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Interaction Affinity Between Cytokine Receptor Components on the Cell Surface

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Interaction Affinity Between Cytokine Receptor Components on the Cell Surface Proc. Natl. Acad. Sci. USA Vol. 95, pp. 13165–13170, October 1998 Immunology Interaction affinity between cytokine receptor components on the cell surface ADRIAN WHITTY*, NATALYA RASKIN,DIAN L. OLSON,CHRISTOPHER W. BORYSENKO,CHRISTINE M. AMBROSE, CHRISTOPHER D. BENJAMIN, AND LINDA C. BURKLY* Biogen, Inc., 14 Cambridge Center, Cambridge, MA 02142 Edited by Henry Metzger, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Chevy Chase, MD, and approved August 26, 1998 (received for review May 26, 1998) ABSTRACT The anti-common gamma chain (gc) mAb inhibitors that work by blocking the interaction between CP.B8 is shown to inhibit interleukin 4 (IL-4)-dependent receptor chains. The binding affinity between receptor chains proliferation of phytohemagglutinin (PHA) activated T cells on the surface of cells cannot easily be determined by using noncompetitively with respect to cytokine by blocking the soluble forms of the receptor chains, because of the difficulty IL-4-induced heterodimerization of IL-4Ra and gc receptor of accounting for the entropic consequences of the reduction chains. Affinities for the binding of IL-4 to Cos-7 cells in dimensionality that occurs when a binding event is con- transfected with huIL-4Ra, and to PHA blasts expressing strained to the two dimensions of a cell membrane. Conse- both IL-4Ra and gc, were used to estimate the affinity of the quently, no quantitative measure of the interaction affinity key interaction between gc and the binary IL-4RazIL-4 com- between receptor chains on the cell surface has yet been plex on the cell surface. This affinity was defined in terms of achieved. the dimensionless ratio [IL-4RazIL-4zgc]y[IL-4RazIL-4], We describe here an approach that uses readily obtainable which we designate KR. The results show that on PHA blasts experimental data to derive an estimate of the interaction this interaction is relatively weak; KR ' 9, implying that '10% affinity between receptor chains brought about by the binding of the limiting IL-4Ra chain remains free of gc even at of ligand to the cell, using as an example the heterodimeric saturating concentrations of IL-4. This quantitative treatment receptor for interleukin 4 (IL-4) (6) comprising the IL-4 a a g establishes KR as a key measure of the coupling between ligand receptor chain (IL-4R ) and the common gamma chain ( c) binding and receptor activation, providing a basis for func- (7, 8). This receptor belongs to a subfamily of class I cytokine g tional distinctions between different receptors that are acti- receptors all of which use c, and that also includes receptor a g vated by ligand-induced receptor dimerization. subunits for IL-2, IL-7, IL-9, and IL-15. Both IL-4R and c are structurally and functionally related to hGH-R, and de- To understand, at the molecular level, how receptors allow tailed structural models of a ternary complex between IL-4, a g cells to sense and respond to their external environment is a IL-4R , and c have been constructed on the basis of this central goal of receptor research. This question can be ap- homology (9). Mutational analysis of IL-4 supports a mecha- proached by identifying the mechanism by which binding of a nism of ligand-induced receptor dimerization for its receptor ligand to the extracellular portions of a receptor brings about (10). Here, we confirm this mechanism for the IL-4 receptor an activated state of the receptor inside the cell membrane. on activated T cells by using a method based on monoclonal However, a full understanding additionally requires quantita- antibodies, and we use data for the binding of IL-4 to the tive information about the relationship between receptor receptor and its component subunits to estimate the affinity a g occupancy, receptor activation, and downstream response. with which IL-4R interacts with c on the cell membrane in Insights at this level are becoming achievable for certain the presence of bound IL-4. We show that this interaction is members of the large and diverse family of cytokine and relatively weak, and that this property can be exploited by a growth factor receptors comprising two or more noncovalently noncompetitive inhibitor that blocks IL-4-dependent T cell associated subunits (1). A new mechanistic paradigm was proliferation without competing directly against IL-4 binding. introduced when it was proposed that certain of these recep- tors function by a mechanism of ligand-induced receptor MATERIALS AND METHODS dimerization (2), exemplified by the homodimeric receptor for g human growth hormone (hGH-R) (3, 4), a class I cytokine Materials. The murine anti-human c mAb CP.B8, its receptor. This mechanism of receptor activation, illustrated in isotype control (MOPC 21), and their respective Fab frag- Fig. 1, is believed to apply to a significant number of oligomeric ments were prepared as described elsewhere (11). The block- receptors (1, 5) and, importantly, is simple enough to be ing anti-IL-4Ra mAb, MAB2309, was obtained fromR&D amenable to detailed experimental and theoretical analysis. Systems, and its isotype control, UPC10, was from Cappel. a g The simplicity of this mechanism promises insight into how the Vectors encoding the human IL-4R and c receptor chains affinity of receptor for ligand, and of the receptor chains for were prepared, and other reagents obtained, as described each other upon the binding of ligand, is coupled to the elsewhere (11). sensitivity and dynamic range of the cellular response. Im- Cell Proliferation Measurements. Human peripheral blood proving our understanding of these quantitative features of the mononuclear cells (PBMC) were isolated from healthy donors activation mechanism is not only of theoretical interest; the by Ficoll-Paque density gradient centrifugation (Pharmacia affinity between receptor chains in the presence of bound Biotech), and were enriched for T cells by negative selection ligand has important implications for the development of This paper was submitted directly (Track II) to the Proceedings office. a a g The publication costs of this article were defrayed in part by page charge Abbreviations: IL, interleukin; IL-4R , IL-4 receptor chain; c, common gamma chain; hGH-R, human growth hormone receptor; payment. This article must therefore be hereby marked ‘‘advertisement’’ in PBMC, peripheral blood mononuclear cells; PHA, phytohemaggluti- accordance with 18 U.S.C. §1734 solely to indicate this fact. nin. © 1998 by The National Academy of Sciences 0027-8424y98y9513165-6$2.00y0 *To whom reprint requests should be addressed. e-mail: AdrianoWhitty@ PNAS is available online at www.pnas.org. Biogen.com and [email protected]. 13165 Downloaded by guest on September 25, 2021 13166 Immunology: Whitty et al. Proc. Natl. Acad. Sci. USA 95 (1998) g extracellular portion of human c and inhibits the IL-4- dependent proliferation of PHA-activated T cells with an IC50 of '75 mgyml when tested at a single subsaturating concen- tration of IL-4 (11). The binding site for CP.B8 has been mapped (11) to a conformational epitope close to the junction of the two fibronectin type III-like domains that comprise the g extracellular portion of the c molecule. Based on published structural models of the IL-4 receptor complex (9), binding of g FIG. 1. Schematic representation of the ligand-induced receptor CP.B8 to this position on c would be expected to block the g a dimerization mechanism as it applies to class I cytokine receptors (3, interaction of c with IL-4 and possibly also with the IL-4R 4). In the case of the IL-4 receptor, R1 is the IL-4Ra chain and R2 is g chain. A Fab fragment of CP.B8 also blocks IL-4-dependent c. For homodimeric receptors such as hGH-R, R1 and R2 are proliferation in this assay (11). Fig. 2 shows dose-response identical. curves for the ability of IL-4 to stimulate the proliferation of as described in ref. 11. The T cell-enriched PBMC were PHA-activated human T cells, measured at several fixed concentrations of anti-IL-4Ra mAb or CP.B8. Under these cultured in a humidified incubator for 3 days at 37 °C, 5% CO2 at 106 cellsyml in RPMI medium supplemented with 10% fetal conditions, secretion of growth-supporting cytokines is mini- mal, and addition of IL-4 induces proliferation that is essen- bovine serum, 2 mM L-glutamine, 100 unitsyml of penicillin, A 100 mgyml of streptomycin, and 1 mgyml of phytohemagglu- tially IL-4 dependent (11). Fig. 2 shows that the blocking mAb directed against the IL-4Ra chain displays a competitive tinin (PHA; Difco) to polyclonally activate T cells. The pattern of inhibition; inhibition is dose dependent, and the resulting PHA blasts were washed three times with fresh IL-4 dose-response curves are shifted to the right in proportion medium and recultured overnight at 106 cellsyml in medium to the concentration of mAb (Fig. 2A, Inset). This result shows without PHA. The next day the rested cells were transferred that the inhibitory effect of any given concentration of anti- to 96-well flat-bottom plates, and cultured at 5 3 104 cellsywell IL-4Ra mAb can be overcome, and the full proliferative with mAb (CP.B8, anti-IL-4Ra, or control Ig) at the specified response of the cells achieved, by increasing the IL-4 concen- concentrations. After 45 min at 37 °C, recombinant human tration to sufficiently high levels. In contrast, Fig. 2B shows IL-4 (R & D Systems) was added to final concentrations of y that CP.B8 is a noncompetitive inhibitor of IL-4-dependent T 0.015-100 ng ml. Cells were cultured for 40 hr, and prolifer- ' 3 cell proliferation; the EC50 for IL-4 remains constant at 2 ation was measured by the incorporation of H-thymidine ngyml over the entire range of mAb concentrations (Fig.
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