Cell contact-mediated signaling of monocytes by stimulated T cells: a major pathway for cytokine induction

ARTICLE

INTRODUCTION

Inflammation is usually the consequence of tissue damage and aims at directing plasma factors and immune cells to the lesion site to eradicate infection and repair damaged tissue. In acute inflammation, the first cells to migrate to the inflammatory site are mainly polymophonuclear neutrophils and macrophages which, in case of immunologic stimulation, are followed by lymphocytes. Neutrophils and macrophages of the innate immune system provide a first line of defense against exogenous pathogens including common bacterial infection; they also play a crucial part in the triggering and subsequent direction of the adaptive immune response undertaken by lymphocytes. In such a system, bacteria and bacterial products (e.g. endotoxins) activate macrophages to produce cytokines which are effectors of inflammation. Indeed, inflammation is commonly defined by four notions ­ pain, redness, heat, and swelling ­ all of which reflect effects of cytokines on the local blood vessels. Among cytokines, tumor necrosis factor-alpha(TNF-alpha) and interleukin-1beta (IL-1beta) play an essential role in inflammation. Their production at high levels is induced by endotoxins such as lipopolysaccharides (LPS). However, the factors which induce production of TNF-alpha and IL-1 in chronic inflammation are still elusive. Indeed, as depicted in Figure 1, in chronic inflammation, infiltration of immune cells into the target tissue precedes tissue damage, i.e., the lesion occurs after infiltration of immune cell. Based on observations in animal models of chronic inflammatory diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS), it is usually thought that the first cells to infiltrate the tissue are T lymphocytes, suggesting a pathogenic role for the latter cells. However, T cell cytokines such as IL-4, IL-10, and IL-13 have predominantly anti-inflammatory effects and IFN-gamma alone displays weak activation capacity in terms of IL-1beta and TNF-alpha induction. This suggests that T cells might exert a pathological effect through direct cellular contact with monocyte-macrophages. Studies carried out in our laboratory during the past ten years have proved this premise. This review aims at assessing the importance of contact-mediated monocyte activation by stimulated T lymphocytes in chronic inflammatory conditions as in rheumatoid arthritis (RA) and multiple sclerosis (MS) which are taken as examples.

T cell contact-mediated induction of cytokines in monocytes

The activation of effector cells mediated by T lymphocytes has been abundantly substantiated by the induction of B cell proliferation and antibody secretion, which require both direct cell-cell contact and soluble signals. Indeed, B cells can be activated in the absence of antigen by direct contact with activated T cells [1, 2]; on examining simultaneously the activation of both T and B cells a considerable amount of signaling "cross-talk" was observed, that triggered various synchronized signals resulting in the activation of effector functions in both cell types.

Considering that cells of the monocytic lineage have been considered "professional" antigen-presenting cells (APC or dendritic cells), it is surprising that a great number of studies addressed the question of APC signaling of T cells while only few address the question of T cell signaling of monocyte-macrophages in the context of cell-cell contact. Most studies dealing with the question of monocyte-macrophage activation have focused on the role of natural exogenous soluble factors such as lipopolysaccharides (LPS) and other bacterial products or endogenous products such as IFNgamma and CSFs and to some extent TNF-alphaand IL-1 [3, 4]. Cytokines like TNF-alpha and IL-1 [5] which potently stimulate nearby connective tissue cells to release MMPs [6-10] and PGE₂, have a very weak capacity to induce monocyte-macrophages to produce MMPs [11]. Indeed, it appears that most of the soluble cytokines produced by T cells mainly have an anti-inflammatory capacity on monocyte-macrophage functions.

In the mid-eighties it was observed that the expression of membrane-associated IL-1 (IL-1alpha) in mouse macrophages was mediated by both soluble factors and direct contact with T cells [12]. T cell contact-mediated IL-1 induction in monocytes took place with both Th1 and Th2 cells in the absence of lymphokine release [13]. The production of IL-1beta by human monocytes also required direct contact with anti-CD3-stimulated T cells [14]. Accordingly other observations have shown that the induction of macrophage effector functions mediated by T lymphocytes in living cell co-cultures involved signals delivered by cell-cell contact together with IFNgamma [15-17]. However, fixed, stimulated T cells induced TNF production in macrophages in the absence of IFN-gamma [18]. Furthermore, by using isolated plasma membranes from various stimulated T cell clones it was demonstrated that both stimulated Th1 and Th2 cells were able to induce nitric oxide production in macrophages [19], establishing that direct contact with stimulated T cells was able to activate monocyte-macrophages. The use of double-chamber culture systems has demonstrated that in the presence of the T lymphocyte activator PHA the coculture of viable T lymphocytes and freshly isolated blood monocytes in the same compartment resulted in a massive production of IL-1beta and TNF-alpha by mononuclear phagocytes. This did not apply when cells were physically separated by a permeable membrane [20]. Thus the evidence was obtained that cell-cell contact with stimulated T lymphocytes triggers monocytes to produce proinflammatory cytokines. It was subsequently determined that: (i) direct cell-cell contact with either fixed, stimulated T cells or membranes of stimulated T cells is sufficient to transduce the activating signal; and (ii) cell-surface glycoproteins on stimulated T lymphocytes are involved in target cell activation [21, 22].

Contact-mediated activation of monocyte-macrophages by stimulated T lymphocytes is as potent as LPS or PMA in inducing cytokine production in monocytes and cells of the monocytic lineage such as THP-1 cells (Figure 2). The latter results were obtained by using membranes isolated from T cells stimulated by PHA/PMA which induces contact-activating capacity in most if not all T cell types including T cell clones, freshly isolated T lymphocytes and T cell lines such as HUT-78 cells [20-23]. Besides PHA/PMA, various stimuli induce T cells to activate monocytes by direct cellular contact: (i) cross-linking of CD3 by immobilized anti-CD3 mAb with or without cross-linking of the co-stimulatory molecule CD28 [24-26], (ii) antigen-recognition on antigen-specific T cell clones [25], and (iii) cytokines [27-29]. Furthermore, depending on T cell type and T cell stimulus, direct cell-cell contact with stimulated T cells can induce different patterns of products in monocyte-macrophages (Table 1). This suggests that multiple factors are involved in contact-mediated activation of monocyte-macrophages, that are differentially induced in T cells as a function of the stimulus. In some cases, an unbalanced production of pro-inflammatory versus anti-inflammatory cytokines has been observed, i.e., where Th1 cell clones preferentially induce IL-1beta over IL-1Ra production and cytokine-stimulated T lymphocytes induce TNF-alpha production but not that of IL-10 [25, 27]. Besides, we demonstrated that upon contact with stimulated T cells the balance between IL-1beta and IL-1Ra production in monocytes is controlled by Ser/Thr phosphatase(s) [30] and that contact-activated THP-1 cells express membrane-associated protease(s) neutralizing TNF-alpha activity both by degrad- ing the latter cytokine and by cleaving its receptors at the cell surface [31]. Thus the triggering of these intra- and extra-cellular processes by direct contact with stimulated T lymphocytes may regulate the pro-inflammatory cytokines and their inhibitors, and the balance of their production in monocytes dictates in part the outcome of the inflammatory process [32].

The critical question arising from these observations is the identity of the molecules on the T cell surface that are involved in contact-mediated signaling of monocyte-macrophage activation as well as their counter-ligands. It has been postulated that T cell membrane-associated TNF-alpha was involved in monocyte-macrophage activation [16, 17, 33]. However, fixed, stimulated Th2 cells from a T cell line which did not express membrane-associated TNF were able to induce both TNF and IL-1 production in monocyte-macrophages [34] demonstrating that TNF-alpha might play a part but not a major one. We have shown that neither soluble TNF-alpha receptors nor IL-1Ra block T cell-signaling of the monocytic cell line THP-1. Furthermore, neutralizing antibodies to TNF-alpha, IL-1, IL-2, IFN-gamma and GM-CSF all failed to affect monocyte activation by membranes from stimulated T cells [21, 22, 35]. Similarly, although LT-beta receptor is expressed in macrophages [36], it is not likely that membrane-associated LT is involved in monocyte-macrophage signaling upon contact with stimulated T cells, since Th2 cells do not express LT at either protein or mRNA levels [37].

Beside membrane-associated cytokines, other surface molecules have been assessed as to their ability to activate monocyte-macrophages upon contact with stimulated T cells, e.g., LFA-1/ICAM-1, CD2/LFA3, CD40/CD40L and lymphocyte activation-antigen-3 (LAG-3). Thus CD40/CD40L interaction was shown to be involved in the contact activation of both human and mouse monocyte-macrophages by T lymphocytes stimulated for 6 hours [18, 38]. Furthermore, 6 hours-stimulated peripheral blood T lymphocytes isolated from CD40L knockout mice did not induce monocyte activation. However, when stimulated for 24 hours T lymphocytes isolated from both CD40L knockout and wild type mice triggered monocyte activation, although to a lower extent [39]. We never observed any inhibition of contact-induced cytokine production, whether by blocking antibodies to CD40L or soluble CD40. Furthermore, in our system, human T lymphocytes are stimulated for 48 hours and express a high capacity to induce cytokines in monocyte-macrophages. The most effective human T cell line in inducing signaling of monocytes by direct contact is the human lymphocytic cell line HUT-78 [40] which does not express CD40L mRNA in resting or activated conditions [41]. Finally, THP-1 cells which respond to contact-mediated activation by membranes of stimulated T cells do not express CD40. This suggests that CD40/CD40L might be involved in contact-activation of monocyte-macrophages by T lymphocytes stimulated for short periods of time, contrary to T lymphocytes stimulated for long periods since the latter cells cease to express CD40L beyond a certain time [42]. A recent study of ours shows that in co-cultures of living cells stimulated with IL-15 Th1 but not Th2 clones induce IL-1beta production in monocytes [29]. In the latter system, blockade of the CD40-CD40L interaction results in inhibition of IL-1beta production while IL-1Ra induction is unaffected. This differential effect indicates the selective relevance of CD40-CD40L engagement upon monocyte activation by Th1 clones. However, the levels of CD40L expression did not differ in Th1 and Th2 cell clones, implying that additional, unidentified molecule(s) preferentially expressed by Th1 cells are involved in their IL-1beta induction capacity. LAG-3 might be one of the latter factors since it is able to synergize with low amounts of CD40L to induce TNF-alpha and IL-12 in monocyte-derived dendritic cells [43]. Others found cytokine production to be induced in monocytes by soluble CD23 [44-46]. In monocytes, the counter-ligands of CD23 are CD11b/CD18 and CD11c/CD18 rather than CD21 [46, 47]. Studies from our group and others have demonstrated that LFA-1 (CD11a/CD18) and CD69 play a role in the activation of human monocytic cells by stimulated T cells [21, 48]. The latter data were substantiated by a study showing that IL-15 induced synovial T cells from RA patients to activate the production of TNF-alpha by macrophages. This effect was inhibited by antibodies to CD69, LFA-1 and ICAM-1 [28]. Thus it is possible that some known surface molecules are involved in T cell signaling of monocyte-macrophages. However, inhibitors (e.g. antibodies) of these molecules fail to abolish monocyte activation altogether, suggesting that the required factor(s) for T cell signaling of human monocytes by direct contact remain(s) to be identified. In our hands, antibodies to known cell surface antigens (CD2, CD11a, CD11b, CD11c, CD14, CD18, CD23, CD29, CD40, CD40L, CD54, CD69, CTLA4, CD95, CD95L) or membrane-associated cytokines (IFN-gamma, IL-2, GM-CSF, IL-1, TNF-alpha, LT), and cytokine inhibitors (IL-1Ra, TNF-soluble receptors) failed to abolish the activity of contact-activation factors in monocytes and THP-1 cells [21, 22, 35] (and unpublished data). Only antibodies to CD11a, CD11b, CD11c, and CD69 partially inhibited the activity of contact-activation factors [21, 22]. In addition, unstimulated HUT-78 cells expressing CD69, CD11a and TNF-alpha constitutively at their surface did not induce any contact-mediated signaling in THP-1 cells, whereas PHA/PMA-stimulated HUT-78 cells, whose expression of CD69 and CD11a remained unchanged as compared to unstimulated HUT-78 cells, potently activated THP-1 cells. Metabolic inhibitors such as cycloheximide and tunicamycin inhibited the expression of contact-activation factors on stimulated T cells demonstrating that the contact-activation factors were glycoproteins [21-23]. Inhibitors of N-linked oligosaccharide processing [49] such as Swainsonine and N-methyldeoxynojirimycin did not inhibit the activity of contact-activation factors, implying that N-linked oligosaccharides may not be involved in T cell signaling of THP-1 cells.

Relevance of contact-mediated activation of monocyte-macrophages to chronic inflammatory diseases

T lymphocytes are likely to play a pivotal role in the pathogenesis of chronic inflammatory diseases such as RA and MS. In RA, T lymphocytes displaying a mature helper phenotype (i.e., CD3⁺CD4⁺CD45RO⁺) are the main infiltrating cells in the pannus, at percentages ranging from 16% of total cells in "transitional areas" to 75% in "lymphocyte-rich areas" [50-53]. The latter areas being located in perivascular regions, around "high endothelial venule"-like vessels where T lymphocyte extravasation occurs [53] forming germinal center-like structures [54, 55]. Although they are the most abundant infiltrating cells in the pannus, the importance of T lymphocytes in RA pathogenesis has been mainly proved in animal models. Indeed, T cells from RA patients transferred to SCID mice induced arthritis in the latter animals [56]. In MS, T lymphocytes are thought to be pathogenic since antigen-specific T lymphocytes induce experimental allergic encephalitis (EAE), which is the rodent model for MS [57]. Indeed, activated, but not resting, T lymphocytes spontaneously cross the blood-brain barrier [58]; when these activated T lymphocytes are specific for brain antigens such as myelin basic protein (MBP), they mediate EAE in rodents. Both MS and RA are thought to be Th1 cell-mediated diseases [59-61]. Although evidence suggests that T lymphocytes play a pathogenic part in chronic inflammatory diseases, the mechanism by which the latter cells exert their pathogenicity has not been clearly elucidated. The induction by stimulated T lymphocytes of pro-inflammatory cytokine production in monocyte-macrophages by direct cell-cell might be the mechanism, or one of several, by which T lymphocytes exert their pathogenicity, since pro-inflammatory cytokines such as TNF-alpha and IL-1beta are essential players in the pathogenesis of immuno-inflammatory diseases including RA and MS [62].

In vitro studies of synovial tissue from RA patients suggest that the effects of TNF-alpha are amplified due to its potential to induce other pro-inflammatory cytokines, such as IL-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) [63, 64]. Furthermore, the role of IL-1 and TNF-alpha in RA was recently strengthened by clinical studies showing that the efficacy of treatments resorting to the blockade or inhibition of TNF-alpha and IL-1 in vivo [65-69]. In MS, there is now considerable evidence that proinflammatory cytokines like TNF-alpha and IL-1 contribute to pathogenesis (for review see [60, 70, 71]). Indeed, IL-1beta and TNF-alpha are particularly relevant to autoimmune diseases of the central nervous system (CNS) since they are endogenously produced by astrocytes, microglia (CNS endogenous macrophages), and infiltrating monocytes/macrophages [72-75]. It is also likely that interferon-beta (IFN-beta), the only treatment displaying some efficiency in MS, affects the cytokine profile of immune cells [76]. Since (i) monocyte-macrophages are the main pro-inflammatory cytokine producers, and (ii) with the exception of infectious agents, contact-mediated activation is the only described mechanism that induces cytokine production in monocyte-macrophages, it is very likely that direct contact is relevant to both RA and MS and to other immuno-inflammatory diseases such as Crohn's disease, systemic lupus erythematosus, and atherosclerosis. Last but not least, it has been demonstrated that contact-mediated activation by stimulated T lymphocytes is not only efficient in infiltrating monocyte-macrophages but also in intrinsic macrophages. Indeed, the contact-mediated induction of cytokines in microglial cells has been demonstrated [77, 78], the latter being considered macrophages of the CNS.

Modulation of contact-mediated activation of monocyte-macrophages

A major function of monocyte-macrophages is to release various cytokines including IL-1beta and TNF-alpha which in turn participate in the induction of metalloproteinase (MMP) secretion in fibroblast-like cells and monocyte-macrophages themselves [7, 8]. Therefore, blocking the production of these cytokines at a more distal level (i.e., at the level of monocyte activation) might lead to new therapeutic approaches. Since the contact-mediated activation of monocyte-macrophages is a major pathway inducing cytokine production, the modulation of this mechanism, i.e., the blockade of IL-1 and TNF-alpha production at the triggering level, would be of therapeutic interest. We carried out some studies aiming at establishing that therapeutic agents used in RA and MS patients, i.e., leflunomide (LF) and IFN-beta [76, 79-81], respectively, might affect the contact-mediated activation of monocytes. We found out that both therapeutic agents affected contact-mediated activation of monocytes. LF inhibits the ability of stimulated T lymphocytes to trigger IL-1beta production in monocytes resulting in an enhancement of the IL-1Ra/IL-1beta molar ratio [82]. Interestingly, surface molecules of T lymphocytes that were partially involved in contact-signaling of monocytes (i.e., CD69 and CD11) were not modulated by LF, again suggesting that factors which remain to be identified were involved in the contact-mediated activation of monocytes by stimulated T lymphocytes. Similar results were obtained with IFN-beta, although its effect was assessed in unseparated PBMC stimulated by PHA. In the latter system the production of IL-1beta and TNF-alpha by monocytes was due to contact with stimulated T lymphocytes, as assessed in double-chamber culture plates [20]. Interestingly, IFN-beta not only inhibited IL-1beta and TNF-alpha but as well stimulated IL-1Ra in PHA-stimulated PBMC [83]. Whether IFN-beta affects T lymphocytes or monocytes in the latter culture system remains to be determined. However, preliminary results suggest that both T lymphocytes and monocytes are affected by IFN-beta [84]. Although preliminary, these studies demonstrate that anti-inflammatory agents, whether drugs or cytokines, are able to inhibit cytokine production induced in monocytes by direct contact with stimulated T cells, mimicking effects observed in patients in vivo. This suggests that part of the beneficial effects of these therapeutics might be attributed to the modulation of contact-mediated activation of monocytes. More recently we found a novel mechanism of inhibition due to the hindrance of cellular contact between stimulated T cells and monocytes by high density lipoprotein-associated apolipoprotein A-I [85], the latter mechanism blocking monocyte activation and thus both TNF-alpha and IL-1beta production.

CONCLUSION

To date, direct cell-cell contact with stimulated T lymphocytes is the only described pathway triggering activation of monocyte-macrophages in the absence of infectious agents. The potency of this mechanism suggests that it is a major pathway by which T lymphocytes exert their pathogenic effect in chronic inflammatory diseases of autoimmune etiology. Many more investigations are needed to identify the surface molecules ­ ligands and counter-ligands ­ involved in this process. This may provide the basis for the development of novel agents interfering with the inflammatory response induced by cell-cell contact and leading to tissue destruction in chronic inflammatory diseases.

Acknowledgments.

The author gratefully acknowledges the constant and enthusiastic support of Pr. J.-M. Dayer Head of the Division of Immunology and Allergy, Geneva University Hospital, and her colleagues of the Clinical Immunology Unit. Unpublished results reported here were part of projects supported by grant #31-50930-97 from the Swiss National Science Foundation and grants from the Swiss Society for Multiple Sclerosis, and the Hans Wilsdorf Foundation.

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