Association of the X-linked Lymphoproliferative Disease Gene Product SAP/SH2D1A with 2B4, a Natural Killer Cell-activating Molecule, Is Dependent on Phosphoinositide 3-Kinase

Natural killer (NK) cells express an activating receptor, 2B4, that enhances cellular cytotoxicity. Upon NK cell activation by ligation of 2B4, the intracellular domain of 2B4 associates with the X-linked lymphoproliferative disease (XLP) gene product, signaling lymphocytic activation molecule-associated protein/SH2D1A (SAP/SH2D1A). Defective intracellular association of 2B4 with mutated SAP/SH2D1A is likely to underlie the defects in cytotoxicity observed in NK cells from patients with XLP. We report here a role for phosphoinositide 3-kinase (PI3K) in the recruitment and association of SAP/SH2D1A to 2B4 in human NK cells. The activation of normal NK cells by ligation of 2B4 leads to the phosphorylation of 2B4, recruitment of SAP/SH2D1A, and association of the p85 regulatory subunit of PI3K. The inhibition of PI3K enzymatic activity with either wortmannin or LY294002 prior to 2B4 ligation does not alter the association of 2B4 with the p85 subunit but prevents the recruitment of SAP/SH2D1A to 2B4. In addition, PI3K inhibitors significantly diminish the cytotoxic function of primary NK cells. This observed inhibition of cytotoxicity, present in normal NK cells, was less apparent or absent in NK cells derived from a patient with XLP. These data indicate that the cytotoxicity of activated NK cells is mediated by the association of 2B4 and SAP/SH2D1A, and that this association is dependent upon the activity of PI3K. Natural killer (NK) cells express an activating receptor, 2B4, that enhances cellular cytotoxicity. Upon NK cell activation by ligation of 2B4, the intracellular domain of 2B4 associates with the X-linked lymphoproliferative disease (XLP) gene product, signaling lymphocytic activation molecule-associated protein/SH2D1A (SAP/SH2D1A). Defective intracellular association of 2B4 with mutated SAP/SH2D1A is likely to underlie the defects in cytotoxicity observed in NK cells from patients with XLP. We report here a role for phosphoinositide 3-kinase (PI3K) in the recruitment and association of SAP/SH2D1A to 2B4 in human NK cells. The activation of normal NK cells by ligation of 2B4 leads to the phosphorylation of 2B4, recruitment of SAP/SH2D1A, and association of the p85 regulatory subunit of PI3K. The inhibition of PI3K enzymatic activity with either wortmannin or LY294002 prior to 2B4 ligation does not alter the association of 2B4 with the p85 subunit but prevents the recruitment of SAP/SH2D1A to 2B4. In addition, PI3K inhibitors significantly diminish the cytotoxic function of primary NK cells. This observed inhibition of cytotoxicity, present in normal NK cells, was less apparent or absent in NK cells derived from a patient with XLP. These data indicate that the cytotoxicity of activated NK cells is mediated by the association of 2B4 and SAP/SH2D1A, and that this association is dependent upon the activity of PI3K. natural killer signaling lymphocytic activation molecule-associated protein interleukin-2 phosphoinositide 3-kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase extracellular signal-regulated kinase major histocompatibility complex Natural killer (NK)1 cells are an integral component of the antiviral immune response acting to limit viral replication through both cellular cytotoxic mechanisms and the secretion of cytokines (1.Biron C.A. Nguyen K.B. Pien G.C. Cousens L.P. Salazar-Mather T.P. Annu. Rev. Immunol. 1999; 17: 189-220Crossref PubMed Scopus (1774) Google Scholar, 2.Trinchieri G. Semin. Immunol. 1995; 7: 83-88Crossref PubMed Scopus (128) Google Scholar). A large number of activating and inhibitory receptors are expressed on the surface of NK cells, and there is a general agreement that the effector function of NK cells is determined by a balance of positive and negative intracellular signals (3.Moretta A. Bottino C. Vitale M. Pende D. Cantoni C. Mingari M.C. Biassoni R. Moretta L. Annu. Rev. Immunol. 2001; 19: 197-223Crossref PubMed Scopus (1500) Google Scholar, 4.Lanier L.L. Annu. Rev. Immunol. 1998; 16: 359-393Crossref PubMed Scopus (1486) Google Scholar). An important activating receptor of NK cells is 2B4, a member of the CD2 subset of the immunoglobulin superfamily (5.Garni-Wagner B.A. Purohit A. Mathew P.A. Bennett M. Kumar V. J. Immunol. 1993; 151: 60-70PubMed Google Scholar,6.Mathew P.A. Garni-Wagner B.A. Land K. Takashima A. Stoneman E. Bennett M. Kumar V. J. Immunol. 1993; 151: 5328-5337PubMed Google Scholar). Upon 2B4 activation by a natural ligand, CD48, or with a monoclonal antibody, NK cells are induced to augment their cytotoxicity, secrete interferon-γ, and increase calcium flux, phosphoinositol turnover, and perforin degranulation. (7.Nakajima H. Cella M. Langen H. Friedlein A. Colonna M. Eur. J. Immunol. 1999; 29: 1676-1683Crossref PubMed Scopus (205) Google Scholar, 8.Brown M.H. Boles K. van der Merwe P.A. Kumar V. Mathew P.A. Barclay A.N. J. Exp. Med. 1998; 188: 2083-2090Crossref PubMed Scopus (355) Google Scholar, 9.Chuang S.S. Kim M.H. Johnson L.A. Albertsson P. Kitson R.P. Nannmark U. Goldfarb R.H. Mathew P.A. Immunology. 2000; 100: 378-383Crossref PubMed Scopus (47) Google Scholar). The cytoplasmic tail of 2B4 contains four tyrosine-based motifs that allow for phosphorylation and subsequent binding by molecules containing src-homology 2 (SH2) domains (6.Mathew P.A. Garni-Wagner B.A. Land K. Takashima A. Stoneman E. Bennett M. Kumar V. J. Immunol. 1993; 151: 5328-5337PubMed Google Scholar, 10.Stepp S.E. Schatzle J.D. Bennett M. Kumar V. Mathew P.A. Eur. J. Immunol. 1999; 29: 2392-2399Crossref PubMed Scopus (64) Google Scholar, 11.Nakajima H. Colonna M. Hum. Immunol. 2000; 61: 39-43Crossref PubMed Scopus (71) Google Scholar). Thus, following stimulation, human 2B4 has been shown to be phosphorylated (12.Tangye S.G. Lazetic S. Woollatt E. Sutherland G.R. Lanier L.L. Phillips J.H. J. Immunol. 1999; 162: 6981-6985PubMed Google Scholar, 13.Watzl C. Stebbins C.C. Long E.O. J. Immunol. 2000; 165: 3545-3548Crossref PubMed Scopus (95) Google Scholar) and associate with a number of SH2 proteins including the SHP-1 and SHP-2 phosphatases (12.Tangye S.G. Lazetic S. Woollatt E. Sutherland G.R. Lanier L.L. Phillips J.H. J. Immunol. 1999; 162: 6981-6985PubMed Google Scholar, 14.Bakker A.B. Wu J. Phillips J.H. Lanier L.L. Hum. Immunol. 2000; 61: 18-27Crossref PubMed Scopus (111) Google Scholar, 15.Schatzle J.D. Sheu S. Stepp S.E. Mathew P.A. Bennett M. Kumar V. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3870-3875Crossref PubMed Scopus (104) Google Scholar) and p62dok (Dok1) (16.Sylla B.S. Murphy K. Cahir-McFarland E. Lane W.S. Mosialos G. Kieff E. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 7470-7475Crossref PubMed Scopus (53) Google Scholar) as well as with the linker for the activation of T-lymphocytes (LAT), an adaptor protein that acts as a substrate for SH2 proteins (17.Bottino C. Augugliaro R. Castriconi R. Nanni M. Biassoni R. Moretta L. Moretta A. Eur. J. Immunol. 2000; 30: 3718-3722Crossref PubMed Scopus (75) Google Scholar). In addition, 2B4 associates with signaling lymphocytic activation molecule-associated protein/SH2D1A (SAP/SH2D1A), an adaptor molecule containing a single SH2 domain (18.Tangye S.G. Phillips J.H. Lanier L.L. Nichols K.E. J. Immunol. 2000; 165: 2932-2936Crossref PubMed Scopus (229) Google Scholar). SAP/SH2D1A is expressed in both NK cells and T-lymphocytes, and the mutations of SAP/SH2D1A are associated with the immunodeficiency syndrome, X-linked lymphoproliferative disease (XLP) (19.Coffey A.J. Brooksbank R.A. Brandau O. Oohashi T. Howell G.R. Bye J.M. Cahn A.P. Durham J. Heath P. Wray P. Pavitt R. Wilkinson J. Leversha M. Huckle E. Shaw-Smith C.J. Dunham A. Rhodes S. Schuster V. Porta G. Yin L. Serafini P. Sylla B. Zollo M. Franco B. Bentley D.R. et al.Nat. Genet. 1998; 20: 129-135Crossref PubMed Scopus (651) Google Scholar, 20.Sayos J. Wu C. Morra M. Wang N. Zhang X. Allen D. van Schaik S. Notarangelo L. Geha R. Roncarolo M.G. Oettgen H. De Vries J.E. Aversa G. Terhorst C. Nature. 1998; 395: 462-469Crossref PubMed Scopus (813) Google Scholar, 21.Nichols K.E. Harkin D.P. Levitz S. Krainer M. Kolquist K.A. Genovese C. Bernard A. Ferguson M. Zuo L. Snyder E. Buckler A.J. Wise C. Ashley J. Lovett M. Valentine M.B. Look A.T. Gerald W. Housman D.E. Haber D.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13765-13770Crossref PubMed Scopus (447) Google Scholar). Consistent with the expression of SAP/SH2D1A in NK cells and its intracellular association with 2B4, XLP patients manifest defects in NK cytotoxic function, particularly following 2B4 activation (18.Tangye S.G. Phillips J.H. Lanier L.L. Nichols K.E. J. Immunol. 2000; 165: 2932-2936Crossref PubMed Scopus (229) Google Scholar, 22.Parolini S. Bottino C. Falco M. Augugliaro R. Giliani S. Franceschini R. Ochs H.D. Wolf H. Bonnefoy J.Y. Biassoni R. Moretta L. Notarangelo L.D. Moretta A. J. Exp. Med. 2000; 192: 337-346Crossref PubMed Scopus (416) Google Scholar, 23.Benoit L. Wang X. Pabst H.F. Dutz J. Tan R. J. Immunol. 2000; 165: 3549-3553Crossref PubMed Scopus (136) Google Scholar, 24.Nakajima H. Cella M. Bouchon A. Grierson H.L. Lewis J. Duckett C.S. Cohen J.I. Colonna M. Eur. J. Immunol. 2000; 30: 3309-3318Crossref PubMed Scopus (150) Google Scholar). However, the detailed intracellular mechanisms by which SAP/SH2D1A influences 2B4 signaling and NK function are unclear, and in particular, the involvement of phosphoinositide 3-kinase (PI3K) in 2B4-mediated cytotoxicity is unknown. Class I PI3K, the isoform most linked to lymphocytes, comprises both a catalytic (p110α, β, γ, or δ) and a regulatory (p85α, p85β, p101, or p55 γ) subunit (25.Rameh L.E. Cantley L.C. J. Biol. Chem. 1999; 274: 8347-8350Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar, 26.Fruman D.A. Meyers R.E. Cantley L.C. Annu. Rev. Biochem. 1998; 67: 481-507Crossref PubMed Scopus (1323) Google Scholar). In the case of tyrosine-phosphorylated membrane receptors such as 2B4, PI3K activation begins with the formation of a high affinity interaction between SH2 domains of either p85α or p85β and tyrosine-phosphorylated cytoplasmic domains of the membrane receptor. The association of the p85 subunit recruits the p110 catalytic subunit, which can phosphorylate the D-3 position of the inositol ring of phosphoinositol lipids. The phosphorylated inositol lipids and other metabolites including phosphatidylinositol 3,4-biphosphate are termed 3′-phosphoinositides and act as second messengers in signal transduction. A role for PI3K and 3′-phosphoinositides is suggested because PI3K is known to participate in antibody-dependent cellular cytotoxicity of NK cells (27.Kanakaraj P. Duckworth B. Azzoni L. Kamoun M. Cantley L.C. Perussia B. J. Exp. Med. 1994; 179: 551-558Crossref PubMed Scopus (89) Google Scholar,28.Bonnema J.D. Karnitz L.M. Schoon R.A. Abraham R.T. Leibson P.J. J. Exp. Med. 1994; 180: 1427-1435Crossref PubMed Scopus (123) Google Scholar), and inhibition of PI3K activity has been shown to decrease the cellular cytotoxicity of an NK cell line, NK92 (29.Jiang K. Zhong B. Gilvary D.L. Corliss B.C. Hong-Geller E. Wei S. Djeu J.Y. Nat. Immunol. 2000; 1: 419-425Crossref PubMed Scopus (289) Google Scholar). In this study, we investigated the role of PI3K in the downstream signaling events of 2B4 following the activation of primary human NK cells. We that the p85 regulatory subunit of PI3K associates with 2B4, and that the association of 2B4 with SAP/SH2D1A is by the inhibition of PI3K enzymatic We that PI3K activity induced by 2B4 is absent in NK cells mutated we that PI3K inhibitors diminish the cytotoxicity of NK cells from but or on the cytotoxicity of NK cells from an XLP to human SAP/SH2D1A was by with a to and inhibitors LY294002 and protein kinase (19.Coffey A.J. Brooksbank R.A. Brandau O. Oohashi T. Howell G.R. Bye J.M. Cahn A.P. Durham J. Heath P. Wray P. Pavitt R. Wilkinson J. Leversha M. Huckle E. Shaw-Smith C.J. Dunham A. Rhodes S. Schuster V. Porta G. Yin L. Serafini P. Sylla B. Zollo M. Franco B. Bentley D.R. et al.Nat. Genet. 1998; 20: 129-135Crossref PubMed Scopus (651) Google Scholar, 20.Sayos J. Wu C. Morra M. Wang N. Zhang X. Allen D. van Schaik S. Notarangelo L. Geha R. Roncarolo M.G. Oettgen H. De Vries J.E. Aversa G. Terhorst C. Nature. 1998; 395: 462-469Crossref PubMed Scopus (813) Google Scholar, 21.Nichols K.E. Harkin D.P. Levitz S. Krainer M. Kolquist K.A. Genovese C. Bernard A. Ferguson M. Zuo L. Snyder E. Buckler A.J. Wise C. Ashley J. Lovett M. Valentine M.B. Look A.T. Gerald W. Housman D.E. Haber D.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 13765-13770Crossref PubMed Scopus (447) Google Scholar, 22.Parolini S. Bottino C. Falco M. Augugliaro R. Giliani S. Franceschini R. Ochs H.D. Wolf H. Bonnefoy J.Y. Biassoni R. Moretta L. Notarangelo L.D. Moretta A. J. Exp. Med. 2000; 192: 337-346Crossref PubMed Scopus (416) Google Scholar, 23.Benoit L. Wang X. Pabst H.F. Dutz J. Tan R. J. Immunol. 2000; 165: 3549-3553Crossref PubMed Scopus (136) Google Scholar, 24.Nakajima H. Cella M. Bouchon A. Grierson H.L. Lewis J. Duckett C.S. Cohen J.I. Colonna M. Eur. J. Immunol. 2000; 30: 3309-3318Crossref PubMed Scopus (150) Google Scholar, L.E. Cantley L.C. J. Biol. Chem. 1999; 274: 8347-8350Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar, 26.Fruman D.A. Meyers R.E. Cantley L.C. Annu. Rev. Biochem. 1998; 67: 481-507Crossref PubMed Scopus (1323) Google Scholar, P. Duckworth B. Azzoni L. Kamoun M. Cantley L.C. Perussia B. J. Exp. Med. 1994; 179: 551-558Crossref PubMed Scopus (89) Google Scholar), and The was by the of and was from prior to NK cells from containing to and A by in of with human and These cells for and an NK or killer cell to NK cells for in inhibition inhibitors protein kinase of or for The for wortmannin and LY294002 determined by response not NK cells for with and NK cells as and in either an or activated with and as effector cells. The cells either the cell line, or the cell line, cells in with and for The effector to was to in a of The cells for and of was from well for was as L. Wang X. Pabst H.F. Dutz J. Tan R. J. Immunol. 2000; 165: 3549-3553Crossref PubMed Scopus (136) Google Scholar). NK cells for with in and inhibitors The was for and the was by with protein for to the binding of proteins to The protein of the was by the and in or the with a of the The immune by the of protein and the was in in by and with in containing with the of phosphorylation was to the containing The with primary in and with for 2 either a or substrate PI3K as A. B. J. Immunol. 1999; 162: Google Scholar). NK cells either or with wortmannin as and in or with and for with and with containing and and with containing and and with containing The protein with of of phosphatidylinositol and of The was by the of of and for was to this for an The was by the of of and of The was from the and was on and in to and phosphatidylinositol by indicate that the activation of NK cell by the ligation of 2B4 is by 2B4 phosphorylation and the recruitment of SAP/SH2D1A (12.Tangye S.G. Lazetic S. Woollatt E. Sutherland G.R. Lanier L.L. Phillips J.H. J. Immunol. 1999; 162: 6981-6985PubMed Google Scholar, C. Augugliaro R. Castriconi R. Nanni M. Biassoni R. Moretta L. Moretta A. Eur. J. Immunol. 2000; 30: 3718-3722Crossref PubMed Scopus (75) Google Scholar). NK cells from we that activation of primary NK cells with an to 2B4 G. J. Exp. Med. 1993; PubMed Scopus Google Scholar) in 2B4 phosphorylation 2 of and the recruitment of SAP/SH2D1A The association of 2B4 and SAP/SH2D1A is present following ligation with but is significantly is a interaction between 2B4 and and that downstream of signaling are important for the recruitment of SAP/SH2D1A The association between 2B4 and SAP/SH2D1A begins following NK activation and In cells from an XLP patient an to of SAP/SH2D1A L. Wang X. A. D. Tan R. 2001; 97: PubMed Scopus Google Scholar) to SAP/SH2D1A to 2B4 following activation The of association between 2B4 and SAP/SH2D1A was not because of an of SAP/SH2D1A expression in mutated cells, there was a of expression PI3K has been in both NK cytotoxicity (29.Jiang K. Zhong B. Gilvary D.L. Corliss B.C. Hong-Geller E. Wei S. Djeu J.Y. Nat. Immunol. 2000; 1: 419-425Crossref PubMed Scopus (289) Google Scholar) and A. B. J. Immunol. 1999; 162: Google G. P. T. 2000; PubMed Scopus Google Scholar), we investigated PI3K associates with 2B4 in activated NK cells. The PI3K isoform in of a regulatory subunit which contains SH2 and a catalytic subunit which as a The of SH2 domains the regulatory subunit a association between phosphorylated 2B4 and PI3K. NK cells from either or activated with and with and with that the p85 subunit of PI3K associates with 2B4 following NK activation and between and The observed association between 2B4 and the p85 subunit of PI3K a role for 2B4 in the of PI3K activity and the subsequent of phosphorylated membrane lipids. that the complex has associated enzymatic we from NK cells and 2B4 and determined the of the to A substrate was to the in the of and the by and by the role of SAP/SH2D1A in the activation of PI3K, we normal and NK cells. 2B4 stimulation, derived from normal to phosphoinositide that PI3K associated with 2B4 is the of wortmannin this kinase activity However, in to cells derived from from NK cells a mutated of SAP/SH2D1A PI3K activity The of PI3K activity was not because of a of association between 2B4 and PI3K, this association was in NK cells We investigated the of PI3K wortmannin or on the association of 2B4 with PI3K p85 The of NK cells with either not the association of the p85 subunit with 2B4 the expression of mutated SAP/SH2D1A the association function of PI3K in NK cells, and PI3K activity is absent following 2B4-mediated activation of NK cells. the role of PI3K following 2B4 we the of wortmannin on the association between 2B4 and SAP/SH2D1A NK cells from or with and and the because 2B4 is phosphorylated following activation 2B4 and SAP/SH2D1A associated in NK cells, the of cells with PI3K inhibitors but not with other kinase inhibitors in a of this SAP/SH2D1A has been shown to associate with phosphorylated 2B4 J. Nguyen K.B. Wu C. Stepp S.E. D. Schatzle J.D. Kumar V. C.A. Terhorst C. Immunol. 2000; PubMed Scopus Google Scholar), we determined the of wortmannin on 2B4 NK cells from with wortmannin and activated with to 2B4 phosphorylation was In normal NK cells, wortmannin not alter the phosphorylation of 2B4 or the of 2B4 that However, in cells, the of wortmannin in significantly less phosphorylated 2B4 both and that of 2B4 was in XLP cells. These observed between and XLP NK cells not because of in the of the cells the of 2B4 expression data a and role for PI3K in the recruitment of SAP/SH2D1A to 2B4. In the we determined that the inhibition of PI3K activity prevents an association of SAP/SH2D1A with 2B4, and we that NK cells with a of SAP/SH2D1A PI3K enzymatic the of PI3K we NK cytotoxicity cells derived from normal and an XLP We that NK cells the in SAP/SH2D1A cytotoxicity cells L. Wang X. Pabst H.F. Dutz J. Tan R. J. Immunol. 2000; 165: 3549-3553Crossref PubMed Scopus (136) Google Scholar). In the of by NK cells was a of NK cells present in XLP a for NK cells and by in high we been to NK of from both and an XLP patient We the cytotoxic function of effector cells, both normal and and with or 2B4 NK cytotoxicity cells was not significantly between the that NK cells from XLP patients are of cells. However, that express surface NK cells from normal cytotoxicity XLP NK cells NK cells activated with the in cytotoxicity significantly apparent both and cells. These data indicate that NK cells cells in normal but cytotoxicity cells In addition, as NK cells manifest a in cytotoxicity. the we investigated the of PI3K inhibitors on the cytotoxicity of normal and NK cells. NK cells in the or of PI3K inhibitors prior to cytotoxicity with or 2B4 We that both wortmannin and LY294002 significantly the cytotoxicity of normal NK cells cells with or 2B4 activation and in with wortmannin or However, the in cytotoxicity was less in NK cells that the XLP and cells, normal NK cells significantly by wortmannin or LY294002 and in but the inhibition of NK cytotoxicity was and These that a of SAP/SH2D1A the that PI3K inhibitors on NK cytotoxicity. We investigated the role of PI3K in 2B4-mediated signal following NK cell In agreement with (12.Tangye S.G. Lazetic S. Woollatt E. Sutherland G.R. Lanier L.L. Phillips J.H. J. Immunol. 1999; 162: 6981-6985PubMed Google Scholar, 13.Watzl C. Stebbins C.C. Long E.O. J. Immunol. 2000; 165: 3545-3548Crossref PubMed Scopus (95) Google Scholar), we that 2B4 is phosphorylated 2B4 stimulation, and we that phosphorylation of 2B4 is by the association of PI3K and by the association of SAP/SH2D1A These of association are with a report J. Nguyen K.B. Wu C. Stepp S.E. D. Schatzle J.D. Kumar V. C.A. Terhorst C. Immunol. 2000; PubMed Scopus Google Scholar) that SAP/SH2D1A with the phosphorylated of 2B4. we that by PI3K activity either with wortmannin or with the association of SAP/SH2D1A to 2B4 was that PI3K either or the binding of SAP/SH2D1A to 2B4. In an XLP patient with an of SAP/SH2D1A, 2B4 and PI3K to be associated but PI3K activity was not present that PI3K activity is dependent on These a complex of events following 2B4 association is dependent on PI3K activity and PI3K activity is dependent on These events that SAP/SH2D1A has binding to phosphorylated 2B4 and to or other motifs that PI3K was shown that associates with 2B4, and that the ligation of 2B4 leads to the phosphorylation of and the recruitment of other intracellular proteins to the complex (17.Bottino C. Augugliaro R. Castriconi R. Nanni M. Biassoni R. Moretta L. Moretta A. Eur. J. Immunol. 2000; 30: 3718-3722Crossref PubMed Scopus (75) Google Scholar). has been suggested in cells that the p85 subunit of PI3K associates with or with the tyrosine-phosphorylated tyrosine-based of the the SH2 domains of p85 J.M. S. A. van van T. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, SAP/SH2D1A PI3K activation through its association with 2B4 (17.Bottino C. Augugliaro R. Castriconi R. Nanni M. Biassoni R. Moretta L. Moretta A. Eur. J. Immunol. 2000; 30: 3718-3722Crossref PubMed Scopus (75) Google Scholar). the that PI3K an important role in the cytotoxicity of NK cells. PI3K and its downstream been in cell that NK cytotoxicity including G. P. T. 2000; PubMed Scopus Google Scholar), of (29.Jiang K. Zhong B. Gilvary D.L. Corliss B.C. Hong-Geller E. Wei S. Djeu J.Y. Nat. Immunol. 2000; 1: 419-425Crossref PubMed Scopus (289) Google Scholar), and membrane S. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). is as to which of is most important in the of 2B4-mediated NK cytotoxicity, because mechanisms the recruitment and activation of PI3K NK membrane In of this K. C.S. T. R. K. H. J. Immunol. 2000; PubMed Scopus Google Scholar, A. C. Allen 1999; PubMed Scopus Google Scholar) that which is to 2B4, in between cells and cells, and that the of CD2 are mediated by the formation of formation in both activated cells, a subset of which express 2B4, A. C. Allen 1999; PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar) and in NK cells M. Cohen O. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar, D. Leibson P.J. J. Exp. Med. 2000; PubMed Scopus Google Scholar), and was dependent on PI3K activity M. M.C. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, 2B4 and the downstream of both SAP/SH2D1A and PI3K in which is for signaling and cytotoxicity. In addition, defects of the NK cell cytotoxicity. In this Djeu and (29.Jiang K. Zhong B. Gilvary D.L. Corliss B.C. Hong-Geller E. Wei S. Djeu J.Y. Nat. Immunol. 2000; 1: 419-425Crossref PubMed Scopus (289) Google Scholar, S. J.H. Djeu J.Y. J. Exp. Med. 1998; PubMed Scopus (136) Google Scholar) shown that intracellular of perforin is dependent on PI3K and its downstream and extracellular signal-regulated In to the association of 2B4 with SAP/SH2D1A, wortmannin and LY294002 to significantly the cytotoxicity of normal NK cells This inhibition was less apparent or absent in NK cells from a patient with that a in signaling the of PI3K was by a the of SAP/SH2D1A The of this is that PI3K and SAP/SH2D1A participate in the signaling we a the activation of PI3K SAP/SH2D1A to associate with 2B4, and we that this association is for NK cell effector In XLP SAP/SH2D1A is to to 2B4. Thus, inhibition of PI3K has on cytotoxicity, and we that the major of wortmannin and LY294002 on cytotoxicity the association of with 2B4. This is with that NK cells mutated SAP/SH2D1A PI3K activity following 2B4 the is unknown. of the role of PI3K in NK cytotoxicity, we as (18.Tangye S.G. Phillips J.H. Lanier L.L. Nichols K.E. J. Immunol. 2000; 165: 2932-2936Crossref PubMed Scopus (229) Google Scholar, 24.Nakajima H. Cella M. Bouchon A. Grierson H.L. Lewis J. Duckett C.S. Cohen J.I. Colonna M. Eur. J. Immunol. 2000; 30: 3309-3318Crossref PubMed Scopus (150) Google Scholar) that NK cells mutated SAP/SH2D1A cells as as normal NK cells. The in cytotoxicity between normal and XLP cells cells or NK cells activated with between cells and cells is that the cells or I surface cells express D.R. Hum. Immunol. 2000; 61: PubMed Scopus Google Scholar). of is that NK cells from XLP patients are of but because SAP/SH2D1A, are to the of NK cells. cells are likely to NK inhibitory NK cells are to We that viral expression of I on cells and that apparent XLP of viral replication of We of the Tan and Wang for and We Pabst for patient and and C. for the

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