Abstract
Surface immunoglobulin (sIg) expression has been conserved as a critical checkpoint in B lymphocyte development. In the chicken embryo, only sIg+ B cells are selectively expanded in the bursa of Fabricius, a primary lymphoid organ unique to the avian species. We have previously demonstrated that an interaction between the antigen-binding sites of sIg and a specific bursal ligand(s) is not required to regulate this developmental checkpoint. Rather, the requirement for sIg expression can be attributed to the surface expression of the Igα/β heterodimer associated with sIg. More specifically, ligand-independent signaling downstream of the Igα cytoplasmic domain drives all bursal stages of B cell development during embryogenesis. We discuss here a site-directed mutagenesis approach to identify the critical membrane proximal events involved in ligand-independent signaling during B cell development.
Similar content being viewed by others
References
Ratcliffe MJH, Lassila O, Pink JR, Vainio O: Avian B cell precursors: surface immunoglobulin expression is an early, possibly bursa-independent event. Eur J Immunol 1986;16:129–133.
Mansikka A, Sandberg M, Lassila O, Toivanen P: Rearrangement of immunoglobulin light chain genes in the chicken occurs prior to colonization of the embryonic bursa of Fabricius. Proc Natl Acad Sci USA 1990; 87:9416–9420.
McCormack WT, Tjoelker LW, Barth CF, et al: Selection for B cells with productive IgL gene rearrangements occurs in the bursa of Fabricius during chicken embryonic development. Genes Dev 1989;3:838–847.
Reth M: Antigen receptors on B lymphocytes. Annu Rev Immunol 1992;10:97–121.
Reth M: Antigen receptor tail clue. Nature 1989;338:383–384.
Cambier JC: New nomenclature for the Reth motif (or ARH1/TAM/ARAM/YXXL). Immunol Today 1995;16:110.
Clark MR, Johnson SA, Cambier JC: Analysis of Igα tyrosine kinase interaction reveals two levels of binding specificity and tyrosine phosphorylated Igα stimulation of Fyn activity. EMBO J 1994;13:1911–1919.
Muller R, Wienands J, Reth M: The serine and threonine residues in the Igα cytoplasmic tail negatively regulate immunoreceptor tyrosine-based activation motif-mediated signal transduction. Proc Natl Acad Sci USA. 2000;97:8451–8454.
Engels N, Wollscheid B, Wienands J: Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Igα. Eur J Immunol 2001; 31:2126–2134.
Kabak S, Skaggs BJ, Gold MR, et al: The direct recuritment of BLNK to immunoglobulin α couples the B-cell antigen receptor to distal signaling pathways. Mol Cell Biol 2002;22:2524–2535.
Johnson SA, Pleiman CM, Pao L, Schneringer J, Hippen K, Cambier JC: Phosphorylated immunoreceptor signaling motifs (ITAMs) exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases. J Immunol 1995;155:4596–4603.
Cheng PC, Dykstra ML, Mitchell RN, Pierce SK: A role for lipid rafts in B cell antigen receptor signaling and antigen targeting. J Exp Med 1999;190:1549–1560.
Cheng PC, Cherukuri A, Dykstra M, et al: Floating the raft hypothesis: the roles of lipid rafts in B cell antigen receptor function. Semin Immunol 2001;13:107–114.
Baumann, G, Maier D, Freuler F, Tschopp C, Baudisch K, Wienands J: In vitro characterization of major ligands for Src homology 2 domains derived from protein tyrosine kinases, from the adaptor protein SHC and from GTPase-activating protein in Ramos B cells. Eur J Immunol 1994;24:1799–1807.
Wienands J, Freuler F, Baumann G: Tyrosine-phosphorylated forms of Igβ, CD22, TCR zeta and HOSS are major ligands for tandem SH2 domains of Syk. Int Immunol 1995;7:1701–1708.
Rowley RB, Burkhardt AL, Chao HG, Matsueda GR, Bolen JB: Syk protein-tyrosine kinase is regulated by tyrosine-phosphorylated Ig alpha/Ig beta immunoreceptor tyrosine activation motif binding and autophosphorylation. J Biol Chem 1995;270:11590–11594.
Kurosaki T: Genetic analysis of B cell antigen receptor signaling. Annu Rev Immunol 1999;17:555–592.
Pao LI, Famiglietti SJ, Cambier JC: Asymmetrical phosphorylation and function of immunoreceptor tyrosine-based activation motif tyrosines in B cell antigen receptor signal transduction. J Immunol 1998;160:3305–3314.
Kim TJ, Kim YT, Pillai S: Association of activated phosphatidylinositol 3-kinase with p120cbl in antigen receptor-ligated B cells. J Biol Chem 1995;270:27504–27509.
Ingham RJ, Holgado-Madruga M, Siu C, Wong AJ, Gold MR: The Gab1 protein is a docking site for multiple proteins involved in signaling by the B cell antigen receptor. J Biol Chem 1998;273:30630–30637.
Buhl AM, Cambier JC: Phosphorylation of CD19Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. J Immunol 1999;162:4438–4446.
Okada T, Maeda A, Iwamatsu A, Gotoh K, Kurosaki T: BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Immunity 2000;13:817–827.
Gold MR: To make antibodies or not: signaling by the B-cell antigen receptor. Trends Pharmacol Sci 2002;23:316–324.
Salim K, Bottomley MJ, Querfurth E, et al: Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton's tyrosine kinase. EMBO J 1996;15:6241–6250.
Varnai P, Rother KI, Balla T: Phosphatidylinositol 3-kinase-dependent membrane association of the Bruton's tyrosine kinase pleckstrin homology domain visualized in single living cells. J Biol Chem 1999;274:10983–10989.
Saito K, Scharenberg AM, Kinet JP: Interaction between the Btk PH domain and phosphatidylinositol-3,4,5-trisphosphate directly regulates Btk. J Biol Chem 2001;276:16201–16206.
Mahajan S, Fargnoli J, Burkhardt AL, Kut SA, Saouaf SJ, Bolen JB: Src family protein tyrosine kinases induce autoactivation of Bruton's tyrosine kinase. Mol Cell Biol 1995;15:5304–5311.
Rawlings DJ, Scharenberg AM, Park H, et al: Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science 1996;271:822–825.
Kurosaki T, Maeda A, Ishiai M, Hashimoto A, Inabe K, Takata M: Regulation of the phospholipase C-gamma2 pathway in B cells. Immunol Rev 2000;176:19–29.
Ishiai M, Kurosaki M, Pappu R, et al: BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells. Immunity 1999;10:117–125.
Hashimoto S, Iwamatsu A, Ishiai M, et al: Identification of the SH2 domain binding protein of Bruton's tyrosine kinase as BLNK-functional significance of Btk-SH2 domain in B-cell antigen receptor-coupled calcium signaling. Blood 1999;94:2357–2364.
Kurosaki T, Tsukada S: BLNK: connecting Syk and Btk to calcium signals. Immunity 2000;12:1–5.
Kurosaki T, Maeda A, Ishiai M, Hashimoto A, Inabe K, Takata M: Regulation of the phospholipase C-gamma2 pathway in B cells. Immunol Rev 2000;176:19–29.
Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI: Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 1997;386:855–858.
Saijo K, Mecklenbrauker I, Santana A, Leitger M, Schmedt C, Tarakhovsky A: Protein kinase C beta controls nuclear factor kappa B activation in B cells through selective regulation of the IkappaB kinase alpha. J Exp Med 2002;195:1647–1652.
Su TT, Guo B, Kawakami Y, et al: PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling. Nat Immunol 2002;3:780–786.
Niiro H, Clark EA: Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol 2002;2:945–956.
Dieterlen-Lievre F: Hemopoietic cell progenitors in the avian embryo: origin and migrations. Ann NY Acad Sci 1987;511:77–87.
Le Douarin NM, Dieterlen-Lievre F, Oliver PD: Ontogeny of primary lymphoid organs and lymphoid stem cells. Am J Anat 1984;170:261–299.
Reynaud CA, Imhof BA, Anquez V, Weill JC: Emergence of committed B lymphoid progenitors in the developing chicken embryo. EMBO J 1992;11:4349–4358.
Benatar T, Tkalec L, Ratcliffe MJH: Stochastic rearrangement of immunoglobulin variable region genes in chicken B-cell development. Proc Natl Acad Sci USA 1992;89:7615–7619.
Reynaud CA, Anquez V, Dahan A, Weill JC: A single rearrangement event generates most of the chicken immunoglobulin light chain diversity. Cell 1985;40:283–291.
Thompson CB, Neiman PE: Somatic diversification of the chicken immunoglobulin light chain gene is limited to the rearranged variable gene segment. Cell 1987; 48:369–378.
Reynaud CA, Dahan A, Anquez V, Weill JC: Somatic hyperconversion diversifies the single Vh gene of the chicken with a high incidence in the D region. Cell 1989;59:171–183.
Reynaud CA, Anquez V, Grimal H, Weill JC: A hyperconversion mechanism generates the chicken light chain preimmune repertoire. Cell 1987;48:379–388.
Reynaud CA, Bertocci B, Dahan A, Weill JC: Formation of the chicken B-cell repertoire: ontogenesis, regulation of Ig gene rearrangement, and diversification by gene conversion Adv Immunol 1994;57:353–378.
McCormack WT, Thompson CB: Somatic diversification of the chicken immunoglobulin light chain gene. Adv Immunol 1990;48:41–67.
Carlson LM, McCormack WT, Postema CE, Humphries EH, Thompson CB: Templated insertions in the rearranged chicken IgL V gene segment arise by intrachromsomal gene conversion. Genes Dev 1990;4:536–547.
Sayegh CE, Demaries SL, Iacampo S, Ratcliffe MJH: Development of B cells expressing surface immunoglobulin molecules that lack V(D)J-encoded determinants in the avian embryo bursa of fabricius. Proc Natl Acad Sci USA 1999;96:10806–10811.
Hughes SH, Greenhouse JJ, Petropoulos CJ, Sutrave P: Adaptor plasmids simplify the insertion of foreign DNA into helper-independent retroviral vectors. J Virol 1987;61:3004–3012.
Monroe JG: Ligand-independent tonic signaling in B cell receptor function. Curr Opin Immunol 2004;16:288–295.
Fuentes-Panana EM, Bannish G, Monroe JG: Basal B-cell receptor signaling in B lymphocytes: mechanisms of regulation and role in positive selection, differentiation, and peripheral survival. Immunol Rev 2004;197:26–40.
Mizuno K, Tagawa Y, Mitomo K, et al: Src homology region 2 (SH2) domain-containing phosphatase-1 dephosphorylates B cell linker protein/SH2 domain leukocyte protein of 65 kDa and selectively regulates c-Jun NH2-terminal kinase activation in B cells. J Immunol 2000;165:1344–1351.
Adachi T, Flaswinkel H, Yakura H, Reth M, Tsubata T: The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-1 upon tyrosine phosphorylation. J Immunol 1998;160:4662–4665.
Pike KA, Iacampo S, Friedmann JE, Ratcliffe MJH: The cytoplasmic domain of Igα is necessary and sufficient to support efficient early B cell development. J Immunol 2004;172:2210–2218.
Pike KA, Ratcliffe MJH: Dual requirement for the Igα immunoreceptor tyrosine-based activation motif (ITAM) and a conserved non-Igα ITAM tyrosine in supporting Igα/β mediated B cell development. J Immunol 2005;174:2012–2020.
Wienands J, Larbolette O, Reth M: Evidence for a preformed transducer complex organized by the B cell antigen receptor. Proc. Natl Acad Sci USA 1996;93: 7865–7870.
Ohnishi K, Melchers F: The nonimmunoglobulin portion of lambda5 mediates cell-autonomous pre-B cell receptor signaling. Nat Immunol 2003;4:849–856.
Shaffer AL, Schlissel MS: A truncated heavy chain protein relieves the requirement for surrogate light chains in early B cell development. J Immunol 1997;159: 1265–1275.
Muljo SA, Schlissel MS: The variable, C(H)1, C(H)2 and C(H)3 domains of Ig heavy chain are dispensable for pre-BCR function in transgenic mice. Int Immunol 2002;14:577–584.
Tolar P, Sohn HW, Pierce SK: The initiation of antigen-induced B cell antigen receptor signaling viewed in living cells by fluorescence resonance energy transfer. Nat Immunol 2005;6:1168–1176.
Guo B, Kato RM, Garcia-Lloret M, Wahl MI, Rawlings DJ: Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex. Immunity 2000;13:243–253.
Fuentes-Panana EM, Bannish G, van der V, King LB, Monroe JG: Igα/Igβ complexes generate signals for B cell development independent of selective plasma membrane compartmentalization. J Immunol 2005;174:1245–1252.
Cassard S, Salamero J, Hanau D, et al: A tyrosine-based signal present in Igα mediates B cell receptor constitutive internalization. J Immunol 1998;160:1767–1773.
Cheng AM, Rowley B, Pao W, Hayday A, Bolen JB, Pawson T: Syk tyrosine kinase required for mouse viability and B-cell development. Nature 1995;378:303–306.
Turner M, Mee PJ, Costello PS, et al: Perinatal lethality and blocked B cell development in mice lacking the tyrosine kinase Syk. Nature 1995;378:298–302.
Kohler F, Storch B, Kulathu Y, et al: A leucine zipper in the N terminus confers membrane association to SLP-65. Nat Immunol 2005;6:204–210.
Chiu CW, Dalton M, Ishiai M, Kurosaki T, Chan AC: BLNK: molecular scaffolding through ‘cis’-mediated organization of signaling proteins. EMBO J 2002;21:6461–6472.
Schneider K, Kothlow S, Schneider P, et al: Chicken BAFF—a highly conserved cytokine that mediates B cell survival. Int Immunol 2004;16:139–148.
Koskela K, Nieminen P, Kohonen P, Salminen H, Lassila O: Chicken B cell activating factor: regulator of B-cell survival in the bursa of Fabricius. Scand J Immunol 2004;59:449–457.
Paramithiotis E, Jacobsen KA, Ratcliffe MJH: Loss of surface immunoglobulin expression precedes B cell death by apoptosis in the bursa of Fabricius. J Exp Med 1995;181:105–113.
Jacobsen KA, Paramithiotis E, Ewert DL, Ratcliffe MJH: Apoptotic cell death in the chicken bursa of Fabricius. Adv Exp Med Biol 1996;406:155–165.
Sayegh CE, Rao MA, Ratcliffe MJH: Avian B cell development: lessons from transgenic models. Vet Immunol Immunopathol 1999;72:31–37.
Fleming HE, Paige CJ: Pre-B cell receptor signaling mediates selective response to IL-7 at the pro-B to pre-B cell transition via an ERK/MAP kinase-dependent pathway. Immunity 2001;15:521–531.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pike, K.A., Ratcliffe, M.J.H. Ligand-independent signaling during early avian B cell development. Immunol Res 35, 103–115 (2006). https://doi.org/10.1385/IR:35:1:103
Issue Date:
DOI: https://doi.org/10.1385/IR:35:1:103