Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

The signaling lymphocytic activation molecule family of receptors has been implicated in the pathophysiology of autoimmunity in humans and mice. One member of the family, Ly108, was strongly linked to lupus susceptibility in mice. High expression of a Ly108 isoform, Ly108-1, was observed in lymphocytes of lupus-prone mice. Herein, we examined the molecular basis for the influence of Ly108 on lupus susceptibility by studying Ly108 signal transduction in T cells. We observed that Ly108 was able to mediate a tyrosine phosphorylation signal implicating Ly108, Vav-1, and c-Cbl in a manner strictly dependent on engagement of the extracellular domain of Ly108 and co-expression of the Src homology 2 (SH2) domain-containing adaptor signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). Evaluation of T cells from mice carrying mutations in the SAP-FynT pathway indicated that Ly108-triggered protein tyrosine phosphorylation was due to the capacity of SAP to recruit FynT. Importantly, Ly108-1 was more apt at triggering tyrosine phosphorylation signals in T cells when compared with the predominant Ly108 isoform found in non-lupus-prone mice, Ly108-2. This difference was due in part to the presence in Ly108-1 of a unique intra-cytoplasmic tyrosine-based motif that promoted Ly108 signal transduction. Together these data provided a molecular explanation for the involvement of Ly108 in lupus susceptibility in mice. The signaling lymphocytic activation molecule family of receptors has been implicated in the pathophysiology of autoimmunity in humans and mice. One member of the family, Ly108, was strongly linked to lupus susceptibility in mice. High expression of a Ly108 isoform, Ly108-1, was observed in lymphocytes of lupus-prone mice. Herein, we examined the molecular basis for the influence of Ly108 on lupus susceptibility by studying Ly108 signal transduction in T cells. We observed that Ly108 was able to mediate a tyrosine phosphorylation signal implicating Ly108, Vav-1, and c-Cbl in a manner strictly dependent on engagement of the extracellular domain of Ly108 and co-expression of the Src homology 2 (SH2) domain-containing adaptor signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). Evaluation of T cells from mice carrying mutations in the SAP-FynT pathway indicated that Ly108-triggered protein tyrosine phosphorylation was due to the capacity of SAP to recruit FynT. Importantly, Ly108-1 was more apt at triggering tyrosine phosphorylation signals in T cells when compared with the predominant Ly108 isoform found in non-lupus-prone mice, Ly108-2. This difference was due in part to the presence in Ly108-1 of a unique intra-cytoplasmic tyrosine-based motif that promoted Ly108 signal transduction. Together these data provided a molecular explanation for the involvement of Ly108 in lupus susceptibility in mice. Susceptibility to autoimmune diseases such as systemic lupus erythematosus and diabetes is greatly influenced by genetic factors. In studies of lupus-susceptible mouse strains like NZM2410, several gene loci cooperate toward disease predisposition (1Kumar K.R. Li L. Yan M. Bhaskarabhatla M. Mobley A.B. Nguyen C. Mooney J.M. Schatzle J.D. Wakeland E.K. Mohan C. Science. 2006; 312: 1665-1669Crossref PubMed Scopus (205) Google Scholar). One locus, Sle1, causes a loss of immune tolerance, leading to production of anti-nuclear antibodies. Sle1 is composed of four sub-loci, termed Sle1a–d, that all contribute to disease susceptibility. Of these, the best studied and most influential locus is Sle1b, which corresponds to the slam family locus on mouse chromosome 1 (2Wandstrat A.E. Nguyen C. Limaye N. Chan A.Y. Subramanian S. Tian X.H. Yim Y.S. Pertsemlidis A. Garner Jr., H.R. Morel L. Wakeland E.K. Immunity. 2004; 21: 769-780Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). The slam family of genes encodes six immune cell-specific receptors named signaling lymphocytic activation molecule (SLAM) 3The abbreviations used are: SLAM, signaling lymphocytic activation molecule; SRR, SLAM-related receptor; NK, natural killer; SAP, SLAM-associated protein; NTB-A, natural killer, T- and B-cell antigen; SH2, Src homology 2; TH1, T helper 1; DC, dendritic cell; mAb, monoclonal antibody; IL, interleukin. 3The abbreviations used are: SLAM, signaling lymphocytic activation molecule; SRR, SLAM-related receptor; NK, natural killer; SAP, SLAM-associated protein; NTB-A, natural killer, T- and B-cell antigen; SH2, Src homology 2; TH1, T helper 1; DC, dendritic cell; mAb, monoclonal antibody; IL, interleukin. (CD150), 2B4 (CD244), Ly-9 (CD229), CD84, Ly108 (also named natural killer, T- and B-cell antigen (NTB-A) in humans) and CD2-like receptor activating cytotoxic cells (CRACC, also referred to as CD319) (3Veillette A. Nat. Rev. Immunol. 2006; 6: 56-66Crossref PubMed Scopus (175) Google Scholar, 4Nichols K.E. Ma C.S. Cannons J.L. Schwartzberg P.L. Tangye S.G. Immunol. Rev. 2005; 203: 180-199Crossref PubMed Scopus (179) Google Scholar). SLAM-related receptors (SRRs) possess immunoglobulin (Ig)-like domains in their extracellular region, a single transmembrane domain and a cytoplasmic region bearing multiple tyrosine-based motifs. With the exception of 2B4, which binds CD48, all SRRs are self-ligands. Through tyrosine phosphorylation sites in their cytoplasmic domain, SRRs associate with the SLAM-associated protein (SAP) family of adaptors that includes SAP, EAT-2, and ERT (3Veillette A. Nat. Rev. Immunol. 2006; 6: 56-66Crossref PubMed Scopus (175) Google Scholar, 4Nichols K.E. Ma C.S. Cannons J.L. Schwartzberg P.L. Tangye S.G. Immunol. Rev. 2005; 203: 180-199Crossref PubMed Scopus (179) Google Scholar). These adaptors are composed primarily of a Src homology 2 (SH2) domain and link SRRs to intracellular signals. In the case of SAP, a second binding surface in the SH2 domain enables SAP to couple SRRs to the Src-related protein-tyrosine kinase FynT, thereby triggering protein tyrosine phosphorylation signals (5Latour S. Roncagalli R. Chen R. Bakinowski M. Shi X. Schwartzberg P.L. Davidson D. Veillette A. Nat. Cell Biol. 2003; 5: 149-154Crossref PubMed Scopus (223) Google Scholar, 6Latour S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar, 7Chan B. Lanyi A. Song H.K. Griesbach J. Simarro-Grande M. Poy F. Howie D. Sumegi J. Terhorst C. Eck M.J. Nat. Cell Biol. 2003; 5: 155-160Crossref PubMed Scopus (234) Google Scholar, 8Davidson D. Shi X. Zhang S. Wang H. Nemer M. Ono N. Ohno S. Yanagi Y. Veillette A. Immunity. 2004; 21: 707-717Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). EAT-2 and ERT possess one or two carboxyl-terminal tyrosines that undergo phosphorylation and link SRRs to alternative signals (9Roncagalli R. Taylor J.E. Zhang S. Shi X. Chen R. Cruz-Munoz M.E. Yin L. Latour S. Veillette A. Nat. Immunol. 2005; 6: 1002-1010Crossref PubMed Scopus (113) Google Scholar). Interestingly, SAP is mutated in X-linked lymphoproliferative a by a immune to named is a member of the family on T cells at in natural cells PubMed Scopus Google Scholar, C. M. S. R. S. R. L. A. J. 2001; PubMed Scopus Google Scholar). studies that engagement of Ly108 was able to natural by cells C. M. S. R. S. R. L. A. J. 2001; PubMed Scopus Google Scholar, M. F. D. F. G. L. A. C. J. Immunol. 2004; PubMed Scopus Google Scholar, S. C. Immunol. 2006; PubMed Scopus Google Scholar, S. C. J. Immunol. 2004; PubMed Scopus Google Scholar). was that of T cells by monoclonal T helper 1 Wang H. D. A. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). of mice with a protein to the of autoimmune disease autoimmune These that Ly108 implicated in the pathophysiology of autoimmune diseases by production by T cells. of T cells from mice to most of the extracellular domain of Ly108 that Ly108 a in T helper 2 production D. M. A. S. C. Terhorst C. J. Immunol. 2005; PubMed Scopus Google Scholar). the basis for these to these data a that Ly108 in and autoimmune for the that Ly108 is in autoimmune diseases was with the of the locus in the lupus-susceptible mouse (2Wandstrat A.E. Nguyen C. Limaye N. Chan A.Y. Subramanian S. Tian X.H. Yim Y.S. Pertsemlidis A. Garner Jr., H.R. Morel L. Wakeland E.K. Immunity. 2004; 21: 769-780Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). This several in slam family genes and mice. The most was a in This in expression of isoform of as as expression of isoform, in T cells and cells of In T cells these with of antigen in we examined the molecular basis for the of T cells of the Ly108 isoform, We found that all Ly108 able to mediate tyrosine phosphorylation signals in T cells that Ly108 Vav-1, and to a These signals dependent on of the extracellular domain of Ly108 and co-expression of In the of SAP to recruit the Src-related protein-tyrosine kinase FynT. Importantly, Ly108-1 was more apt at triggering protein tyrosine phosphorylation This difference was due in part to the presence of tyrosine-based motif in the cytoplasmic domain of is a mouse N. Veillette A. PubMed Scopus Google Scholar). of Ly108 or with or SAP by S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar). or in with SAP S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar, R. F. Roncagalli R. A. R. Latour S. Veillette A. Biol. 2004; PubMed Scopus Google Scholar). T dendritic cells and cells from mice or the indicated mouse to cells was to In mice with the of or S. 2005; PubMed Scopus Google Scholar). cells by cells in with Ly108 by of cells with a a cytoplasmic of the used as mice, mice, and mice the SAP D. Shi X. Zhang S. Wang H. Nemer M. Ono N. Ohno S. Yanagi Y. Veillette A. Immunity. 2004; 21: 707-717Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, L. J. Li C. M. Sumegi J. Wang G. J. 2003; PubMed Scopus Google Scholar, P.L. S. Full Text PDF PubMed Scopus Google Scholar). and Ly108 was from Ly108-1 and by from from the data and the as in which the the extracellular and transmembrane of Ly108 by of by expression in T cells or in the expression which to The expression SAP was S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar). The for the was by mouse and a from as mutations or of the cytoplasmic the most of the cytoplasmic in the or to that mutations Ly108 by with a protein the cytoplasmic domain of SAP, FynT, Vav-1, and S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar, R. F. Roncagalli R. A. R. Latour S. Veillette A. Biol. 2004; PubMed Scopus Google Scholar, D. M. Veillette A. J. PubMed Scopus Google Scholar, M. Davidson D. R. Veillette A. J. PubMed Scopus Google Scholar). the extracellular domain of was from mouse Ly108 was in the protein as This Ly108 the SRRs is was from to to the by the and from or mouse and from PubMed Scopus Google Scholar, J. S. T. F. D. Tangye S.G. G. K.E. J.E. A. J. Immunol. Google Scholar). or was Cell of on was as S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar). of Ly108 on cells for the indicated at with or by or S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar). of Ly108 on from mice for at with or a cytoplasmic of Ly108, in was by cells from the cells in is and 2 with and and and as in A. Full Text PDF PubMed Scopus Google Scholar). protein protein or from signals a Ly108 on T and on was used to the expression of Ly108 on mouse immune cells In Ly108 was on and cells all cells in these Ly108, which a these cells of to In all T T and cells also Ly108 This expression was when T cells or cells in and In a of cells Ly108 This was for cells from mice and mice with the These cells when cells and in with The of Ly108 on most mouse cells was that cells of NTB-A, the Ly108 C. M. S. R. S. R. L. A. J. 2001; PubMed Scopus Google Scholar, M. F. D. F. G. L. A. C. J. Immunol. 2004; PubMed Scopus Google Scholar, S. C. Immunol. 2006; PubMed Scopus Google Scholar, S. C. J. Immunol. 2004; PubMed Scopus Google Scholar). Ly108 was on all in with a C. S. Wang N. A. Terhorst C. A. Immunity. Full Text Full Text PDF PubMed Scopus Google Ly108 was on all on in the Ly108 is on T and on most cells. Ly108 a in T the signals by Ly108, Ly108 was in the or in the presence of SAP in the mouse T This was Ly108 and SAP was used to the linked to SRRs (5Latour S. Roncagalli R. Chen R. Bakinowski M. Shi X. Schwartzberg P.L. Davidson D. Veillette A. Nat. Cell Biol. 2003; 5: 149-154Crossref PubMed Scopus (223) Google Scholar, 6Latour S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar, R. F. Roncagalli R. A. R. Latour S. Veillette A. Biol. 2004; PubMed Scopus Google Scholar). The of Ly108 on protein tyrosine phosphorylation was studied by of with SAP cells Ly108 in protein tyrosine phosphorylation compared with cells Ly108 with SAP a in tyrosine phosphorylation of of and in tyrosine phosphorylation of to a was also in cells SAP the basis of is signal due to signaling a in in cells The was with Ly108 with and by The in cells Ly108 and SAP was with or antibodies. was in cells SAP We also SAP was with Ly108 by Ly108 with SAP was in with and antibodies. NTB-A, mouse Ly108 is a the data of engagement of Ly108 was to SAP binding and tyrosine we a receptor in which the extracellular and transmembrane of Ly108 by of receptor with a tyrosine phosphorylation signal of and in cells and SAP Importantly, in protein tyrosine phosphorylation was in the of that Ly108 engagement was to the signals. when was the of Ly108 with SAP, by with In the of engagement was with more was observed The of the was in to the and SAP S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar). Ly108 engagement was to and protein tyrosine phosphorylation in T cells. Ly108 by the Src-related studies indicated that the of and 2B4 to mediate tyrosine phosphorylation signals in the presence of SAP was in part by the capacity of SAP to the Src-related protein-tyrosine kinase (5Latour S. Roncagalli R. Chen R. Bakinowski M. Shi X. Schwartzberg P.L. Davidson D. Veillette A. Nat. Cell Biol. 2003; 5: 149-154Crossref PubMed Scopus (223) Google Scholar, 6Latour S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar, 8Davidson D. Shi X. Zhang S. Wang H. Nemer M. Ono N. Ohno S. Yanagi Y. Veillette A. Immunity. 2004; 21: 707-717Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, M. Lanyi A. Howie D. Poy F. J. M. Sumegi J. Eck M.J. Terhorst C. Immunol. 2004; PubMed Scopus Google Scholar). This a second binding surface in the SAP SH2 domain that is on of SAP and with the domain of FynT. a more that alternative also SRRs to mediate tyrosine phosphorylation signals S. G. Wang N. S. M. B. Mooney J. Schatzle J. Terhorst C. Lanyi A. 2006; PubMed Scopus Google Scholar). Ly108 signaling was by FynT, Ly108-triggered protein tyrosine phosphorylation was examined in T cells from mice carrying mutations in the SAP-FynT which the SAP-FynT was of a of to and mice from these or with and Ly108 tyrosine phosphorylation was by of Ly108 with The of Ly108 with SAP was also by of Ly108 with In 1 and was Ly108 tyrosine phosphorylation and in the of Ly108 of Ly108 Ly108 tyrosine phosphorylation and binding of Ly108 to SAP The Ly108 tyrosine phosphorylation in the of Ly108 engagement was at with the in cells the basis for is the of Ly108 in cells This Ly108 the of Ly108 to undergo tyrosine phosphorylation was in SAP and Importantly, was also in cells the SAP to and was also a of the of SAP to with Ly108 and in to SAP 1 and is that was due to a of Ly108 toward SAP of the of the SAP SH2 domain (5Latour S. Roncagalli R. Chen R. Bakinowski M. Shi X. Schwartzberg P.L. Davidson D. Veillette A. Nat. Cell Biol. 2003; 5: 149-154Crossref PubMed Scopus (223) Google Scholar, 7Chan B. Lanyi A. Song H.K. Griesbach J. Simarro-Grande M. Poy F. Howie D. Sumegi J. Terhorst C. Eck M.J. Nat. Cell Biol. 2003; 5: 155-160Crossref PubMed Scopus (234) Google Scholar, 8Davidson D. Shi X. Zhang S. Wang H. Nemer M. Ono N. Ohno S. Yanagi Y. Veillette A. Immunity. 2004; 21: 707-717Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). This was by the tyrosine phosphorylation of in and the of Ly108 to undergo tyrosine phosphorylation and associate with SAP was Ly108-triggered protein tyrosine phosphorylation was by the capacity of SAP to FynT. We to that Ly108 tyrosine in also by the of that Ly108 from mice at in the presence of or a cytoplasmic of Ly108 Ly108 tyrosine phosphorylation was as for This that of with Ly108 a of tyrosine phosphorylation of Ly108 in in to Ly108 phosphorylation of Ly108 on T cells in the of Ly108 from and and to Ly108, T cells SRRs A. Latour S. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). Ly108 and mediate signals in these the tyrosine phosphorylation signals by the two receptors compared due to the extracellular domains of the receptors used in these the tyrosine phosphorylation of of and engagement of in the of of and to a The of the adaptor and and SH2 domain-containing S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar). We also compared the signal by Ly108 with that by 2B4, a found on cells and T cells A. Latour S. Immunity. Full Text Full Text PDF PubMed Scopus Google and of the the tyrosine phosphorylation of of and as Vav-1, and R. F. Roncagalli R. A. R. Latour S. Veillette A. Biol. 2004; PubMed Scopus Google Scholar). This of tyrosine phosphorylation was to that by The that the Ly108-triggered and with or and the was by and phosphorylation of was of cells and SAP of tyrosine phosphorylation was in cells a was observed in cells bearing when tyrosine phosphorylation of c-Cbl was examined in T Ly108 a tyrosine phosphorylation signal and This signal was from that by was to the one by Ly108-1, the with Susceptibility in a in T T cells two Ly108 Ly108-1 and (2Wandstrat A.E. Nguyen C. Limaye N. Chan A.Y. Subramanian S. Tian X.H. Yim Y.S. Pertsemlidis A. Garner Jr., H.R. Morel L. Wakeland E.K. Immunity. 2004; 21: 769-780Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, PubMed Scopus Google Scholar). These are by alternative of for the cytoplasmic domain of Ly108 and are by their carboxyl-terminal T cells from lupus-susceptible mice bearing the locus of Ly108-1 in to (2Wandstrat A.E. Nguyen C. Limaye N. Chan A.Y. Subramanian S. Tian X.H. Yim Y.S. Pertsemlidis A. Garner Jr., H.R. Morel L. Wakeland E.K. Immunity. 2004; 21: 769-780Abstract Full Text Full Text PDF PubMed Scopus (225) Google we studied the that Ly108-1 and in their signaling receptors the cytoplasmic domain of Ly108-1 or in T cells in the presence of of for of the Ly108-1 2 and in a tyrosine phosphorylation in to triggering of the and This was for phosphorylation of the receptor to a and that these in the of protein tyrosine a of was also of in more protein tyrosine phosphorylation of is in these we compared the of the two Ly108 with SAP This was cells Ly108 in of the as the cells more binding of Ly108 to With several of Ly108-1 or and the of SAP was more with Ly108-1 was the difference in tyrosine phosphorylation of Ly108-1 and that the in SAP binding the in Ly108 tyrosine is in of Ly108-1 and one unique tyrosine-based motif in cytoplasmic domain In two unique tyrosine-based in cytoplasmic we the signaling of Ly108-1 and to these tyrosine-based motifs. the unique tyrosines by and the of the to tyrosine phosphorylation signals was of the unique tyrosine of Ly108-1 with in the of Ly108-1 to tyrosine phosphorylation signals. was as the signals that to of of the two unique tyrosines found in with in the in the signaling of Ly108-1 and was in part by the unique tyrosine found in the of tyrosine was is that also of lupus-susceptible mice provided that in Ly108, are implicated in the pathophysiology of autoimmune diseases (2Wandstrat A.E. Nguyen C. Limaye N. Chan A.Y. Subramanian S. Tian X.H. Yim Y.S. Pertsemlidis A. Garner Jr., H.R. Morel L. Wakeland E.K. Immunity. 2004; 21: 769-780Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). was observed that lymphocytes from lupus-prone mice of Ly108-1 to when compared with lymphocytes from This difference with T antigen in the by which of these influenced T and lupus we their signaling a we like family Ly108 was to protein tyrosine phosphorylation signals in T cells. of a T Ly108 with or SAP, we found that Ly108 was apt at intracellular protein tyrosine in a manner that was strictly on a receptor in which the extracellular domain of Ly108 was by the extracellular of was that the of Ly108 to associate with SAP as as to mediate tyrosine phosphorylation signals was strongly dependent on engagement of This was in to SLAM, which with SAP in a manner S. Gish G. Helgason C.D. Humphries R.K. Pawson T. Veillette A. Nat. Immunol. 2001; 2: 681-690Crossref PubMed Scopus (222) Google Scholar). we examined the of the SAP and the Src family kinase in Ly108 signal transduction. T cells from mice carrying mutations in was observed that protein tyrosine phosphorylation was in SAP, in with the with the T signal was also in SAP a SAP to FynT. was in from mice. these data provided that Ly108-triggered protein tyrosine phosphorylation was of SAP to by of the motif of T cells of the family in to Ly108, was to the signals provided by these receptors and Ly108 we on SLAM, the best family receptor in T cells. engagement of Ly108 tyrosine phosphorylation of to a triggering of the tyrosine phosphorylation of and a of tyrosine phosphorylation was by these that Ly108 and in T cells. is that Ly108 signals to by 2B4, family 2B4 is found in T is in cells. The in the signals by Ly108 and 2B4 in cells in a manner C. M. S. R. S. R. L. A. J. 2001; PubMed Scopus Google Scholar, M. F. D. F. G. L. A. C. J. Immunol. 2004; PubMed Scopus Google Scholar, S. C. Immunol. 2006; PubMed Scopus Google Scholar, S. C. J. Immunol. 2004; PubMed Scopus Google Scholar). the tyrosine phosphorylation signal by Ly108 in T we the two Ly108 Ly108-1 and in their capacity to Interestingly, we observed that Ly108-1, the isoform in in lupus-prone mice, was more apt at triggering tyrosine phosphorylation signals. This was for tyrosine phosphorylation of Ly108 was also observed for and the with these the of the their that of are of of in the of with which cooperate to the of Ly108-1 and to tyrosine phosphorylation signals their influence on lupus susceptibility. the of tyrosine phosphorylation signal by Ly108 the to Ly108 in T cells as as the of Ly108-1 and on T We that is to the that of Ly108, in to a T and a as a or a or two T cells as A. Latour S. Immunity. Full Text Full Text PDF PubMed Scopus Google signals that with from the T antigen The Vav-1, is a for and that T activation H. T. M. Chan G. S. D. M. A. J.M. Biol. Full Text Full Text PDF PubMed Google Scholar, M. Nat. Rev. Immunol. 2: PubMed Scopus Google Scholar). is by tyrosine phosphorylation and is for T antigen and These the of on antigen T in T cells and the in observed in T cells Wang H. D. A. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, D. M. A. S. C. Terhorst C. J. Immunol. 2005; PubMed Scopus Google Scholar). also the signals in T cells Ly108-1 (2Wandstrat A.E. Nguyen C. Limaye N. Chan A.Y. Subramanian S. Tian X.H. Yim Y.S. Pertsemlidis A. Garner Jr., H.R. Morel L. Wakeland E.K. Immunity. 2004; 21: 769-780Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). the of c-Cbl tyrosine phosphorylation in is c-Cbl is a that T activation L. A. M. H. Immunity. 2004; 21: Full Text Full Text PDF PubMed Scopus Google Scholar). c-Cbl was also to as adaptor molecule tyrosine the of signaling and is of that the of Ly108 engagement on c-Cbl was as as that on c-Cbl as a as in Ly108 is also that c-Cbl in a at the of Ly108 engagement in T cells. In of c-Cbl tyrosine phosphorylation in to Ly108 engagement to with tyrosine phosphorylation and for is the basis for the signaling Ly108-1 and the two the carboxyl-terminal of their cytoplasmic domain, we the that unique tyrosine-based in these studies that of the tyrosine in the unique motif of Ly108-1 of protein tyrosine In of the tyrosines in the two found in These that part of the in the signals by Ly108-1 and due to the unique tyrosine-based motif in is that motif tyrosine which the of such as SAP and the or of Ly108, of tyrosine thereby the of Ly108 to of the unique tyrosine of Ly108-1 the Ly108-triggered signal to the as that with is that also in their signaling these we examined the signaling of Ly108 isoform named This isoform a of carboxyl-terminal from of Ly108-1 and that a tyrosine phosphorylation signal that was of Ly108-1 and with that in the unique carboxyl-terminal of from the unique also in the signaling of the two the by which Ly108-1 signals more in T cells is of Ly108-1 are in T also in of mice bearing the lupus susceptibility locus (2Wandstrat A.E. Nguyen C. Limaye N. Chan A.Y. Subramanian S. Tian X.H. Yim Y.S. Pertsemlidis A. Garner Jr., H.R. Morel L. Wakeland E.K. Immunity. 2004; 21: 769-780Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). T cells of Ly108-1 found to antigen (1Kumar K.R. Li L. Yan M. Bhaskarabhatla M. Mobley A.B. Nguyen C. Mooney J.M. Schatzle J.D. Wakeland E.K. Mohan C. Science. 2006; 312: 1665-1669Crossref PubMed Scopus (205) Google Scholar). was that such a in thereby the of cells. the by which a of Ly108-1 in cells and T cells is explanation is to T most cells Ly108 is to in cells. One is EAT-2, a adaptor that recruit and SRRs to signals (9Roncagalli R. Taylor J.E. Zhang S. Shi X. Chen R. Cruz-Munoz M.E. Yin L. Latour S. Veillette A. Nat. Immunol. 2005; 6: 1002-1010Crossref PubMed Scopus (113) Google Scholar). In data indicated that in lupus susceptibility in mice (2Wandstrat A.E. Nguyen C. Limaye N. Chan A.Y. Subramanian S. Tian X.H. Yim Y.S. Pertsemlidis A. Garner Jr., H.R. Morel L. Wakeland E.K. Immunity. 2004; 21: 769-780Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). in the expression of Ly108-1 was observed in T cells and cells from lupus-prone mice. Herein, we found that Ly108-1 was more at signals to a c-Cbl in T cells. This a molecular explanation for the T by expression of Ly108-1 in mice. Interestingly, a lupus susceptibility locus in humans also or to the gene family R. Jr., Li L. J. C. PubMed Scopus Google Scholar, J.E. H. C. N. J. J. S. D. M. R. G. L. T. C. M. S. A. PubMed Scopus Google Scholar, Chen H. R. Chen N. Song J. PubMed Scopus Google Scholar). to expression of leading to in signaling in also contribute to autoimmune disease susceptibility in with

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