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The Journal of Immunology, 1998, 161: 5800-5803.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: A Role for p21ras/MAP Kinase in TCR-Mediated Activation of LFA-11

Anne M. O’Rourke2, Hui Shao and Jonathan Kaye

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
LFA-1 is a ß2 integrin that plays well-characterized roles in adhesion of T lymphocytes to APC, T cell-mediated cytolysis, and leukocyte-endothelial cell interactions. Although it is clear that LFA-1 must undergo affinity or avidity changes to bind its cellular ligand ICAM-1, the intracellular signaling pathways involved are not well characterized. Here, we show that the Ras-mitogen-activated protein kinase (MAPK) signaling pathway is also involved in TCR-activated LFA-1 adhesion. Expression of a dominant negative form of p21ras in a thymocyte cell line inhibits, while constitutively active p21ras both enhances and sustains, subsequent TCR-triggered adhesion to isolated ICAM-1. However, the Ras/MAPK pathway alone is not sufficient for activating T cell LFA-1, as inhibition of both downstream MAPK/extracellular regulated kinase kinase (MEK) activity and phosphatidylinositol 3-kinase activity is required for complete inhibition of adhesion.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Lymphocyte function-associated Ag-1 (LFA-1) (aLß2; CD11a/CD18) present on resting T lymphocytes binds poorly to its ligands ICAM-1, -2, and -3, but undergoes rapidly increased ligand binding when T cells are activated through the TCR (1). Although several signaling pathways have been implicated in coupling TCR occupancy to activated LFA-1-mediated adhesion, a clear understanding of the processes involved has not yet been attained (2, 3, 4, 5). The Ras, MEK,3 MAPK/ERK signaling pathway is rapidly activated upon TCR occupancy and has been shown to be critical for mature T cell activation (6, 7), as well as immature T cell differentiation (8, 9). To investigate whether this pathway is involved in TCR-activated LFA-1 adhesion, we took advantage of the CD4+CD8+ DPK murine thymocyte cell line that undergoes TCR-mediated differentiation to the CD4 single-positive stage in vitro (10). This cell line shows many characteristics of normal thymocytes and has previously been employed as a model system with which to dissect signaling pathways involved in thymocyte-positive selection, including the Ras/MAPK pathway (11, 12, 13). In this report, we show that TCR-activated adhesion to ICAM-1 is dependent on signals through p21ras and MEK, and further show that inhibition of both phosphatidylinositol (PI) 3-kinase and MEK activities are necessary for complete inhibition of LFA-1-mediated adhesion.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cells and FACS analyses

The derivation of the DPK thymocyte cell line has been described previously (10). DPK cells stably expressing H-ras61L or H-ras17N, constitutively active and dominant negative mutants of p21ras, respectively, were generated by retroviral-mediated gene transfer as previously described (12, 13). Resting CD4+ T cells were isolated from total lymph node cells of H-2b AND TCR transgenic mice (14) by incubation with mAbs to CD8{alpha}, CD8ß, B220, and I-Ab class II MHC followed by magnetic depletion. Purified mAbs directed against LFA-1 and FITC-anti-rat Ig were purchased from PharMingen (San Diego, CA). Stained cells were analyzed using CellQuest software on a FACSort (Becton Dickinson, Mountain View, CA).

Adhesion assay

A soluble form of murine ICAM-1, described previously (15), was used in adhesion assays. We coated 96-well tissue-culture plates (Corning, Corning, NY) overnight at 4°C by mixing the indicated concentrations of ICAM-1 or BSA with hamster-anti-mouse CD3{epsilon} mAb (145-2C11) or control hamster IgG to a final volume of 0.1 ml/well. All wells were then blocked with 1 mg ml-1 BSA. Cells were added to wells at 106/ml in 50 µL of RPMI 1640 medium supplemented with 0.1 mg ml-1 BSA and were allowed to attach for 30, 60, or 120 min at 37°C. Unbound cells were removed by repeated washing and bound cells were then fixed in 2% glutaraldehyde. Cell attachment was determined by staining of fixed cells with crystal violet, washing, and elution of dye in 0.1 M citrate, pH 4.5, in 20% methanol, followed by enumeration of absorbance at 570 nm. Percentage cells bound in each experiment was determined by comparison with a standard curve generated with known numbers of cells attached to polyL-lysine-coated wells. All results are mean ± SD of triplicate wells, and are representative of multiple experiments. Where appropriate, cells were preincubated with the indicated concentrations of PD98059 or wortmannin (Calbiochem, San Diego, CA) or 0.1% (v/v) DMSO as vehicle control for 30 min at 37°C before addition to wells.


   Results and Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
DPK cells exhibit low basal adhesion to ICAM-1, but upon TCR activation with anti-CD3 mAb this adhesion is markedly increased (Fig. 1Go, A and B). To determine whether the Ras signaling pathway plays a role in TCR-activated adhesion, we analyzed a DPK line expressing a dominant negative mutant of p21ras, DPKras17N (12). Inhibition of Ras signaling in DPK cells has no effect on cell growth, but profoundly inhibits TCR-mediated differentiation (12). DPKras17N and wild-type DPK cells displayed comparable levels of basal adhesion to ICAM-1 alone (Fig. 1Go, A and B). However, in sharp contrast to wild-type DPK, DPKras17N cells activated by anti-CD3 mAb failed to significantly increase adhesion to ICAM-1 (Fig. 1Go, A and B). Cell surface expression of both the TCR/CD3 complex and LFA-1 was similar in DPKras17N and parental cells (Fig. 1GoD and data not shown). The inhibition of DPKras17N adhesion was specific, because chelation of extracellular Ca2+ in the presence of high extracellular concentrations of Mg2+, which can directly induce a high-affinity form of LFA-1 (13, 14, 16), also induced binding of DPKras17N cells to ICAM-1 (Fig. 1GoC).



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  		FIGURE 1. Inhibition of TCR-activated ICAM-1 binding by expression of dominant negative Ras. A, Adhesion of wild-type DPK or DPKras17N to ICAM-1 was triggered by 1 µg/ml anti-CD3 mAb or isotype control hamster Ig. B, Adhesion of wild-type DPK or DPKras17N to anti-CD3 mAb coimmobilized with BSA or ICAM-1 at 3 µg/ml. C, Adhesion of wild-type DPK or DPKras17N cells to ICAM-1 in buffer containing 1 mM CaCl2 plus 0.3 mM MgCl2 or 5 mM MgCl2 plus 1 mM EGTA. For A–C, cell adhesion was determined after 30 min at 37°C, as described in Materials and Methods. D, Cell-surface LFA-1 expression on wild-type DPK, DPKras17N, or DPKras61L cells.

 
To determine whether activation of p21ras was sufficient to mediate cell adhesion to ICAM-1, DPK cells that stably express an active form of Ras (DPKras61L) were analyzed. TCR-activated adhesion to ICAM-1 by DPKras61L cells was consistently greater in magnitude and more sustained than for wild-type DPK (Fig. 2Go, A–C). These data point to a role for Ras in regulating the duration as well as avidity of LFA-1 binding to ICAM-1. DPKras61L transfectants displayed a modest but significant up-regulation in cell surface LFA-1 expression (Fig. 1GoD), consistent with the partial differentiation of these cells (11, 17). Despite this, nonstimulated ICAM-1 binding by DPKras61L cells was unaltered (Fig. 2Go, A–C), suggesting that the enhanced TCR-activated ICAM-1 adhesion was not simply due to increased LFA-1 expression but required Ras and/or a downstream target of activated Ras.



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  		FIGURE 2. TCR-activated ICAM-1 binding is increased and sustained by constitutively active Ras, and reversed by inhibition of MEK activity. A–C, Adhesion of wild-type DPK or DPKras61L to ICAM-1 coimmobilized with hamster Ig or anti-CD3 mAb, each at 1 µg/ml. D–F, DPKras61L cells were pretreated with DMSO vehicle (solid lines) or with 50 µM PD98059 (dashed lines) for 30 min at 37°C before addition to coated wells. Results are from one experiment and comparable results were obtained in three additional experiments.

 
The adhesion-enhancing effect of activated Ras was mediated via activation of the downstream MAPK/ERK signaling pathway, as acute treatment with PD98059, a pharmacological inhibitor of upstream MEK activity (18), significantly reduced DPKras61L TCR-activated adhesion to ICAM-1 and reversed the kinetics of cell adhesion to that displayed by the wild-type DPK cells (Fig. 2Go, D–F). Thus, the enhancement of adhesion induced by expression of active Ras is mediated at least in part by MEK, and presumably MAPK, activation. This result also argues against the up-regulation of LFA-1 expression or the differentiation state of the cells as the cause of the enhanced adhesion of DPK61L cells to ICAM-1.

The effect of MEK inhibition on TCR-activated ICAM-1 binding was not restricted to cells transfected with activated Ras or to thymocytes. Treatment of resting CD4+ lymph node T cells with PD98059 also led to reduced TCR-triggered ICAM-1 adhesion (Fig. 3GoA). However, PD98059 treatment, unlike expression of dominant negative Ras, failed to completely abolish ICAM-1 binding of either CD4+ T cells or DPK cells (Figs. 2Go, D–F and 3A), suggesting an additional requirement for MEK-independent events. Consistent with this possibility, there is strong evidence that activation of PI 3-kinase activity is one mediator of integrin avidity modulation in a variety of cell types (4, 5), and PI 3-kinase is a potential downstream Ras effector molecule (19). To determine whether activation of MEK and PI 3-kinase may collaborate in T cell adhesion to ICAM-1, TCR-activated binding of resting CD4+ cells to ICAM-1 was examined under conditions where both MEK and PI 3-kinase activities were blocked with PD98059 and wortmannin, respectively. While T cell treatment with maximally effective concentrations of PD98059 or wortmannin alone partially inhibited TCR-activated adhesion to ICAM-1, complete inhibition was observed only when T cells were treated with both inhibitors (Fig. 3GoB).



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  		FIGURE 3. Inhibition of MEK and PI 3-kinase activity blocks TCR-activated mature CD4+ T cell adhesion to ICAM-1. A, CD4+ T cells were preincubated for 30 min at 37°C with 50 µM PD98059 or DMSO vehicle before addition to anti-CD3 plus 3 µg/ml ICAM-1-coated wells. B, CD4+ T cells were preincubated for 30 min at 37°C with DMSO, 50 µM PD98059, 100 nM wortmannin, or with both 50 µM PD98059 plus 100 nM wortmannin, as shown. Percentage cells bound was determined after 60 min incubation, and comparable results were obtained in three separate experiments.

 
In this study, we have shown that Ras activation plays a critical role in TCR-activated adhesion of T cells. The fact that expression of active Ras is not sufficient to activate adhesion to ICAM-1 in the absence of a TCR signal implicates other signaling pathways as well. The data are consistent with an obligatory role for PI 3-kinase activation, either downstream of Ras or via a separate route after TCR engagement; our data do not distinguish between these two possibilities. On the surface, the ability of dominant-negative Ras to cause a more profound inhibition of activated LFA-1 adhesion than does treatment with PD98059 appears paradoxical. However, MEK-independent pathways downstream of Ras, possibly including PI 3-kinase activation, may also be necessary. Alternatively, pharmacological agents such as PD98059 and wortmannin may be unable to completely inhibit activities of the target enzymes at the concentrations used in culture. As with all pharmacological agents, we cannot rule out the possibility that PD98059 may affect additional pathways. With regard to the effect of MEK inhibition, it is interesting to note that two independently derived mutants of the Jurkat T cell line that displayed reduced ß1 and ß2 integrin function also possessed unusual forms of the downstream Ras-effector ERK1 (20).

TCR-mediated activation of adhesion is transient, presumably allowing functional binding and then release of T cells and APCs. The biochemical basis for this phenomenon is unknown. We have observed that constitutive activation of Ras prolongs activated adhesion of DPK cells to ICAM-1. Thus, the temporal pattern of Ras and downstream effector activation and subsequent decay may play an important role in regulating the duration of binding between T cells and other cells.

The mechanism by which activated Ras enhances LFA-1 adhesion is unknown, but may include affects on formation of high-affinity receptors (21), LFA-1 clustering (22), attachment to cytoskeletal and regulatory proteins (23, 24, 25), or cell spreading (26). Interestingly, the adhesion-promoting effects of Ras activation appear to vary with the integrin and cell type under study (27, 28). In this regard, lymphocyte-specific signaling mechanisms for LFA-1 activation have also been suggested (29). Collectively, the data presented here shed light on the intracellular pathways controlling LFA-1 function and suggest a new role for activation the Ras/MAPK pathway in T cells.


   Acknowledgments
 
We thank Elyssa Rubin and Paul Filipowitz for technical assistance.


   Footnotes
 
1 This work was supported by Grants AI34684 (A.M.O.) and AI31231 (J.K.) from the National Institutes of Health. This is manuscript no. 11755-IMM from The Scripps Research Institute. Back

2 Address correspondence and reprint requests to Dr. Anne O’Rourke, Department of Immunology-IMM-8, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; E-mail address: Back

3 Abbreviations used in this paper: MAPK, mitogen-activated protein kinase; ERK, extracellular regulated kinase; MEK, MAPK/ERK kinase; PI, phosphatidylinositol. Back

Received for publication August 19, 1998. Accepted for publication September 24, 1998.


   References
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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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