[Frontiers in Bioscience 2, d197-206, May 1, 1997]

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Robert D. Stout1 and Jill Suttles2

Program in Immunology, Departments of Microbiology1 and Biochemistry2, James H. Quillen College of Medicine at East Tennessee State University, Johnson City, TN, USA

Received 4/15/97; Accepted 4/18/97; On-line 5/1/97


1. Abstract
2. Introduction
3. Multiple roles of macrophages in inflammatory disease
4. Mechanisms of T cell-mediated induction of macrophage function
5. Contact-dependent signaling of macrophage activation
6. Role of contact-dependent signaling in autoimmune disease
7. Perspective
8. Acknowledgments
9. References


Macrophages play diverse roles in episodic T cell-mediated inflammatory diseases such as multiple sclerosis and rheumatoid arthritis, function as accessory cells for T cell activation, as pro-inflammatory cells, as effector cells which mediate tissue damage, and as anti-inflammatory cells which promote wound healing. In addition to the many roles of T cell-derived cytokines in differentially modulating these diverse macrophage activities, research over the last few years has demonstrated that contact-dependent signaling which occurs during T cell-macrophage adhesion is a critical triggering event in the activation of macrophage function. Substantial research emphasis has been placed on CD40 as a mediator of contact-dependent signaling. However, other membrane-anchored receptor:ligand pairs may also contribute to the stimulation of macrophage function. This is a brief review of the rapidly expanding, but still incomplete, knowledge of how T cells, through both contact-dependent and cytokine signals, regulate macrophage function during inflammatory disease.


Research over the past decade has only begun to unravel the complex interactions between T cells and macrophages that are involved in the pathogenesis of cell-mediated inflammatory diseases such as multiple sclerosis. The cellular infiltrates of active sclerotic lesions include CD4+ T cells (Th1 with some Th0 and Th2), CD8+ T cells, and macrophages (microglia and monocytes) (1-8). The types of cells present reflect the state of progression of the inflammatory lesion. Macrophages play critical accessory, inflammatory, and effector roles in this non-septic T cell-mediated inflammatory disease (5-9) and tend to be present throughout the inflammatory process. The development of a cell-mediated response is currently hypothesized to depend on the differentiation of interferon (IFN)-gamma producing Th1 cells from activated Th0 precursors (10,11). The production of interleukin (IL)-12 by macrophages clearly plays an important role in the maturation of Th1 cells (10). Upon maturation, these Th1 cells, as well as inflammatory CD8+ cells, both of which produce IFN-gamma and tumor necrosis factor (TNF)-alpha/beta, play a dominant role in macrophage activation and pathogenesis of the inflammatory lesion (1,3,12-15). In contrast, IL4/IL10-producing T cells are hypothesized to play a role in down-regulation of the inflammatory response (1,3,16). It is these "type 2" CD8+ cells that appear to be active in the cellular infiltrate of sclerotic lesions that are in remission (1,3).

In addition to the many roles of T cell-derived cytokines in stimulation and inhibition of macrophage function (13), research over the last few years has demonstrated that the critical triggering event in activation of macrophage cytokine production and effector function is contact-dependent signaling during T cell:macrophage adhesion (17-24). Substantial research emphasis was placed on CD40 as a mediator of contact-dependent signaling of macrophages. CD40 ligation has been reported to contribute to the induction of accessory molecules such as CD80 and CD86 (25-27), to the induction of inflammatory cytokines and chemokines (27-29), and to the induction of nitric oxide generation (24) and metalloproteinase secretion (30). However, the observation that T cells from CD40L-deficient mice are capable of contact-dependent signaling of macrophages (31) establishes that membrane-anchored receptor:ligand pairs other than CD40:CD40L can be involved in T cell signaling of macrophages. In the following sections, we try to provide a succinct account of T cell signaling of macrophages which, although brief and simplified for the sake of clarity, emphasizes the complexity of the cascading cell-cell interactions involved in a relapsing inflammatory autoimmune disease.


The cellular infiltrates of active sclerotic lesions are dominated by cells of the monocytic lineage (macrophages and microglial cells) (6-8). These macrophages can display very diverse functions in sclerotic lesions (Fig. 1). They can function as accessory cells, presenting antigen and providing co-stimulatory ligands (e.g., CD80, CD86, and CD48) and co-stimulatory cytokines (e.g., IL-1 and IL-12) to the infiltrating T cells (10,13,32-36). Macrophages can be activated to produce prodigious amounts of pro-inflammatory cytokines such as TNF-alpha, IL-1, and IL-6, chemoattractant cytokines such as IL-8 and macrophage inflammatory protein (MIP)-1 alpha/beta (13,37), and pro-inflammatory products of arachidonic acid metabolism (13,38).

Figure 1. The diverse functions of macrophages. Macrophages are capable of many functional activities and contribute both to the initiation of cell-mediated immune response and to the effector limb of those responses. During the course of the response, macrophages can display, at different times, both inflammatory and anti-inflammatory activities.

TNF-alpha, in particular, appears to play a critical role in the pathogenesis of experimental allergic encephalomyelitis, the murine model of multiple sclerosis, insofar as administration of anti-TNF-alpha antibodies in vivo inhibits the development of experimental allergic encephalomyelitis (39).

Interestingly, in addition to the inflammatory and destructive activities listed above, macrophages have the potential to contribute to the remission of the inflammatory episode, although the degree to which they participate in remission has not yet been directly assessed. Macrophages can be induced to generate toxic reactive oxygen and nitrogen intermediates(13,40-45) and to secrete "tissue restructuring" metalloproteinases (13,46-48), each of which have been hypothesized to directly contribute to the demyelinization process (49-51). Macrophages also can be induced to secrete cytokines which inhibit macrophage accessory, inflammatory, and effector functions. IL-10, which is produced by both macrophages and T cells, down-regulates expression of costimulatory molecules such as CD86 (52,53), inhibits the production of IL-1 and TNF-alpha and reduces generation of reactive oxygen and nitrogen intermediates (54-57). Transforming growth factor-beta (TGF-beta), which is produced by many cell types including macrophages and T cells, also inhibits generation of reactive oxygen and nitrogen intermediates (58,59), especially in synergy with IL-10 (43,57,60), and is hypothesized to play a critical role in resolution of inflammatory lesions in experimental allergic encephalomyelitis (61-63).


The induction of these diverse macrophage functions is complex, differentially regulated, and poorly understood. Cytokines can stimulate or inhibit many of the macrophage functions described above but the modulating effect of many of the cytokines depends on the state of activation of the target macrophage population, the triggering signal, and timing (13,64,65). Although some exceptions have been noted, T cell cytokines such as IFN-gamma, IL-4, GM-CSF, and IL-3 generally can enhance accessory and co-stimulatory activity (13,29,66-69) and IFN-gamma, GM-CSF, and IL-3 can augment oxidative burst capacity (70-73). The combination of IL-2 plus IFN-gamma has been shown to induce TNF-alpha production and the combination of TNF-alpha and IFN-gamma have been shown to induce nitric oxide production (74-79). Thus, cytokines, especially the Th1 cytokines (IL2, TNF-alpha, IFN-gamma), can stimulate inflammatory and tissue destructive activities in macrophages.

In contrast, IL-10, TGF-beta, and, to a lesser degree, IL-4 (Th2 cytokines) inhibit the induction of oxidative burst and nitric oxide generation (54,57-59,80) and inhibit inflammatory cytokine production by macrophages (54-56,61,81), but do not affect (or enhance) IL-1Ra (IL-1 Receptor antagonist), IL-10 and TGF-beta production (61,82,83). Thus activated macrophages modulated by TGF-beta may display predominantly anti-inflammatory activities, such as secretion of IL-1Ra, IL-10, and TGF-beta.

Although these cytokines play an important role in modulating macrophage function, it is now clear that a critical mechanism by which T cells trigger these macrophage functions involves engagement of membrane-anchored receptor:ligand pairs during heterotypic adhesion between T cells and macrophages. Macrophage accessory, inflammatory, effector, and inhibitory functions have all been shown to be stimulated by paraformaldehyde fixed activated T cells or plasma membranes isolated from activated T cells (13,17-24,44,45,47). In each of these systems, pre-activation of the T cells is a requirement for cell contact-dependent signaling, suggesting the involvement of activation-induced membrane-anchored ligands on the T cells.


CD40:CD40L is the receptor:ligand pair that has received the most attention in the context of contact-dependent signaling of B cells and macrophages (34,84-87). CD40L is expressed transiently upon activation of T cells, with maximum expression usually observed at 5-10 hrs (88,89). Anti-CD40L antibody interferes with T cell signaling of macrophage accessory function, cytokine production and nitric oxide generation (24,25,28). Conversely, anti-CD40 antibody (28), CD40L-transfected cells (29), or soluble trimeric CD40L (27) induce expression of accessory molecules and production of a full array of cytokines (IL-1, TNF-alpha, IL-6, IL-10, IL-12) by macrophages. However, although anti-CD40L antibody nearly completely blocks induction of IL-1 release and CD80 expression by isolated T cell membranes or fixed T cells (25,28), it only partially blocks nitric oxide generation and CD86 expression (24,25). These observations suggested that CD40 ligation is not solely responsible for T cell contact-dependent signaling. This was confirmed by the observation that T cells from CD40L-deficient mice can activate macrophage nitric oxide generation via contact-dependent signaling (31). Although CD40L-deficient T cells, paraformaldehyde-fixed after being activated for 5 hrs on anti-CD3, lacked the ability to signal macrophage nitric oxide production, CD40L-deficient T cells, fixed after being activated for 24 hrs on anti-CD3, were able to signal macrophage nitric oxide production as effectively as similarly activated normal T cells (31). This indicates that CD40 ligation may dominate signaling early in T cell-macrophage interaction but that other receptors may become involved later in the interaction.

Receptors other than CD40 that have been reported to signal macrophage function include CD23 (90,91), CD31 (92), CD38 (93), CD44 (94), CD45 (45,94), CD69 (95,96), and LFA-3 (94). The most abundant data is on CD23. CD23 is the low affinity Fc RII and thus is capable of binding complexes of antigen and IgE antibody. In addition, CD23 binds CD21 (97) and, according to one report, also binds CD11b and CD11c (98). Ligation of membrane CD23 on macrophages induces production of TNF-alpha, IL-6, and nitric oxide (97,99,100). Interestingly, ligation of CD21 on the macrophage membrane by soluble CD23 also has been reported to induce the production of TNF-alpha and IL-1 by macrophages (101,102). CD21 (90) and, under more restricted conditions, CD23 (103) have been reported to be expressed by activated but not by resting T cells. It is therefore possible that the CD23:CD21 receptor:ligand pair is involved in T cell-mediated signaling of some inflammatory macrophage functions. Ligation of CD40 on myeloid cells, endothelial cells, and fibroblasts can induce a wide range of functional activities which could contribute to essentially every aspect of cell-mediated inflammatory responses.


The role of contact-dependent signaling in the development of experimental allergic encephalomyelitis has been shown dramatically using transgenic B10.PL mice expressing the T cell receptor reactive with the encephalitogenic peptide (Ac1-11) of myelin basic protein. Transgenic CD40L-deficient mice, unlike +/+ transgenic mice, do not develop acute experimental allergic encephalomyelitis upon immunization with Ac1-11 (104). This nonresponsiveness was ascribed to the inability of CD40L-deficient T cells to induce CD80 expression on dendritic cells. The adoptive transfer of CD80-positive accessory cells into CD40L-deficient mice restored their ability to respond to antigen and to develop experimental allergic encephalomyelitis. This indicates that, unless an undiscovered second ligand for CD40 exists, T cells are capable of driving the inflammatory process by CD40-independent receptor:ligand and/or cytokine signaling.

Although the above studies with transgenic CD40L-deficient mice suggest that CD40 ligation is not required for the development of sclerotic lesions once the CD80 costimulus is provided, studies with normal animals indicate that CD40:CD40L

interactions play a significant role throughout the inflammatory process. Administration of anti-CD40L antibody as late as 7-9 days after immunization of SJL mice with encephalitogenic peptide reduced the extent and severity of lesions by more than 50% (6). This is not surprising because CD40:CD40L interactions are known to play many roles in cell-mediated inflammatory responses, including stimulation of expression of adhesion and homing molecules on vascular endothelium, stimulation of chemokine and inflammatory cytokine production, stimulation of the production of IL-12, which is critical for maturation of the inflammatory Th1 subset, and stimulation of fibroblasts (105) (Table 1). Several of the above activities are critical for the development of experimental allergic encephalomyelitis. VCAM-1 plays a critical role in the inflammatory process of experimental allergic encephalomyelitis (106); ligation of CD40 on endothelial cells induces VCAM-1 expression (107). Blockade of CD80 expression has been shown to prevent clinical relapses and chronicity of experimental allergic encephalomyelitis (108-110); antibody blockade of CD40:CD40L interactions completely blocks T cell contact-induction of CD80 expression (25). Since neither IL-10 nor TGF-beta appear to down-regulate CD80 expression (52,53), the down-regulation of CD40L, and hence CD40L stimulation of CD80 expression, may therefore be a pivotal event in the shift from inflammatory to anti-inflammatory activities in the sclerotic lesion.

Table 1: The Roles of CD40:CD40L Interactions in Cell-Mediated Inflammatory Disease
Interacting CellFunctions InducedRole in Inflammatory Response
Dendritic CellsCD80 ExpressionIL-1 Production
Stimulation of Immune Response
Histiocytes, MonocytesIL-12 ProductionDevelopment of Th1 Cells
Histiocytes, MonocytesInflammatory Cytokine ProductionEnhancement of Inflammatory Response
Vascular Endothelial CellsHoming/Adhesion Molecule Expression (e.g., VCAM)Enhanced Recruitment of T Cells into Inflamed Tissue
Monocytes/MacrophagesProduction of NO, O3-, and metalloproteinasesTissue Destruction
Macrophages/fibroblastsProduction of TGF-beta/ProliferationTissue Repair/Remission


The studies on experimenal allergic encephalomyelitis to date strongly support critical roles for CD40 and TNF-alpha (CD40-induced?) in the pathogenesis of sclerotic lesions and for TGF-beta in remission of the inflammatory episode. Although receptors other than CD40 (e.g., CD23 and CD69) have been shown to stimulate macrophage production of inflammatory cytokines in vitro, their role in the pathogenesis of inflammatory disease is still unexplored. The studies on T cell receptor transgenic and CD40L-deficient mice (105) indicate that CD40-independent receptor:ligand pairs and/or cytokines are sufficient to drive the development of disease once the T cells are activated. This is supported by the observation that administration of anti-CD40L antibodies after immunization with encephalitogenic peptide only partially interferes with the development of disease. The identification of these CD40-independent receptors and of their role in the pathogenesis of inflammatory disease will be a major area of research interest throughout the next decade.


This work was supported by grants from the National Institutes of Health (R01 AI34875) and from the Arthritis Foundation (Biomedical Sciences).


1 A. O'Garra, & K. Murphy: T-cell subsets in autoimmunity. Curr Opin Immunol 5,880-6 (1993)

2 H. Wekerle: Immunopathogenesis of multiple sclerosis. Acta Neurol 13,197-204 (1991)

3 D. Mason, & D. Fowell: T-cell subsets in autoimmunity. Curr Opin Immunol 4,728-32 (1992)

4 C.S. Raine, U. Traugott, & S.H. Stone: Suppression of chronic allergic encephalomyelitis: relevance to multiple sclerosis. Science 201,445-8 (1978)

5 R. Martin, H.F. McFarland, & D.E. McFarlin: Immunological aspects of demyelinating diseases. Ann Rev Immunol 10,153-87 (1992)

6 K. Gerritse, R.J. Noelle, A. Aruffo, J. Ledbetter, J.D. Laman, W.J.A. Boersma, & E. Claassen: CD40:CD40 ligand interactions in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci USA 93,2499-504 (1996)

7 I. Huitanga, S.R. Ruuls, S. Jung, N. Van Rooijen, H.-P. Hartung, & C.D. Dijkstra: Macrophages in T cell line-mediated demyelinating and chronic relapsing experimental autoimmune encephalitis in Lewis rats. Clin Exp Immunol 100,344-51 (1995)

8 J. Bauer, T. Sminia, F.G. Wouterlood, & C.D. Dijkstra: Phagocytic activity of macrophages and microglial cells during the course of acute and chronic relapsing experimental autoimmune encephalomyelitis. J Neurosci Res 38,365-75 (1994)

9 S.D. Miller, & W.J. Karpus: The immunopathogenesis and regulation of T cell-mediated demyelinating diseases. Immunol Today 15,356-61 (1994)

10 R. Manetti, P. Parronchi, M.-G. Giudizi, M.-P. Piccinni, E. Maggi, G. Trinchieri, & S. Romagnani: Natural killer cell stimulatory factor (interleukin 12) induces T helper type 1-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med 177,1199-204 (1993)

11 F.W. Fitch, M.D. McKisic, D.W. Lancki, & T.F. Gajewski: Differential regulation of murine T lymphocyte subsets. Annu Rev Immunol 11,29-48 (1993)

12 T.R. Mosmann, & R.L. Coffman: Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol 46,111-48 (1989)

13 R.D. Stout, & J. Suttles: T cell signaling of macrophage activation. Cell contact-dependent and cytokine signals. R. G. Landes Company; Springer-Verlag, Austin, (1995)

14 E. De Maeyer, & J. De Maeyer-Guignard: Interferon-gamma. Curr Opin Immunol 4,321-6 (1992)

15 M.A. Farrar, & R.D. Schreiber: The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol 11,571-611 (1993)

16 P. Salgame, J.S. Abrams, C. Clayberger, H. Goldstein, J. Convit, R.L. Modlin, & B.R. Bloom: Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 254,279-82 (1991)

17 R.D. Stout, & K. Bottomly: Antigen specific activation of effector macrophages by interferon-gamma producing (Th1) T cell clones. Failure of IL-4 producing (Th2) T cell clones to activate effector function in macrophages. J Immunol 142,760-5 (1989)

18 R.D. Stout, & J. Suttles: T cell-macrophage cognate interaction in the activation of macrophage effector function by Th2 cells. J Immunol 150,5330-7 (1993)

19 X. Tao, & R.D. Stout: T cell-mediated cognate signaling of nitric oxide production by macrophages. Requirements for activation of macrophages by plasma membranes isolated from T cells. Eur J Immunol 23,2916-21 (1993)

20 J. Suttles, R.W. Miller, X. Tao, & R.D. Stout: T cells which do not express membrane tumor necrosis factor-alpha activate macrophage effector function by cell contact-dependent signaling of macrophage tumor necrosis factor-alpha production. Eur J Immunol 24,1736-42 (1994)

21 J.P. Sypek, M.M. Matzilevich, & D.J. Wyler: Th2 lymphocyte clone can activate macrophage antileishmanial defense by a lymphokine-independent mechanism in vitro and can augment parasite attrition in vivo. Cell Immunol 133,178-86 (1991)

22 J.-M. Li, P. Isler, J.-M. Dayer, & D. Burger: Contact-dependent stimulation of monocytic cells and neutrophils by stimulated human T cell clones. Immunology 84,571-6 (1995)

23 U. Shu, M. Kiniwa, C.Y. Wu, C. Maliszewski, N. Vezzio, J. Hakimi, M. Gately, & G. Delespesse: Activated T cells induce interleukin-12 production by monocytes via CD40-CD40 ligand interaction. Eur J Immunol 25,1125-8 (1995)

24 L. Tian, R.J. Noelle, & D.A. Lawrence: Activated T cells enhance nitric oxide production by murine splenic macrophages through gp39 and LFA-1. Eur J Immunol 25,306-9 (1995)

25 M. Roy, A. Aruffo, J. Ledbetter, P. Linsley, M. Kehry, & R.J. Noelle: Studies on the interdependence of gp39 and B7 expression and function during antigen-specific immune responses. Eur J Immunol 25,596-603 (1995)

26 M.K. Kennedy, K.M. Mohler, K.D. Shanebeck, P.R. Baum, K.S. Picha, C.A. Otten-Evans, C.A. Janeway, & K.H. Grabstein: Induction of B cell costimulatory function by recombinant murine CD40 ligand. Eur J Immunol 24,116-23 (1994)

27 P.A. Kiener, P. Moran-Davis, B.M. Rankin, A.F. Wahl, A. Aruffo, & D. Hollenbaugh: Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes. J Immunol 155,4917-25 (1995)

28 D.H. Wagner, R.D. Stout, & J. Suttles: Role of the CD40-CD40 ligand interaction in CD4+ T cell contact-dependent activation of monocyte IL-1 synthesis. Eur J Immunol 24,3148-54 (1994)

29 M.R. Alderson, R.J. Armitage, T.W. Tough, L. Strockbine, W.C. Fanslow, & M.K. Spriggs: CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40. J Exp Med 178,669-74 (1993)

30 N. Malik, B.W. Greenfield, A.F. Wahl, & P.A. Kiener: Activation of human monocytes through CD40 induces matrix metalloproteinases. J Immunol 156,3952-60 (1996)

31 R.D. Stout, J. Suttles, J. Xu, I.S. Grewal, & R.A. Flavell: Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice. J Immunol 156,8-12 (1996)

32 C.D. Gimmi, G.J. Freeman, J.G. Gribben, K. Sugita, A.S. Freedman, C. Morimoto, & L.M. Nadler: B-cell surface antigen B7 provides a costimulatory signal that induces T cells to proliferate and secrete interleukin 2. Proc Natl Acad Sci USA 88,6575-9 (1991)

33 G.J. Freeman, F. Borriello, R.J. Hodes, H. Reiser, J.G. Gribben, J.W. Ng, J. Kim, J.M. Goldberg, K. Hathcock, G. Laszlo, L.A. Lombard, S. Wang, G.S. Gray, L.M. Nadler, & A.H. Sharpe: Murine B7-2, an alternative CTLA-4 counter-receptor that costimulates T cell proliferation and interleukin 2 production. J Exp Med 178,2185-92 (1993)

34 E.A. Clark, & J.A. Ledbetter: How B and T cells talk to each other. Nature 367,425-8 (1994)

35 A.J. Kaplan, K.D. Chavin, H. Yagita, M.S. Sandrin, L.-H. Qin, J. Lin, G. Lindenmayer, & J.S. Bromberg: Production and characterization of soluble and transmembrane murine CD2. Demonstration that CD48 is a ligand for CD2 and that CD48 adhesion is regulated by CD2. J Immunol 151,4022-32 (1993)

36 S.B. Mizel: Interleukin 1 and T cell activation. Immunol Today 8,330(1987)

37 J.J. Oppenheim, C.O.C. Zachariae, N. Mukaida, & K. Matsushima: Properties of the novel proinflammatory supergene "intercrine" cytokine family. Ann Rev Immunol 9,617-48 (1991)

38 P. Davies, P.J. Bailey, & M.M. Goldenberg: The role of arachidonic acid oxygenation products in pain and inflammation. Ann Rev Immunol 2,335-57 (1984)

39 N.H. Ruddle, C.M. Bergman, K.M. McGrath, E.G. Lingenheld, M.L. Grunnet, S.J. Padula, & R.B. Clark: An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med 172,1193-9 (1990)

40 S.J. Green, M.S. Meltzer, J.B. Hibbs, & C.A. Nacy: Activated macrophages destroy intracellular Leishmania major amastigotes by an L-arginine-dependent killing mechanism. J Immunol 144,278 (1990)

41 D.J. Stuehr, & O.W. Griffith: Mammalian nitric oxide synthases. Adv Enzymol Molec Biol 65,287-364 (1992)

42 R.B. Johnston, Jr., S. Kitagawa, C.K. Edwards, III, J.Y. Channon, H. Suzuki, & M.J. Pabst: The respiratory burst in activated macrophages: Studies of its molecular basis and evidence for downregulation in chronic infection. Adv Exp Med Biol 239,63-72 (1988)

43 R.T. Gazzinelli, I.P. Oswald, S. Hieny, S.L. James, & A. Sher: The microbicidal activity of interferon-gamma-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-beta. Eur J Immunol 22,2501-6 (1992)

44 R. Rothlein, T.K. Kishimoto, & E. Mainolfi: Crosslinking of ICAM-1 induces co-signaling of an oxidative burst from mononuclear leukocytes. J Immunol 152,2488-95 (1994)

45 W.C. Liles, J.A. Ledbetter, A.W. Waltersdorph, & S.J. Klebanoff: Cross-linking of CD45 enhances activation of the respiratory burst in response to specific stimuli in human phagocytes. J Immunol 155,2175-84 (1995)

46 L.M. Wahl, C.E. Olsen, A.L. Sandberg, & S.E. Mergenhagen: Prostaglandin regulation of macrophage collagenase production. Proc Natl Acad Sci USA 74,4955-8 (1977)

47 S. Lacraz, P. Isler, E. Vey, H.G. Welgus, & J.-M. Dayer: Direct contact between T lymphocytes and monocytes is a major pathway for induction of metalloproteinase expression. J Biol Chem 269,22027-33 (1994)

48 A.M.M. Miltenburg, S. Lacraz, H.G. Welgus, & J.-M. Dayer: Immobilized anti-CD3 antibody activates T cell clones to induce the production of interstitial collagenase, but not tissue inhibitor of metalloproteinases, in monocytic THP-1 cells and dermal fibroblasts. J Immunol 154,2655-67 (1995)

49 A.K. Hewson, T. Smith, J.P. Leonard, & M.L. Cuzner: Suppression of experimental allergic encephalomyelitis in the Lewis rat by the matrix metalloproteinase inhibitor Ro31-9790. Inflamm Res 44,345-9 (1995)

50 T.P. Misko, J.L. Trotter, & A.H. Cross: Mediation of inflammation by encephalitogenic cells: interferon gamma induction of nitric oxide synthase and cyclooxygenase 2. J Neuroimmunol 61,195-204 (1995)

51 Y. Okuda, Y. Nakatsuji, H. Fujimura, H. Esumi, T. Ogura, T. Yanagihara, & S. Sakoda: Expression of the inducible isoform of nitric oxide synthase in the central nervous system of mice correlates with the severity of actively induced experimental allergic encephalomyelitis. J Neuroimmunol 62,103-12 (1995)

52 L. Ding, P.S. Linsley, L.Y. Huang, R.N. Germain, & E.M. Shevach: IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol 151,1224-34 (1993)

53 C. Buelens, F. Willems, A. Delvaux, G. Peirard, J.-P. Delville, T. Velu, & M. Goldman: Interleukin-10 differentially regulates B7-1 (CD80) and B7-2 (CD86) expression on human peripheral blood dendritic cells. Eur J Immunol 25,2668-72 (1995)

54 C. Bogdan, Y. Vodovotz, & C. Nathan: Macrophage deactivation by interleukin 10. J Exp Med 174,1549-55 (1991)

55 I.P. Oswald, T.A. Wynn, A. Sher, & S.L. James: Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation. Proc Natl Acad Sci USA 89,8676-80 (1992)

56 C. Bogdan, J. Paik, Y. Vodovotz, & C. Nathan: Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem 267,23301-8 (1992)

57 R.T. Gazzinelli, I.P. Oswald, S.L. James, & A. Sher: IL-10 inhibits parasite killing and nitrogen oxide production by IFN-gamma-activated macrophages. J Immunol 148,1792-6 (1992)

58 S. Tsunawaki, M. Sporn, A. Ding, & C. Nathan: Deactivation of macrophages by transforming growth factor-beta. Nature 334,260-2 (1988)

59 A. Ding, C.F. Nathan, J. Graycar, R. Derynck, D.J. Stuehr, & S. Srimal: Macrophage deactivating factor and transforming growth factors-beta1, -beta2, and -beta3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma. J Immunol 145,940-4 (1990)

60 I.P. Oswald, R.T. Gazzinelli, A. Sher, & S.L. James: IL-10 synergizes with IL-4 and transforming growth factor-beta to inhibit macrophage cytotoxic activity. J Immunol 148,3578-82 (1992)

61 J. Link, B. He, V. Navikas, W. Palasik, S. Fredrikson, M. Soderstrom, & H. Link: Transforming growth factor-beta 1 suppresses autoantigen-induced expression of pro-inflammatory cytokines but not of interleukin-10 in multiple sclerosis and myasthenia gravis. J Neuroimmunol 58,21-35 (1995)

62 D.B. Stevens, K.E. Gould, & R.H. Swanborg: Transforming growth factor-beta 1 inhibits tumor necrosis factor-alpha/lymphotoxin production and adoptive transfer of disease by effector cells of autoimmune encephalomyelitis. J Neuroimmunol 51,77-83 (1994)

63 L. Santambrogio, G.M. Hochwald, B. Saxena, C.H. Leu, J.E. Martz, J.A. Carlino, N.H. Ruddle, M.A. Palladino, L.I. Gold, & G.J. Thorbecke: Studies on the mechanisms by which transforming growth factor-beta (TGF-beta) protects against allergic encephalomyelitis. Antagonism between TGF-beta and tumor necrosis factor. J Immunol 151,1116-27 (1993)

64 D.M. Paulnock: Macrophage activation by T cells. Curr Opin Immunol 4,344-9 (1992)

65 C. Bogdan, & C. Nathan: Modulation of macrophage function by transforming growth factor beta, interleukin-4, and interleukin-10. Ann N Y Acad Sci 685,713-39 (1993)

66 F. Figueiredo, T.J. Koerner, & D.O. Adams: Molecular mechanisms regulating the expression of class II histocompatibility molecules on macrophages. Effects of inductive and suppressive signals on gene transcription. J Immunol 143,3781-6 (1989)

67 G. Frendl, & D.I. Beller: Regulation of macrophage activation by IL-3. I. IL-3 functions as a macrophage-activating factor with unique properties, inducing Ia and lymphocyte function-associated antigen-1 but not cytotoxicity. J Immunol 144,3392-9 (1990)

68 M.R. Alderson, T.W. Tough, S.F. Ziegler, & R.J. Armitage: Regulation of human monocyte cell surface and souluble CD23 (Fc RII) by granulocyte-macrophage colony stimulating factor and interleukin 3. J Immunol 149,1252-7 (1992)

69 A.S. Freedman, G.J. Freeman, K. Rhynhart, & L.M. Nadler: Selective induction of B7/BB-1 on interferon-gamma stimulated monocytes: A potential mechanism for amplification of T cell activation through the CD28 pathway. Cell Immunol 137,429-37 (1991)

70 J.L. Ho, S.H. He, M.J. Rios, & E.A. Wick: Interleukin-4 inhibits human macrophage activation by tumor necrosis factor, granulocyte-monocyte colony-stimulating factor, and interleukin-3 for antileishmanial activity and oxidative burst capacity. J Infect Dis 165,344-51 (1992)

71 J.L. Ho, S.G. Reed, J. Sobel, S. Arruda, S.H. He, E.A. Wick, & K.H. Grabstein: Interleukin-3 induces antimicrobial activity against Leishmania amazonensis and Trypanosoma cruzi and tumoricidal activity in human peripheral blood-derived macrophages. Infect Immunity 60,2331-7 (1992)

72 W.A. Phillips, & J.A. Hamilton: Phorbol ester-stimulated superoxide production by murine bone marrow-derived macrophages requires preexposure to cytokines. J Immunol 142,2445-9 (1989)

73 S.L. Abramson, & J.I. Gallin: IL-4 inhibits superoxide production by human mononuclear phagocytes. J Immunol 144,625-30 (1990)

74 S. Gautam, J.M. Tebo, & T.A. Hamilton: IL-4 suppresses cytokine gene expression induced by IFN-gamma and/or IL-2 in murine peritoneal macrophages. J Immunol 148,1725-30 (1992)

75 S. Narumi, J.H. Finke, & T.A. Hamilton: Interferon gamma and interleukin 2 synergize to induce selective monokine expression in murine peritoneal macrophages. J Biol Chem 265,7036-41 (1990)

76 R.D. Stout: Macrophage activation by T cells: Cognate and noncognate signals. Curr Opin Immunol 5,398-403 (1993)

77 W. Deng, B. Thiel, C.S. Tannenbaum, T.A. Hamilton, & D.J. Stuehr: Synergistic cooperation between T cell lymphokines for induction of the nitric oxide synthase gene in murine peritoneal macrophages. J Immunol 151,322-9 (1993)

78 S.J. Green, R.M. Crawford, J.T. Hockmeyer, M.S. Meltzer, & C.A. Nacy: Leishmania major amastigotes initiate the L-arginine dependent killing mechanism in IFN-stimulated macrophages by induction of TNF-alpha. J Immunol 145,4290 (1990)

79 G.W. Cox, G. Melillo, U. Chattopadhyay, D. Mullet, R.H. Fertel, & L. Varesio: Tumor necrosis factor-alpha-dependent production of reactive nitrogen intermediates mediates IFN-gamma plus IL-2-induced murine macrophage tumoricidal activity. J Immunol 149,3290-6 (1992)

80 R. Appelberg, I.M. Orme, M.I. Pinto de Sousa, & M.T. Silva: In vitro effects of interleukin-4 on interferon-gamma-induced macrophage activation. Immunology 76,553-9 (1992)

81 D. Chantry, M. ATurner, E. Abney, & M. Feldmann: Modulation of cytokine production by transforming growth factor-beta. J Immunol 142,4295-300 (1989)

82 P. Chomarat, E. Vannier, J. Dechanet, M.C. Rissoan, J. Banchereau, C.A. Dinarello, & P. Miossec: Balance of IL-1 receptor antagonist/IL-1 beta in rheumatoid synovium and its regulation by IL-4 and IL-10. J Immunol 154,1432-9 (1995)

83 M. Turner, D. Chantry, P. Katsikis, A. Berger, F.M. Brennan, & M. Feldmann: Induction of the interleukin 1 receptor antagonist protein by transforming growth factor-beta. Eur J Immunol 21,1635-9 (1991)

84 R.J. Armitage, C.R. Maliszewski, M.R. Alderson, K.H. Grabstein, M.K. Spriggs, & W.C. Fanslow: CD40L: a multi-functional ligand. Semin Immunol 5,401-12 (1993)

85 R.A. Kroczek, D. Graf, D. Brugnoni, S. Giliani, U. Korthuer, A. Ugazio, G. Senger, H.W. Mages, A. Villa, & L.D. Notarangelo: Defective expression of CD40 ligand on T cells causes "X-linked immunodeficiency with hyper-IgM (HIGM1)". Immunol Rev 138,39-59 (1994)

86 F.H. Durie, T.M. Foy, S.R. Masters, J.D. Laman, & R.J. Noelle: The role of CD40 in the regulation of humoral and cell-mediated immunity. Immunol Today 15,406-11 (1994)

87 J.E. Buhlmann, T.M. Foy, A. Aruffo, K.M. Crassi, J.A. Ledbetter, W.R. Green, J.C. Xu, L.D. Shultz, D. Roopesian, R.A. Flavell, & et al: In the absence of a CD40 signal, B cells are tolerogenic. Immunity 2,645-53 (1995)

88 M. Roy, T. Waldschmidt, A. Aruffo, J.A. Ledbetter, & R.J. Noelle: The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. J Immunol 151,2497-510 (1993)

89 B.E. Castle, K. Kishimoto, C. Stearns, M.L. Brown, & M.R. Kehry: Regulation of expression of the ligand for CD40 on T helper lymphocytes. J Immunol 151,1777-88 (1993)

90 E. Fischer, C. Delibrias, & M.D. Kazatchkine: Expression of CR2 (the C3dg/EBV receptor, CD21) on normal human peripheral blood T lymphocytes. J Immunol 146,865-9 (1991)

91 L. Flores-Romo, J. Shields, Y. Humbert, P. Graber, J.-P. Aubry, J.-F. Gauchat, G. Ayala, B. Allet, M. Chavez, H. Bazin, M. Capron, & J.-Y. Bonnefoy: Inhibition of an in vivo antigen-specific IgE response by antibodies to CD23. Science 261,1038-41 (1993)

92 W. Chen, W. Knapp, O. Majdic, H. Stockinger, G.A. Bohmig, & G.J. Zlabinger: Co-ligation of CD31 and Fc RII induces cytokine production in human monocytes. J Immunol 152,3991-7 (1994)

93 F. Lund, N. Solvason, J.C. Grimaldi, R.M.E. Parkhouse, & M. Howard: Murine CD38: an immunoregulatory ectoenzyme. Immunol Today 16,469-73 (1995)

94 D.S.A. Webb, Y. Shimizu, G.A. Van Seventer, S. Shaw, & T.L. Gerrard: LFA-3, CD44, and CD45: Physiologic triggers of human monocyte TNF-alpha and IL-1 release. Science 249,1295-7 (1990)

95 P. Isler, E. Vey, J.H. Zhang, & J.M. Dayer: Cell surface glycoproteins expressed on activated human T cells induce production of interleukin-1 beta by monocytic cells: a possible role of CD69. Eur Cytokine Netw 4,15-23 (1993)

96 R. De Maria, M.G. Cifone, R. Trotta, M.R. Rippo, C. Festuccia, A. Santoni, & R. Testi: Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors. J Exp Med 180,1999-2004 (1994)

97 B. Dugas, M.D. Mossalayi, C. Damais, & J.-P. Kolb: Nitric oxide production by human monocytes: evidence for a role of CD23. Immunol Today 16,574-80 (1995)

98 S. Lecoanet Henchoz, J.F. Gauchat, J.P. Aubry, P. Graber, P. Life, N. Paul Eugene, B. Ferrua, A.L. Corbi, B. Dugas, C. Plater Zyberk, & et al: CD23 regulates monocyte activation through a novel interaction with the adhesion molecules CD11b-CD18 and CD11c-CD18. Immunity 3,119-25 (1995)

99 I. Vouldoukis, V. Riveros-Moreno, B. Dugas, F. Quaaz, P. Becherel, P. Debre, S. Moncada, & M.D. Mossalayi: The killing of Leishmania major by human macrophages is mediated by nitric oxide induced after ligation of the Fc RII/CD23 surface antigen. Proc Natl Acad Sci USA 92,7804-8 (1995)

100 N. Paul Eugene, J.P. Kolb, A. Abadie, J. Gordon, G. Delespesse, M. Sarfati, J.M. Mencia Huerta, P. Braquet, & B. Dugas: Ligation of CD23 triggers cAMP generation and release of inflammatory mediators in human monocytes. J Immunol 149,3066-71 (1992)

101 A. Herbelin, S. Elhadad, F. Ouaaz, D. deGroote, & B. Descamps-Latscha: Soluble CD23 potentiates interleukin-1 induced secretion of interleukin-6 and interleukin-1 receptor antagonist by human monocytes. Eur J Immunol 24,1869-73 (1994)

102 M. Armant, H. Ishihara, M. Rubio, G. Delespesse, & M. Sarfati: Regulation of cytokine production by soluble CD23: costimulation of interferon-gamma secretion and triggering of tumor necrosis factor-alpha release. J Exp Med 180,1005-11 (1994)

103 J.C. Prinz, X. Baur, G. Mazur, & E.B. Rieber: Allergen-directed expressin of Fc receptors for IgE (CD23) on human T lymphocytes is modulated by interleukin 4 and interferon-gamma. Eur J Immunol 20,1259-64 (1990)

104 I.S. Grewal, H.G. Foellmer, D.P. Grewal, J. Xu, F. Hardardottir, J.L. Baron, C.A. Janeway, Jr., & R.A. Flavell: Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis. Science 273,1864-7 (1996)

105 R.D. Stout, & J. Suttles: The many roles of CD40 in cell-mediated inflammatory responses. Immunol Today 17,487-92 (1996)

106 T.A. Yednock, C. Cannon, L.C. Fritz, F. Sanchez-Madrid, L. Steinman, & N. Karin: Prevention of experimental autoimmune encephalomyelitis by antibodies against 4 1 integrin. Nature 356,63-6 (1992)

107 M.J. Yellin, J. Brett, D. Baum, A. Matsushima, M. Szabolcs, D. Stern, & L. Chess: Functional interactions of T cells with endothelial cells: the role of CD40L-CD40-mediated signals. J Exp Med 182,1857-64 (1995)

108 J.A. Bluestone: New perspectives of CD28-B7-mediated T cell costimulation. Immunity 2,555-9 (1995)

109 S.D. Miller, C.L. Vanderlugt, D.J. Lenschow, J.G. Pope, N.J. Karandikar, M.C. Dal Canto, & J.A. Bluestone: Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE. Immunity 3,739-45 (1995)

110 M.K. Racke, D.E. Scott, L. Quigley, G.S. Gray, R. Abe, C.H. June, & P.J. Perrin: Distinct roles for B7-1 (CD-80) and B7-2 (CD-86) in the initiation of experimental allergic encephalomyelitis. J Clin Invest 96,2195-203 (1995)