Tuning Antigen Receptor Signaling by CD22: Integrating Cues from Antigens and the Microenvironment
1997; Cell Press; Volume: 6; Issue: 5 Linguagem: Inglês
10.1016/s1074-7613(00)80339-8
ISSN1097-4180
AutoresJason G. Cyster, Christopher C. Goodnow,
Tópico(s)Cell Adhesion Molecules Research
ResumoCell fate within multicellular organisms is often determined by the concerted action of several extracellular signals. In lymphocytes, a signaling complex that contributes to many cell fate decisions is the antigen receptor, with different extents of antigen receptor engagement leading to such outcomes as cell death, survival, or proliferation. Great strides have been made in the past two decades in understanding how antigen receptor signals are transmitted within cells. It is only in the past few years, however, that an understanding has begun to develop of what regulates the strength and quality of the signal. Most excitingly, this regulation involves the action of multiple transmembrane molecules, leading to the recognition that the strength and quality of signal transmitted by the antigen receptor in response to an antigen may be regulated both by properties of the antigen and the microenvironmental context of the cell. In this review we discuss the most recent studies on a transmembrane regulatory molecule on B cells, CD22, and attempt to put these studies into the context of other transmembrane molecules that regulate antigen receptor signal strength in B cells. Finally we speculate on how these molecules may function to relate microenvironmental information to intracellular signaling from the antigen receptor and cell fate. The core units of the B cell antigen receptor are transmembrane immunoglobulin (Ig) and the associated molecules CD79α and CD79β (Igα and Igβ) (49Reth M Antigen receptors on B lymphocytes.Annu. Rev. Immunol. 1992; 10: 97-121Crossref PubMed Google Scholar). Antigen receptor cross-linking leads to activation of Src-family kinases, including Lyn, Fyn and Blk, and phosphorylation of tyrosines within ITAM motifs in the CD79 cytoplasmic domains. Protein tyrosine kinase Syk associates with the phoshorylated CD79 ITAMs and is activated by phosphorylation. The concerted action of Syk, Src-family kinases, and other downstream kinases leads to the rapid phosphorylation of multiple substrates and to the activation of calcium pathways, the Ras/Erk pathway, additional mitogen-activated protein–family kinases, and possibly other signaling pathways (24Gold M.R DeFranco A.L Biochemistry of B lymphocyte activation.Adv. Immunol. 1994; 55: 221-295Crossref Scopus (116) Google Scholar). Antigen receptor signaling in B cells has different consequences depending on the stage of B cell maturation and the strength and duration of the signal. In immature B cells, extensive antigen receptor cross-linking reversibly arrests development and promotes clonal elimination or receptor editing, whereas engagement of less potently cross-linking antigens does not arrest development but may desensitize the signaling complex, provided a threshold receptor occupancy is achieved (26Goodnow C.C Cyster J.G Hartley S.B Bell S.E Cooke M.P Healy J.I Akkaraju S Rathmell J.C Pogue S.L Shokat K.P Self-tolerance checkpoints in B lymphocyte development.Adv. Immunol. 1995; 59: 279-368Crossref PubMed Scopus (251) Google Scholar). In mature B cells, potent antigen receptor cross-linking, for example by polyclonal anti-IgM antibodies or by T-independent antigens, can induce cells to enter the cell cycle, whereas less multivalent antigens, including most T-dependent antigens, transmit signals that are insufficient to initiate the cell cycle. Cells engaging these antigens are highly receptive to T cell–derived signals, and the T cell and antigen receptor signals synergize to promote B cell proliferation or differentiation into antibody-secreting cells or germinal center cells. As well as regulating cell cycle entry and responsiveness to T cell help, antigen receptor triggering in mature B cells also affects cell migration within lymphoid tissues, causing rapid exit of B cells from follicles or marginal zones and promoting their accumulation in outer T cell zones and other sites (35Liu Y.-J Zhang J Lane P.J.L Chan E.Y.-T MacLennan I.C.M Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens.Eur. J. Immunol. 1991; 21: 2951-2962Crossref PubMed Scopus (591) Google Scholar, 13Cyster J.G Hartley S.B Goodnow C.C Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire.Nature. 1994; 371: 389-395Crossref PubMed Scopus (462) Google Scholar, 12Cyster J.G Goodnow C.C Antigen-induced exclusion from follicles and anergy are separate and complementary processes that influence peripheral B cell fate.Immunity. 1995; 3: 691-701Abstract Full Text PDF Scopus (216) Google Scholar, 55Shokat K.M Goodnow C.C Antigen-induced B-cell death and elimination during germinal center immune responses.Nature. 1995; 375: 334-338Crossref PubMed Scopus (334) Google Scholar, 4Bachmann M.F Odermatt B Hengartner H Zinkernagel R.M Induction of long-lived germinal centers associated with persisting antigen after viral infection.J. Exp. Med. 1996; 183: 2259-2269Crossref PubMed Scopus (150) Google Scholar, 23Fulcher D.A Lyons A.B Korn S.L Cook M.C Koleda C Parish C Fazekas de St. Groth B Basten A The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help.J. Exp. Med. 1996; 183: 2329-2336Crossref Scopus (227) Google Scholar). Signaling from the antigen receptor is likely to be controlled at multiple levels, some molecules acting at the antigen receptor complex itself, regulating signaling via multiple pathways, and others acting further downstream within specific signaling pathways. It is becoming increasingly apparent that several of the proximal regulators of signal strength and quality are transmembrane molecules such as CD22. The B lineage molecule, CD22, is a member of the immunoglobulin superfamily (58Stamenkovic I Seed B The B-cell antigen CD22 mediates monocyte and erythrocyte adhesion.Nature. 1990; 345: 74-77Crossref Scopus (160) Google Scholar, 72Wilson G.L Fox C.H Fauci A.S Kehrl J.H cDNA cloning of the B cell membrane protein CD22 a mediator of B-B cell interactions.J. Exp. Med. 1991; 173: 137-146Crossref Scopus (124) Google Scholar, 62Torres R.M Law C.L Santos-Argumedo L Kirkham P.A Grabstein K Parkhouse R.M Clark E.A Identification and characterization of the murine homologue of CD22, a B lymphocyte-restricted adhesion molecule.J. Immunol. 1992; 149: 2641-2649Google Scholar) and was suggested to participate in antigen receptor signaling following the observation that treatment of cells with anti-CD22 antibodies synergized with antigen receptor cross-linking in promoting B cell proliferation (46Pezzutto A Dorken B Moldenhauer G Clark E.A Amplification of human B cell activation by a monoclonal antibody to the B cell-specific antigen CD22, Bp 130/140.J. Immunol. 1987; 138: 98-103Google Scholar, 47Pezzutto A Rabinovitch P.S Dorken B Moldenhauer G Clark E.A Role of the CD22 human B cell antigen in B cell triggering by anti-immunoglobulin.J. Immunol. 1988; 140: 1791-1795Google Scholar, 65Tuscano J Engel P Tedder T.F Kehrl J.H Engagement of the adhesion receptor CD22 triggers a potent stimulatory signal for B cells and blocking CD22/CD22L interactions impairs T-cell proliferation.Blood. 1996; 87: 4723-4730Crossref Google Scholar). The notion that CD22 contributed positively to antigen receptor signaling gained further support with the discoveries that a fraction of CD22 within B cells can be coprecipitated with the antigen receptor (34Leprince C Draves K.E Geahlen R.L Ledbetter J.A Clark E.A CD22 associates with the human surface IgM-B cell antigen receptor complex.Proc. Natl. Acad. Sci. USA. 1993; 90: 3236-3240Crossref Scopus (164) Google Scholar, 45Peaker C.J Neuberger M.S Association of CD22 with the B cell antigen receptor.Eur. J. Immunol. 1993; 23: 1358-1363Crossref Scopus (139) Google Scholar) and that CD22 becomes rapidly tyrosine phosphorylated following antigen receptor engagement (53Schulte R.J Campbell M.-A Fischer W.H Sefton B.M Tyrosine phosphorylation of CD22 during B cell activation.Science. 1992; 258: 1001-1004Crossref Scopus (118) Google Scholar, 34Leprince C Draves K.E Geahlen R.L Ledbetter J.A Clark E.A CD22 associates with the human surface IgM-B cell antigen receptor complex.Proc. Natl. Acad. Sci. USA. 1993; 90: 3236-3240Crossref Scopus (164) Google Scholar, 45Peaker C.J Neuberger M.S Association of CD22 with the B cell antigen receptor.Eur. J. Immunol. 1993; 23: 1358-1363Crossref Scopus (139) Google Scholar, 71Williams G.T Peaker C.J Patel K.J Neuberger M.S The alpha/beta sheath and its cytoplasmic tyrosines are required for signaling by the B-cell antigen receptor but not for capping or for serine/threonine-kinase recruitment.Proc. Natl. Acad. Sci. USA. 1994; 91: 474-478Crossref Scopus (74) Google Scholar). More recently it has been observed that CD22 can associate with the tyrosine kinases Lyn and Syk and with PI3-kinase and phospholipase C-γ (PLCγ) (32Law C.L Sidorenko S.P Chandran K.A Zhao Z Shen S.H Fischer E.H Clark E.A CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1) upon B cell activation.J. Exp. Med. 1996; 183: 547-560Crossref Scopus (173) Google Scholar, 66Tuscano J.M Engel P Tedder T.F Agarwal A Kehrl J.H Involvement of p72syk kinase, p53/56lyn kinase and phosphatidyl inositol-3 kinase in signal transduction via the human B lymphocyte antigen CD22.Eur. J. Immunol. 1996; 26: 1246-1252Crossref Scopus (72) Google Scholar). The positive regulatory activity of CD22 was brought into question, however, when it was observed that the SHP-1 protein tyrosine phosphatase (PTPase; previously PTP1C), which negatively regulates antigen receptor signaling (11Cyster J.G Goodnow C.C Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection.Immunity. 1995; 2: 13-24Abstract Full Text PDF Scopus (342) Google Scholar), rapidly associates with CD22 following antigen receptor engagement (9Campbell M.A Klinman N.R Phosphotyrosine-dependent association between CD22 and protein tyrosine phosphatase 1C.Eur. J. Immunol. 1995; 25: 1573-1579Crossref Scopus (111) Google Scholar, 17Doody G.M Justement L.B Delibrias C.C Matthews R.J Lin J Thomas M.L Fearon D.T A role in B cell activation for CD22 and the protein tyrosine phosphatase SHP.Science. 1995; 269: 242-244Crossref Scopus (469) Google Scholar, 32Law C.L Sidorenko S.P Chandran K.A Zhao Z Shen S.H Fischer E.H Clark E.A CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1) upon B cell activation.J. Exp. Med. 1996; 183: 547-560Crossref Scopus (173) Google Scholar). Characterization of the SHP-1–binding sites in CD22 identified three of the six cytoplasmic tyrosines, each in the motif V/IXYXXL, that when phosphorylated were able to bind and activate SHP-1 (17Doody G.M Justement L.B Delibrias C.C Matthews R.J Lin J Thomas M.L Fearon D.T A role in B cell activation for CD22 and the protein tyrosine phosphatase SHP.Science. 1995; 269: 242-244Crossref Scopus (469) Google Scholar). This tyrosine-based motif was previously observed as a SHP-1–binding site in Fc receptor (FcR) FcγRIIb (15D'Ambrosio D Hippen K.L Minskoff S.A Mellman I Pani G Siminovitch K.A Cambier J.C Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by FcγRIIB1.Science. 1995; 268: 293-297Crossref Scopus (499) Google Scholar) and has now been identified in the killer-inhibitory receptors on natural killer (NK) cells that also recruit SHP-1 (7Burshtyn D.N Scharenberg A.M Wagtmann N Rajagopalan S Berrada K Yi T Kinet J.P Long E.O Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor.Immunity. 1996; 4: 77-85Abstract Full Text Full Text PDF Scopus (542) Google Scholar). The potential role of CD22 as a negative regulatory molecule was supported by an experiment in which it was cross-linked independently of surface immunoglobulin (sIg) using anti-CD22 coated beads: an enhanced anti-immunoglobulin response was observed, and it was suggested that drawing CD22 away from an interaction with sIg limited the extent to which it could negatively regulate antigen receptor signaling (17Doody G.M Justement L.B Delibrias C.C Matthews R.J Lin J Thomas M.L Fearon D.T A role in B cell activation for CD22 and the protein tyrosine phosphatase SHP.Science. 1995; 269: 242-244Crossref Scopus (469) Google Scholar). This experiment could not fully exclude the possibility that CD22 was transmitting a positive signal that synergized with sIg signaling, and this is where gene knockout experiments have filled an important gap. B cells from mice made deficient in CD22 by targeted gene disruption, established independently by four groups (41O'Keefe T.L Williams G.T Davies S.L Neuberger M.S Hyperresponsive B cells in CD22-deficient mice.Science. 1996; 274: 798-801Crossref Scopus (452) Google Scholar, 43Otipoby K.L Andersson K.B Draves K.E Klaus S.J Garr A.G Kerner J.D Perlmutter R.M Law C.-L Clark E.A CD22 regulates thymus independent responses and the lifespan of B cells.Nature. 1996; 384: 634-637Crossref Scopus (347) Google Scholar, 51Sato S Miller A.S Inaoki M Bock C.B Jansen P.J Tang M.L Tedder T.F CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction altered signaling in CD22-deficient mice.Immunity. 1996; 5: 551-562Abstract Full Text PDF Scopus (377) Google Scholar, 40Nitschke L Carsetti R Ocker B Kohler G Lamers M.C CD22 is a negative regulator of B cell receptor signaling.Curr. Biol. 1997; 7: 133-143Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar), show two characteristic and striking properties: exaggerated elevation in intracellular calcium in response to antigen receptor cross-linking, and spontaneous modulation of sIgM on peripheral B cells. The similarity of this phenotype with that previously observed for B cells deficient in SHP-1 (11Cyster J.G Goodnow C.C Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection.Immunity. 1995; 2: 13-24Abstract Full Text PDF Scopus (342) Google Scholar) supports the view that a major function of CD22 in B cells is to serve as a dock for SHP-1 and negatively regulate antigen receptor signaling (Figure 1 and Figure 2). Candidate targets for SHP-1–mediated dephosphorylation are CD79α and β, Lyn, Syk, CD19, and PLCγ, and a goal of future work will be to identify the specific targets of this phosphatase within the cell after it is recruited to CD22.Figure 2Model of Relationship among CD45, Lyn, CD22, and SHP-1 in B Cell Antigen Receptor SignalingShow full captionCD45-mediated dephosphorylation of Lyn (or related Src-family kinase) activates the kinase domain (red), which then phosphorylates (yellow dots) multiple substrates, including CD22 (green). Igα and Igβ also become tyrosine phosphorylated. Syk associates with phosphorylated Igα/β, and SHP-1 with phosphorylated CD22. Additional associations of these molecules may also occur. The strength and quality of signals transmitted depend on the balance between recruitment of Syk (and other kinases) and SHP-1. The transition to an active complex is promoted by antigen receptor cross-linking but may also occur spontaneously. CD22/SHP-1 promotes inactivation of the signaling complex.View Large Image Figure ViewerDownload Hi-res image Download (PPT) CD45-mediated dephosphorylation of Lyn (or related Src-family kinase) activates the kinase domain (red), which then phosphorylates (yellow dots) multiple substrates, including CD22 (green). Igα and Igβ also become tyrosine phosphorylated. Syk associates with phosphorylated Igα/β, and SHP-1 with phosphorylated CD22. Additional associations of these molecules may also occur. The strength and quality of signals transmitted depend on the balance between recruitment of Syk (and other kinases) and SHP-1. The transition to an active complex is promoted by antigen receptor cross-linking but may also occur spontaneously. CD22/SHP-1 promotes inactivation of the signaling complex. Down-modulation of sIgM on B lymphocytes occurs rapidly following antigen engagement, the extent of modulation increasing with the dose and valency of antigen (25Goodnow C.C Crosbie J Jorgensen H Brink R.A Basten A Induction of self-tolerance in mature peripheral B lymphocytes.Nature. 1989; 342: 385-391Crossref Scopus (405) Google Scholar). The exaggerated down-modulation of sIgM reported in mature CD22-deficient and SHP-1–deficient B cells compared to wild-type cells, in the absence of increased antigen engagement, suggests that basal or constitutive signaling may be elevated in the absence of CD22/SHP-1–mediated negative regulation (11Cyster J.G Goodnow C.C Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection.Immunity. 1995; 2: 13-24Abstract Full Text PDF Scopus (342) Google Scholar, 41O'Keefe T.L Williams G.T Davies S.L Neuberger M.S Hyperresponsive B cells in CD22-deficient mice.Science. 1996; 274: 798-801Crossref Scopus (452) Google Scholar, 43Otipoby K.L Andersson K.B Draves K.E Klaus S.J Garr A.G Kerner J.D Perlmutter R.M Law C.-L Clark E.A CD22 regulates thymus independent responses and the lifespan of B cells.Nature. 1996; 384: 634-637Crossref Scopus (347) Google Scholar, 51Sato S Miller A.S Inaoki M Bock C.B Jansen P.J Tang M.L Tedder T.F CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction altered signaling in CD22-deficient mice.Immunity. 1996; 5: 551-562Abstract Full Text PDF Scopus (377) Google Scholar, 40Nitschke L Carsetti R Ocker B Kohler G Lamers M.C CD22 is a negative regulator of B cell receptor signaling.Curr. Biol. 1997; 7: 133-143Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar). Recruitment of SHP-1 to CD22 may not be restricted to the period following antigen receptor engagement by antigen but may occur at a low level continuously, counteracting the "spontaneous firing" of the receptor (Figure 1). Following antigen receptor engagement, CD22 phosphorylation is increased, and a much larger battery of SHP-1 molecules is recruited and activated (Figure 1). SHP-1 is recruited to the cell membrane by multiple receptor systems and in each case it appears to play a negative role (52Scharenberg A.M Kinet J.P The emerging field of receptor-mediated inhibitory signaling SHP or SHIP?.Cell. 1996; 87: 961-964Abstract Full Text Full Text PDF Scopus (139) Google Scholar). Within B lymphocytes, SHP-1 is recruited to the cytoplasmic domain of FcγRII following co–cross-linking of sIg and FcγRII (15D'Ambrosio D Hippen K.L Minskoff S.A Mellman I Pani G Siminovitch K.A Cambier J.C Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by FcγRIIB1.Science. 1995; 268: 293-297Crossref Scopus (499) Google Scholar), and SHP-1 recruitment may account for the down-regulation of signaling that occurs upon immunoglobulin–FcR co–cross-linking. However, recent studies suggest that SHP-1 cannot account for all of the negative regulatory activity of FcγRII and that the lipid phosphatase, SHIP, that is also recruited to the receptor participates in the negative function (42Ono M Bolland S Tempst P Ravetch J.V Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc(gamma)RIIB.Nature. 1996; 383: 263-266Crossref PubMed Scopus (626) Google Scholar). Because SHIP is recruited to the same tyrosine-phosphorylated motif in FcγRIIb as SHP-1, it is possible that SHIP may also be recruited by other molecules that have been found to bind SHP-1, such as CD22. This possibility warrants further investigation since it bears on the issue of whether transmembrane regulatory molecules control the quality as well as strength of antigen receptor signaling (52Scharenberg A.M Kinet J.P The emerging field of receptor-mediated inhibitory signaling SHP or SHIP?.Cell. 1996; 87: 961-964Abstract Full Text Full Text PDF Scopus (139) Google Scholar). However, the similar albeit less severe phenotype of B cells deficient in CD22 compared to SHP-1 deficiency argues that CD22 negatively regulates antigen receptor signaling largely by recruiting SHP-1. The identification of a negative function for CD22 does not exclude the possibility that it may also have a positive signaling role. Two tyrosine-containing motifs in the CD22 cytoplasmic domain are similar to the ITAM motifs of CD3 and CD79 molecules (34Leprince C Draves K.E Geahlen R.L Ledbetter J.A Clark E.A CD22 associates with the human surface IgM-B cell antigen receptor complex.Proc. Natl. Acad. Sci. USA. 1993; 90: 3236-3240Crossref Scopus (164) Google Scholar, 45Peaker C.J Neuberger M.S Association of CD22 with the B cell antigen receptor.Eur. J. Immunol. 1993; 23: 1358-1363Crossref Scopus (139) Google Scholar), and one or other of these motifs may participate in recruiting Lyn, Syk, PI3-kinase, and PLCγ1 (32Law C.L Sidorenko S.P Chandran K.A Zhao Z Shen S.H Fischer E.H Clark E.A CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1) upon B cell activation.J. Exp. Med. 1996; 183: 547-560Crossref Scopus (173) Google Scholar, 66Tuscano J.M Engel P Tedder T.F Agarwal A Kehrl J.H Involvement of p72syk kinase, p53/56lyn kinase and phosphatidyl inositol-3 kinase in signal transduction via the human B lymphocyte antigen CD22.Eur. J. Immunol. 1996; 26: 1246-1252Crossref Scopus (72) Google Scholar). Complexes of CD22 containing Syk, PLCγ1, and SHP-1 have been reported (32Law C.L Sidorenko S.P Chandran K.A Zhao Z Shen S.H Fischer E.H Clark E.A CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1) upon B cell activation.J. Exp. Med. 1996; 183: 547-560Crossref Scopus (173) Google Scholar). The reduced proliferative response of CD22-deficient B cells following antigen receptor cross-linking may reflect a lack of positive regulation by CD22 (43Otipoby K.L Andersson K.B Draves K.E Klaus S.J Garr A.G Kerner J.D Perlmutter R.M Law C.-L Clark E.A CD22 regulates thymus independent responses and the lifespan of B cells.Nature. 1996; 384: 634-637Crossref Scopus (347) Google Scholar, 51Sato S Miller A.S Inaoki M Bock C.B Jansen P.J Tang M.L Tedder T.F CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction altered signaling in CD22-deficient mice.Immunity. 1996; 5: 551-562Abstract Full Text PDF Scopus (377) Google Scholar). However, reduced proliferation was not a consistent observation in CD22-deficient cells, with one study demonstrating increased proliferation (41O'Keefe T.L Williams G.T Davies S.L Neuberger M.S Hyperresponsive B cells in CD22-deficient mice.Science. 1996; 274: 798-801Crossref Scopus (452) Google Scholar), and an alternate explanation may be that CD22-deficient B cells transmit exaggerated signals for cell death as well as cell cycle entry, a possibility directly demonstrated in one study (40Nitschke L Carsetti R Ocker B Kohler G Lamers M.C CD22 is a negative regulator of B cell receptor signaling.Curr. Biol. 1997; 7: 133-143Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar). The more rapid turnover of peripheral B cells in CD22-deficient mice (43Otipoby K.L Andersson K.B Draves K.E Klaus S.J Garr A.G Kerner J.D Perlmutter R.M Law C.-L Clark E.A CD22 regulates thymus independent responses and the lifespan of B cells.Nature. 1996; 384: 634-637Crossref Scopus (347) Google Scholar, 40Nitschke L Carsetti R Ocker B Kohler G Lamers M.C CD22 is a negative regulator of B cell receptor signaling.Curr. Biol. 1997; 7: 133-143Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar) and the failure to accumulate normal numbers of mature B cells in SHP-1–deficient mice (11Cyster J.G Goodnow C.C Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection.Immunity. 1995; 2: 13-24Abstract Full Text PDF Scopus (342) Google Scholar) are also consistent with elevated signals leading to increased cell death. Therefore the outcome of proliferation assays may easily be shifted from elevated to reduced proliferative responses depending on the relative amount of cell death, which might be influenced by such features as the type of anti-immunoglobulin cross-linking agent used and the duration of the in vitro assay. The delicate balance between proliferation and death may also account for the reduced in vivo antibody response to type II T-independent antigens but the normal or slightly elevated response to T-dependent antigens in CD22-deficient animals. Type II T-independent antigens, such as the trinitrophenol-Ficoll used in studying the CD22-deficient mice (43Otipoby K.L Andersson K.B Draves K.E Klaus S.J Garr A.G Kerner J.D Perlmutter R.M Law C.-L Clark E.A CD22 regulates thymus independent responses and the lifespan of B cells.Nature. 1996; 384: 634-637Crossref Scopus (347) Google Scholar, 51Sato S Miller A.S Inaoki M Bock C.B Jansen P.J Tang M.L Tedder T.F CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction altered signaling in CD22-deficient mice.Immunity. 1996; 5: 551-562Abstract Full Text PDF Scopus (377) Google Scholar, 40Nitschke L Carsetti R Ocker B Kohler G Lamers M.C CD22 is a negative regulator of B cell receptor signaling.Curr. Biol. 1997; 7: 133-143Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar), are multivalent polymers and are thought to induce B cell responses by extensively cross-linking the antigen receptor. The reduced response in some of the studies (43Otipoby K.L Andersson K.B Draves K.E Klaus S.J Garr A.G Kerner J.D Perlmutter R.M Law C.-L Clark E.A CD22 regulates thymus independent responses and the lifespan of B cells.Nature. 1996; 384: 634-637Crossref Scopus (347) Google Scholar, 40Nitschke L Carsetti R Ocker B Kohler G Lamers M.C CD22 is a negative regulator of B cell receptor signaling.Curr. Biol. 1997; 7: 133-143Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar) might therefore reflect exaggerated signaling in TNP-specific B cells causing their elimination. T-dependent antigens, by contrast, generally have a lower valency and might be less likely to induce apoptosis of CD22-deficient B cells. Furthermore, presentation of the antigen to T cells should permit rescue signals to be transmitted by various costimulatory molecules, such as CD40, whose function remains intact in CD22-deficient B cells (41O'Keefe T.L Williams G.T Davies S.L Neuberger M.S Hyperresponsive B cells in CD22-deficient mice.Science. 1996; 274: 798-801Crossref Scopus (452) Google Scholar, 43Otipoby K.L Andersson K.B Draves K.E Klaus S.J Garr A.G Kerner J.D Perlmutter R.M Law C.-L Clark E.A CD22 regulates thymus independent responses and the lifespan of B cells.Nature. 1996; 384: 634-637Crossref Scopus (347) Google Scholar, 51Sato S Miller A.S Inaoki M Bock C.B Jansen P.J Tang M.L Tedder T.F CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction altered signaling in CD22-deficient mice.Immunity. 1996; 5: 551-562Abstract Full Text PDF Scopus (377) Google Scholar, 40Nitschke L Carsetti R Ocker B Kohler G Lamers M.C CD22 is a negative regulator of B cell receptor signaling.Curr. 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