-C.View ArticlePubMedGoogle Scholar
- Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999, 401: 708-712. 10.1038/44385.View ArticlePubMedGoogle Scholar
- Ott VL, Cambier JC, Kappler J, Marrack P, Swanson BJ: Mast cell-dependent migration of effector CD8(+) T cells through production of leukotriene B(4). Nat Immunol. 2003, 4: 974-981. 10.1038/ni971. * See noteView ArticlePubMedGoogle Scholar
- Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB: Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science. 2002, 297: 1689-1692. 10.1126/science.1073176. * See noteView ArticlePubMedGoogle Scholar
- Woolley DE: The mast cell in inflammatory arthritis. N Engl J Med. 2003, 348: 1709-1711. 10.1056/NEJMcibr023206.View ArticlePubMedGoogle Scholar
- Woolley DE, Tetlow LC: Mast cell activation and its relation to proinflammatory cytokine production in the rheumatoid lesion. Arthritis Res. 2000, 2: 65-74. 10.1186/ar70.PubMed CentralView ArticlePubMedGoogle Scholar
- Griffiths RJ, Smith MA, Roach ML, Stock JL, Stam EJ, Milici AJ, Scampoli DN, Eskra JD, Byrum RS, Koller BH, McNeish JD: Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice. J Exp Med. 1997, 185: 1123-1129. 10.1084/jem.185.6.1123.PubMed CentralView ArticlePubMedGoogle Scholar
- Griffiths RJ, Pettipher ER, Koch K, Farrell CA, Breslow R, Conklyn MJ, Smith MA, Hackman BC, Wimberly DJ, Milici AJ, Scampoli DN, Cheng JB, Pillar JS, Pazoles CJ, Doherty NS, Melvin LS, Reiter LA, Biggars MS, Falkner FC, Mitchell DY, Liston TE, Showell HJ: Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis. Proc Natl Acad Sci USA. 1995, 92: 517-521.PubMed CentralView ArticlePubMedGoogle Scholar
- Cannetti CA, Leung BP, Culshaw S, McInnes IB, Cunha FQ, Liew FY: IL-18 enhances collagen-induced arthritis by recruiting neutrophils via TNF-alpha and leukotriene B4. J Immunol. 2003, 171: 1009-1015.View ArticlePubMedGoogle Scholar
- * These papers have been highlighted by Faculty of 1000, a web-based literature awareness service. F1000 evaluations for these papers are available on our website at http://arthritis-research.com/viewpoints/reflinks5_06.asp