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    PIIS0022202X9091362F

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    Nathalia Regalado Araujo

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    Interleukin-2 and the IL-2 Receptor: New Insights Into Structure and Function William A. Kuziel, Ph.D., and Warner C. Medical Center, Ducham, North Carolina, US.A. Interleukin-2 (IL-2) was originally identified in 1976 as a growth factor for T lymphocytes. Since that time it has he- Comean important mediator of immune function through its effects on the growth, development, and activity of T and B lymphocytes, natural killer cells, and lymphokine-activated killer cells. Only cells that bear a specific receptor for IL-2 respond to its immunoregulatory effects. Of all the lympho- kine-receptor systems in immunology, perhaps most is known about the structure, function, and binding properties, of IL-2 and its cognate receptor. There are two distinct, membrane-associated IL-2 binding components in the high= affinity IL-2 receptor: an @ subunit and a B subunit, which associate in a non-covalent manner. Each of these polypep- tides can occur on the cell surface in the absence of the other and bind IL-2, although with only low or intermediate afin- ity relative to the high-affinity receptor complex. The pri- nso he coneuncesof taton of ring Iymaghocyee by sign or mutogen the pci tion and secretion of interleukin 2 (IL-2) 41-2 is 15-kD glycoprotein that plays a central role in the ination and development of an immune sponse to antigen through its direct effets Gn the sciaton, provi and Aiferentation of T and B lymphocytes (1-3). Hed ab activates other cell ofthe immane syet, mou notably nacre (NIE) cells [4] and lymphokine-activated killer (LAK) precursor cells [5} ‘Consistent with its activity as a growth factor for T cells [1 ‘ated ells form the major nt exclusive cellular sures oF IL-2 However, recenc evidence suggests that mouse splenic B eels and Bell nor line may alto pesuce UL-2 when stated with ual maiiaappboills Goe-4e) (e] Taw Geen evilonce barlomensed supporting IL-2 production by NK cells. Reprint requests to: Dr. Wamer C. Greene, Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Du ham, NC 27710. ‘Abbreviations ‘DNA: complementary DNA HTLV: human T-cell leukemia virus g: immunoglobulin 1: imerlewk 2R interleukin? re AK: Iymphokine-activat mRNA: menenger RNA NK: natural killer PHA: phytohemagglutinin PKC: protein kinase C TTNF: tumnor necrosis factor ene, M.D., Ph.D, Howard Hughes Medical Institute, Department of Medicine and Department of Microbiology and In nunology, Duke University mary structure of each chain has now been deduced from full-length cDNA. The rapid rate of association between IL-2and the IL-2Rasubunit is important in the formation of high-affinity binding sites, and the inducibility of the ax gene contributes to the highly regulated and transient display of high-affinity TL-2R. The IL-2Rf chain controls the slow dissociation rate of IL-2 from the high-affinity receptor. Also, IL-2Rf appears centrally involved in internalization of IL-2and signal transduction, functions mediated presumably through its long intracytoplasmic domain. However, the ac- tual mechanism of signal transduction in the IL-2/1L-2R system remains undefined. IL-2Rf is a member of a novel family of cytokine-receptor proteins that includes receptors for IL-4, IL-6, and erythropoietin. J Invest Dermatol 94:275 ~ 328, 1990 Like other polypeptide hormones, IL-2 exerts its biologic effects by binding to specific receptors present on the surface of target cells Antigen- or mitogen-driven T-cell activation stimulates IL-2 pro- duction and the expression of high-affinity receptors for 1-2, which allows the cell to receive an IL-2 growth signal in either an autocrine or paracrine fashion. In turn, this interaction between, xrowth factor and receptor induces the rapid clonal expansion of the E2ll popataton erignclly active. Eveoral termination of the ‘T-cell immune response involves both the decline in IL-2 produc~ tion and high-affinity receptor display. Independent of its effect on ‘T-cell proliferation, IL-2 also stimulates T cells to secrete other lymphokines, such as 1L-4 [7] and y-interferon [8]. Resting B cells activated by antigen also express high-afinty IL-2 receptors, al though at a 5~10 times lower level than T cells [9]. IL-2 may promote the growth of these B cellsas well as induce differentiation processes, such as secretion of Ig. One interesting mechanism for this latter response involves the induction of J chain mRNA, which allows the formation and secretion of IgM pentamers [10]. Freshly- isolated NK cells appear to express constitutively a form of the IL-2 receptor; these cells respond to high doses of IL-2 with enhanced cytolytic activity, proliferation, production of and the display of fully functional high-affinity IL (11,12) Because IL-2 has profound effects on multiple cell types involved in immune responses and because of its potential clinical applic tions, for example, in cancer immunotherapy [5], considerable fort has been focused on the biochemical and molecular character ization of both this lymphokine and its receptor, the nature of their interactions and the regulation of their genes, Recently, important advances have been made in defining the multicomponent struc- ture and ligand-binding properties of the high-affinity IL-2 recep- tor complex. The high-affinity form of the IL-2 receptor has now nterferon, receptors (0022-202X,/90/803.50 Copyright © 1990 by The Society for Investigative Dermatology, Inc 278 28S _KUZIEL AND GREENE teen shown to consist of two distinet IL-2 bindin sociated components: an @ chain (IL-2Ray Tac, p55) and a chain (IL-2Rf, p70-75). The identification, structure, and function of tach of these receptor subunits will be reviewed in the following of the IL-2Receptor Progressin the biochemical ilar characterization of the human IL-2 receptor was facilitated by the development of a sensitive IL-2 bioassay [13] and receptor-binding assay [14] using highly purified, radiolabeled IL-2 isolated either from constitutively IL-2-producing cel lines [15] or expression ofthe cloned IL-2 DNA [16]. A second major advance was the generation of anti-receptor monoclonal antibodies. The first such anti-receptor monoclonal antibody was raised using the tumor cells ofa patient with adult T-cell leukemia as the immuno gen [17] This antibody was termed anti-Tac because itreacted with Iitogen-activated normal T cells but not with resting T cells. Anti- ‘Tac was shown to recognize the IL-2 binding site of the IL-2 recep- tor because it blocked IL-2 binding to high-affinity receptors on activated T cells and tumor cells and, conversely, IL-2 blocked binding of anti-Tac. Anti-Tac immunoprecipitated a 55-KD glyco- protein from the sueface of high-affinity IL-2 binding cells [18]. [Affinity columns prepared either with immobiliz rac OF IL-2 reacted with the same p55 protein, and amino-terminal amino acid sequence information derived from the purified p55 polypep- tide permitted the isolation of full-length IL-2Ra DNA clones [19-21] Full-lengeh Tac cDNA clones have an open reading frame that specifies a primary translation product of 272 amino acids. After cleavage of the 21 amino acid signal peptide, the mature 251 amino acid Tac polypeptide exhibits a molecular mass of 33 kD. Extensive t-translational processing of this polypeptide involving glycosy- Beton, sulfation, and serine/threonine phosphorylation resales in surface display ofthe 55-kD IL-2Rax subunit [22,23]. The majority of the IL-2Rar polypeptide (219 aminoacids) i extracellular (Fig 1) There are 11 cysteine residues, some of which are involved in disul- fide bonds essential for IL-2 and anti-Tac binding [24]. The Tac protein docs not exhibit significant sequence similarity to members Of the Ig superfamily and therefore is not expected to contain the Characteristic Ig loops formed by intrachain disulfide bonds. There are multiple potential sites for O-linked glycosylation and two sites for N-linked sugar addition. Both of the latter sites are utilized; however, one or both ofthese sites can be deleted without affecting intracellular transport ofthe receptor or its ligand-binding proper- ties 25]. Near the carboxyl-terminus ofthe protein isa stretch of 19 hydrophobic amino acids which forms the single transmembrane domain. The intracytoplasmic region, consequently, consists of only 13 amino acids. Although this region is too short to encode tyrosine kinase enzymatic activity, which is a feature of several other growth factor receptors, the cytoplasmic tal of Tac does con- tain six positively charged residues which presumably anchor the receptor protein within the plasma membrane. The short intracyto~ plasmic domain of the Tac polypeptide, in fact, strongly suggested that the participation of additional protein subunits was required for the expression of functional high-affinity IL-2 receptors. ‘The #Chain of the IL-2 Receptor Soon aficr the cloning of the ‘Tac protein cDNA, several groups observed that IL-2 can bind to certain cells through a membrane receptor distinct from the Tac antigen. Certain cell populations, such as NK cells and SKW6.4 B cells, were shown to respond to high concentrations of IL-2 even in the presence of anti-Tac [11,12,26]. Other cell populations, such as the gibbon ape MLA 144 T'celis and the human NK like YT cells ‘were found to bind IL-2 with intermediate afnity yet failed to react with anti-Tac. Subsequent chemical cross-linking studies using 331-112 revealed the presence of a novel IL-2 binding protein ap- proximately 70~75 kD in size on the surface of NK cells, MLA 144 Eells, and cells expressing high-affinity receptors 2730]. Several ‘monoclonal antibodies were raised against p70 on YT cels, and one Of these antibodies, termed Mik [31], was successfully used in THE JOURNAL OF INVESTIGATIVE DERMATOLOGY FFigure 1. Schematic representation ofthe recognized subunits ofthe high aftnity human IL-2 receptor. This receptor complex is composed of two ‘membrane-assocated, ligand-binding chains, IL-2Rar (li) and 1L-2Rf (tight). The extracellular region of both subunits i similar in length, 219 ‘imino aids (2) for HL-2Rarand 214 amino acids for TL-2RB. Each subunit pests to have a single membrane spanning region: 19 amino acids for TL"2Rav and 25 amino acis for beta. The polypeptides difer markedly in their intracytoplasmic regions, the IL-2Rat chain conains only 13 amino acids while IL-2 Bencompasies 286 amino acis. The potential extracellu lar sites for N-linked glycosylation are also indicated. expression screening of YT ¢DNA library leading to the isolation of p70 cDNA clones [32] Full-length p70 cDNA contain an open reading frame which defines a primary translation product of 551 amino acids. The puta- tive signal peptide is 26 amino acids long, which leaves a mature got 929 amino acid with a alate molecular mas 8 1D. There is an extracellular domain of 214 amino acids, which is almost as long asthe corresponding domain in the Tac protein (i.e 219 amino aes) (Pg 1). Th extacelllar region of p70 contains fight cysteine residues and four potential sites for N-linked glyco- sylation. A hydrophobic stretch of 255 residues (amino acids 215 ~ 239 of the mature protein) presumably forms the membrane span- ting rgioa and the itarelilr domain 286 anioo acs, mach Tonger than the corresponding region of the Tac protein. The intra- cytoplasmic domain of p70 is ich in proline (42 residues) and serine (G0 residues) and contains significantly more negatively charged ($0 residues) than positively charged (18 residues) amino acids. How- the consensus sequence for tyrosine kinases (glycine-X-gly- cine-X-X-glycine) [33] is not present and it remains unknown ‘whether the cytoplasmic domain of p70 has protein kinase activ or if any of the above-mentioned structural features are involved in signal transduction pathways Like Tac, p70 is not a member of the Ig superfamily. However, p70 and the recently cloned cell-surface receptors for erythropoietin 54} 1L-4 [35], and IL-6 [36] appear to belong to a novel family of Cytokine receptors [37]. They all share significant amino acid se- quence similarity and certain structural features, such as conserved Cysteine residues and a conserved tryptophan-serine-X-tryptophan- Serine (W-S-X-W-S) motif in the extracellular domain and an abundance of proline and serine residues in the intracytoplasmic region VOL. 98, NO. 6, SUPPLEMENT, JUNE 1990 ‘Three Forms of the IL-2Receptor Tacand p70, r the IL-2Ra and IL-28p subunits, cespectvely,each bind TLS alone or together, thus accounting for three distinct forms ofthe IL-2 receptor. The TL-2Rarchain alone forma the lowathanty roecen, Vindng ligand with a Kd of 10-20 aM. The IL-2Rf chain alone forms the inter- mediate affinity receptor, exhibiting a Kd of 0.51 nM. Together TL-2Rav and IL-2Rf form the high-affinity receptor that binds IL-2 with a Kd of 10-50 pM. Because PHA-activated T cells express about tenfold more IL/2Rat chains than high-affinity receptors| 38), the number of TL-2R@ subunits available may be the limiting factor inthe formation of high-afiniry receptors on these cellsAs NK cells and perhape all esting T cele constetively expres low levels of IL-2R8 chains [28], high-affinity IL-2R display, and thus cell ‘growth, is significantly regulated by de novo induction of the TL-2Ra gene. A variety of stimuli induce expression of the IL-2Ra. gene in feuing T cells including cerain cyrokines such ak TL-t, IL'5, and TNE-a, and sonopecifie mitogens such as IA and PMA [38-43 In resting T cell and NK cell it has been shown that pharmacologic levels of IL-2 (or IL-2 binding to the IL-2RBsubunit alone) induces expression of the IL-2Rer chain gene, permitting the subsequent formation of high-afinity receptors that can generate a proliferative signal in the presence of phystologic concentrations of 0-2 [43,44]. This effect indicates that binding of IL-2 to the TLORG chain alone is suficient to deliver signal that inates certain intracellular processes. Thus, IL-2 binding followed by sig. nalencon cy mei bree high-oemediat a nity receptors but apparently not by low-afinity receptors Inwvo, signal transduction via the IL-2RB subunit alone way be siormully precluded by the limiting amounts of IL-2 avalable for Haag ‘Two Receptor-Binding Epitopes on IL-2 Mature human IL-2 is composed of 133 amino acids. Post-translational processing ap- pears limited to O-linked sugar attachment to the threonine residue at position 3 and to the formation of a disulfide bond between cysteine residues 58 and 105 that isessential for bioactivity [45]. The primary structure of the IL-2 polypeptide from fous different mam- ‘malian species is compared in Fig 2. In general, there is 65-70% similarity between the proteins and conservation of the cysteine fess that participate in the disulfide bond; The Uee-limens oval arene of human IL-2 bs recey been pled co 3 A resolution [46] and has revealed that the polypeptide exists as six alpha helical domains, termed A to F, involving 89 amino acids or (67% of the mature protein (depicted in linear aray in Fig 2), Several experimental approaches have been employed to deter- ‘mine which TL-2 domains or amino acid residues are involved in IL-2 AND THE IL2 RECEPTOR 298, binding to the IL-2Ra and IL-2Rf subunits of the high-affinity receptor complex, and the results strongly suggest that the A helix (amino acids 1119) and the B helix (amino acids 33-56) play important roles. Deletion of amino acids 110 results in loss of 30-50% of bioactivity, whereas deletion of amino acids 1-20 re- sults in loss ofall bioactivity [47]. Also, anti-IL-2 antisera that cross react with synthetic peptides defined by amino acids 8-27 or 33 54 block binding to the high-affinity IL-2R [48]. A more extensive analysis involving introduction of single amino acid substitutions throughout the IL-2 polypeptide suggests that the A helix binds to TL-2R@ and that helix B binds to IL-2Ra, Substicution of lysine (or certain other amino acids) for the aspartic acid (D in the one-letter code for amino acids) at position 20, the residue immediately after helix A and a conserved amino acid in IL-2 from all four species compared in Fig 2, results in loss of binding to IL-2RBor bioactivity but has no effect on binding to IL-2Rer [49,50]. The substitution of lysine for aspartic acid at position 20 docs not grossly affect the overall alpha-helical conformation of IL-2, as there is no diffrence between circular dichroism profiles beeween wild-type and the al- tered protein [49]. Therefore, the substitution blocks binding prob- ably by interfering directly with local contact between IL-2 and the TL-2K§ subunit and not by virtue of changing the tertiary confor- mation of the polypeptide. Substitution of glutamine or alanine for arginine at position 38 does not affect IL-2 proliferative activity but diminishes by more than 20 times the binding of the resultant IL-2 analog to the IL-2Ra subunit [51,52]. Such mutant proteins should facilitate the analysis of IL~2R-mediated signal transduction, Car- boxyl-terminal residues may also contribute to receptor binding by this ligand. Further, the disulfide bond between cysteine 58nd 105 is absolutely required for engagement of the receptor. Receptor Binding Kinetics Of note, IL-2 associates and disso- cites from the IL-2Rat and the IL-2RP subunits with very diferent rates. Specifically, che IL-2Rar chain and IL-2 associate and dissoci- 2ewith pid kines at 4°C, a indicatel by ay for the on and af rate of approximately 4 and 6 sec, respectively [53,54]. In contrast, TL-2RB interacts with IL-2 much more slowly, assceiating with ay cof approximately 45 min and dissociating with 2 ty, of 290 min, Remarkably, the high-affinity receptor exhibits the most favorable kinetic properties of both of its lower affinity subunits: the high- affinity receptor complex associates with IL-2 rapidly, like IL-2Rar (ts is 37 see) bue dissociates from IL-2 very slowly, like IL-2Rf (Gis 285 min). Thus, each receptor subunit importantly contrib- tutes to IL-2 binding; the IL-2Ra chain appears to primarily determine association, whereas the IL-2Rf subunit regulates disso- EA cv Fen Ge de crise Figure 2. Comparison ofthe primary structuce of IL-2 from been deduced from the corresponding cDNA: human [16] hov mammalian species. The amino acid sequences are shown inthe one-ltter code and have (69, ra [70], mouse [71] Direct homologies are shown in boxes and gaps are indicated by ashes. The vertical arrow denotes the signal peptidase cleavage site inthe primary translation produc. Stretches of amino acids that correspond to the sik alpha-helical domains in the three-dimensional sructue of human IL-2 are indicated above the human IL-2 sequence by isdivided into ewo domains, B and Basa result of abend ereatedby the proline reside a position and the free sulfhydryl group on eysteine 125 ae indicated jorizontal lines abeled A to F; helix B “The disulfide bond berween cysteine residues Sand 105 30S. KUZIEL AND GREENE A Stable IL-2 Receptor Ternary Complex. These differences in binding kinetics of the ewo IL-2 receptor subunits coupled with the experimental inability to detect a stable ternary complex com- posed of IL-2, IL-2Ray and IL-2Rf raised the possibility that the TL-2Ra chain might bind IL-2 rapidly, transfer the ligand to TL-2Rf, and then dissociate prior to IL-2Rf-mediated internaliza- tion of ligand. Kinetics evidence on human high-affinity IL-2R- bearing cells seems to suggest that increasing numbers of IL-2Rax chains enhance the association rate of IL-2 to the high-affinity receptor. These data were taken to support a multi-step afl conversion model whereby binding of IL-2 to the IL-2Ra chain is the fist step, followed by association of this IL-2-IL-2Ra complex with IL-2Rf to form the high-affinity ternary complex [55]. How- ver, using mouse cells bearing high-affinity receptors, IL-2Ra.and TL-2Rf can be chemically cross-linked in the absence of IL-2, sug- gesting that high-affinity receptors exist as pre-formed hetero- dimes [5,Ineter case nthe presence of IL-2ehesubunitsof the high-affinity recepeor appear to associate in a stable manner, giving rise to ternary complex that is internalized as an intact unit, a8 suggested by the results of the following experiment. Treatment of human cell lines that bear high-affinity receptors with radiolabeled TL-2 in the presence or absence of 7G7/B6, a non-neutralizing anti-IL-2Ra monoclonal antibody, revealed normal receptor-me- diated endocytosis of radiolabeled IL-2. Thus the presence of the 7G7/B6 monoclonal antibody docs not inhibit postbinding inter- nalization of ligand. In the presence of unlabeled IL-2, radiolabeled 7G7/B6 is internalized, indicating that the TL-2Re subunit is coin- temnalized with IL-2Rf afer IL-2 binding, supporting a stable asso- ciation of 1-2 with both binding subunits [57]. Signal Transduction Although the IL-2Ra and IL-2Rp sub- tnts appear to confer ligand binding upon the high-affinity TL-2R ‘complex, the nature of the signal transduction pathway(s) utilized by this receptor remains undefined. Lymphoid cll that express only IL-2Rf rapidly internalize surface-bound IL-2 with kinetics essentially identical to that measured forthe high-affinity receptor (G, of 1015 min) [58]. Furthermore, the ability of IL-2 to induce tytolytic activity and proliferation in NK cells [44,59] and lg pro- duction in certain B cell lines [26], cell populations which do not bear IL-2Ra, supports the notion that IL-2Rf is capable of signal transduction. The length of the intracytoplasmic region of IL-2Rf is consistent with arole in signal transduction. Receptors for several rrowth factors, such as epidermal growth factor [60] and insulin fot}, contain intracytoplasmic tyrosine kinase domains. However, the intracytoplasmic domain of IL-2R lacks a consensus sequence for tyrosine kinase, although an alanine-proline-glatamic acid triplet is present which forms a consensus motif for the catalytic domain of some protein kinases [33]. Thus far, no evidence for TL-2RB containing protein kinase enzymatic activity has been as- setbled. Six tyrosine residues ae present in the IL-2R cytoplasmic region that might serve as targets for a tyrosine kinase. In chis reeatd,IL-2RB has been recently shows to be modified by phospho. rylation in tyrosine residues [62], and in vitro phosphorylation assays suggest that chs post-translational modification of IL-2RB is induced by IL-2 (63) Protein kinase C (PKC), which is essential in T and B lympho- cytes for responses to antigen-receptor ligands, appears unlikely to Be involved in growth-signl wansducion inthe HL-2/IL-2R sys tem in either cell eype [10,64,65]. In cells, this was demonstrated by using IL-2-dependent T-cell clones that had become depleted of PRC activity cther spontaneously or by prolonged treatment with phorbol esters. These PKC-deficient clones proliferated in response {o IL-2, but when treated with ligands for the T-cell receptor, such as antigen, lectins, or anti-receptor antibodies, the cells did not proliferate or show induction of mRNA for activation associated genes [64,65]. Several recent observations suggest that yet additional receptor subunits are required for the formation of functional intermediate and high-affinity IL-2R. These results stem from transfection ex- periments in which full-length IL-2Ra and/or IL-28B cDNA are THE JOURNAL OF INVESTIGATIVE DERMATOLOGY A Chain @ Chain (p70) (Tac, p56) Figure 3. Proposed multicomponent structure ofthe IL-2 receptor. The pelypepide cums, folded in an arbitrary manner, incl the or and Subunits that bind IL-2 anda proposed third recepeor-associated chain, that ‘confers upon the ability to bind IL-2 and may be involved in sig ‘duction, cluding tyrosine-specifie phosphorylation introduced into various lymphoid and non-lymphoid cells. When TL-2Ra- and IL-2RB-negative lymphoid cells, such as the human, Teeell tumor line Jurkat, arc transfected with the IL-2Rf cDNA, IL-2Rf polypeptides are expressed atthe cell surface, as determined by reactivity with the monoclonal antibody Mik, and interme- dlate-afimnty IL-2 binding sites ae formed [32]. Furthermore, co- transfection ofthese T cells with IL-2Ra and IL-2Rf cDNA results in the appearance of high-affinity receptors. In sharp contrast, transfection of the IL-2Rf eDNA into non-lymphoid cells, such as, NIH-3T3 fibroblasts or monkey COS cells, results in surface ex- pression of IL-2 but the polypeptide appears non-functional, asit fails to bind IL-2 [32]. Transient coexpression of IL-2Ra and TL-2Rfin COS cells suggests that formation of an a/ heterodimer ‘occurs but that the resultant affinity for IL-2 is less than the legiti- imate high-affinity receptor (Kd of 300-400 pM) [32]. Further- more, these receptors appear unable co mediate internalization of ligand (66, These results suggest that cither an alternative process- ing mechanism or an additional effector component(s) present in Iyimphoid cells is necessary for functional IL-2Rf expression, fanc~ tional in terms of both IL-2 binding and signal transduction. Infact, proteins of 95 and 110 kD have been proposed as potential compo- hents inthe human or murine IL-2 receptor [67,68]. A model for a proposed IL-2R complex involving an additional subunit, 7, is Shown in Fig 3. As depicted, the 7 chain would not bind IL-2 but father would promote IL-2 binding by TL-2R and playa role in signal transduction, presumably through interactions with the cy- toplasmic domain of IL-2RB. Even a larger number of subunits is by no means excluded. In fact, if the putative 7 subunit is not the receptor-usocated tyrosine kinase, then 48 subunit prdictcd CONCLUSIONS AND FUTURE DIRECTIONS, Recently, considerable advances have been made in our understand ing of the structure of the IL-2Rar and IL-2R proteins and their role in the assembly of the functional high-affinity IL-2 receptor complex. Future investigations will almost certainly center on the imechanisin of IL-2 growth-signal transduction through this high- affinity receptor, the regulation of IL-2, IL-2Ra, and IL-2Rf gene ‘expression, and further analysis of the subunit structure of the high- affinity IL-2 receptor. Information in all these areas will be central to the future design and development of effective IL-2 agonists and antagonists, As well, the interplay of pathogenic retroviruses with tha growth factr/seeeptor ans wil be parsed. tn puticla, the VOL. 94, NO. 6, SUPPLEMENT, JUNE 1990 role of deregulated IL-2Ra expression in HTLV-1-induced adult ‘T-cell leukemia and the role of the HTLV-1 Tax protein in this process will be an area of active study. REFERENCES 1, Morgan DA, Rusceti FW, Gallo RC: Selective in vitro growth of T lymphocytes from normal human bone-marrow, Science 1931007 - 1008, 1976 2. Smith KA: T-cell growth factor. Immunol Rev 51:337-357, 1980 3._ Jelinek DF, Lipsky PE: Regulation of human Blymphocyte activation, proliferation and diferentaton. Adv Immunol 40:1 59, 1987 4. Brooks CG, Henney CS: Interleukin-2 and regulation of natural killer ‘ell activity in ealeured cell populations. Contemp Top Mol Imi fmanol 1063-92, 1985 5. 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Tigges MA, Casey LS, Koshland ME: Mechanism of interleukin-2 signaling” mediation of different outcomes by single receptor and ttansduction pathway. Science 243-781-786, 1989 11, Trinchieri G, Matsumoto-Kobayashi M, Clark SC, Seehta J, London TL, Perasia Be Response of resting human peripheral load natural killer cells to interleukin 2. J Exp Med 160:1147-1169, 1984 12. OraldoJR, Mason AT, Gerard JP, Henderson LE, Farr W, Hopkins RE, Herberman RB, Rabin Ht Effects of natural and recombinant 1L2 on regulation of IFN gamma production and natural killer activity: lack of involvement of the Tac antigen for these immmano- regulatory effets. J Immunol 133:779-783, 1988 13. Gillis $, Watson J: Biochemical and biological characterization of Iymphocyte eegulatory molecules. V, Identification of an interleu- in-2 prodacing human leukemia T cell ine. J Exp Med 152:1709 — 1719, 1980 14. Robb RJ. Munck A, Smith KA: Tce growth factor receptors: quanti- tation, specificity and biological relevance. J Exp Med 154:1455— 1474, 1981 15, Gills S, Watson J: Biochemical and biological characterization of lymphocyte regulatory molecules. V. Kentification ofan interleu- Kin-2 producing human leukemia T cel line. J Exp Med 152:1709- 1719, 1980 16, Taniguchi T, Matsui H, Fujita, Takaoka C, Kashima N, Yoshimoto , Hamuro J: Structute and expression of acloned cDNA for human, interleukin 2. Nature 302:308- 310, 1983 17. Uchiyama T, Broder S, Waldmann TA:A monoctonal antibody (ti- "Tac) reactive with activated and functionally mature human T cell, Jlmmmanol 126:1293~1297, 1981 18. Leonatd WJ, Depper JM, Uchiyama 7, Smith KA, Waldmann TA, ‘ene WC: A monoclonal antibody that appears to recognize the receptor for human T cell growth factor: partial characterization of the receptor. Nature 300:267 -269, 1982 19. 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