Ephrin-B1 Is Critical in T-cell Development

Eph kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. In this study, we investigated the role of EFNB1 and the Ephs it interacts with (collectively called EFNB1 receptors) in mouse T-cell development. In the thymus, CD8 single positive (SP) and CD4CD8 double positive (DP) cells expressed high levels of EFNB1 and EFNB1 receptors, whereas CD4 SP cells had moderate expression of both. Soluble EFNB1-Fc in fetal thymus organ culture caused significant subpopulation ratio skew, with increased CD4 SP and CD8 SP and decreased DP percentage, while the cellularity of the thymus remained constant. Moreover, in EFNB1-treated fetal thymus organ culture, CD117+, CD25+, DP, CD4 SP, and CD8 SP cells all had significantly enhanced proliferation history, according to bromodeoxyuridine uptake. In vitro culture of isolated thymocytes revealed that EFNB1-Fc on solid-phase protected thymocytes from anti-CD3-induced apoptosis, with concomitant augmentation of several antiapoptotic factors, particularly in CD4 SP and CD8 SP cells; on the other hand, soluble EFNB1-Fc promoted anti-CD3-induced apoptosis, as was the case in vivo. This study reveals that EFNB1 and EFNB1 receptors are critical in thymocyte development. Eph kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. In this study, we investigated the role of EFNB1 and the Ephs it interacts with (collectively called EFNB1 receptors) in mouse T-cell development. In the thymus, CD8 single positive (SP) and CD4CD8 double positive (DP) cells expressed high levels of EFNB1 and EFNB1 receptors, whereas CD4 SP cells had moderate expression of both. Soluble EFNB1-Fc in fetal thymus organ culture caused significant subpopulation ratio skew, with increased CD4 SP and CD8 SP and decreased DP percentage, while the cellularity of the thymus remained constant. Moreover, in EFNB1-treated fetal thymus organ culture, CD117+, CD25+, DP, CD4 SP, and CD8 SP cells all had significantly enhanced proliferation history, according to bromodeoxyuridine uptake. In vitro culture of isolated thymocytes revealed that EFNB1-Fc on solid-phase protected thymocytes from anti-CD3-induced apoptosis, with concomitant augmentation of several antiapoptotic factors, particularly in CD4 SP and CD8 SP cells; on the other hand, soluble EFNB1-Fc promoted anti-CD3-induced apoptosis, as was the case in vivo. This study reveals that EFNB1 and EFNB1 receptors are critical in thymocyte development. Receptors are important cell surface molecules for communication between cells and their environment. Protein-tyrosine kinases are essential components in lymphocyte signaling pathways. Thus, receptor tyrosine kinases have dual pivotal functions in lymphocytes. The Eph kinases are the largest receptor protein-tyrosine kinase family. According to sequence homology, Eph kinases are classified into EphAs (EphA1-EphA9) and EphBs (EphB1-EphB6) (1Committee Eph Nomenclature Cell. 1997; 90: 403-404Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar) (available on the World Wide Web at cbweb.med.harvard.edu/eph-nomenclature/cell_letter.html). Ephrins (EFNs), 4The abbreviations used are: EFN, ephrin; TN, triple negative; SP, single positive; DP, double positive; TCR, T cell receptor; FTOC, fetal thymus organ culture; FITC, fluorescein isothiocyanate; BrdUrd, bromodeoxyuridine; e17 and e20, embryonic day 17 and 20, respectively. ligands of Eph kinases, are cell surface molecules as well and can be classified into A and B subfamilies. EFNAs (EFNA1-EFNA6) are glycosylphosphatidylinositol-anchored proteins and bind to EphA members with loose specificity; EFNBs (EFNB1-EFNB3) are transmembrane proteins and bind to EphBs, again with loose specificity (1Committee Eph Nomenclature Cell. 1997; 90: 403-404Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). EphA4, an exception, can bind to EFNB2 in addition to EFNA members (2Gale N.W. Holland S.J. Valenzuela D.M. Flenniken A. Pan L. Ryan T.E. Henkemeyer M. Strebhardt K. Hirai H. Wilkinson D.G. Pawson T. Davis S. Yancopoulos G.D. Neuron. 1996; 17: 9-19Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar). EFNBs can also function as reciprocal receptors for EphB molecules and reversely transduce signals into cells (3Holland S.J. Gale N.W. Mbamalu G. Yancopoulos G.D. Henkemeyer M. Pawson T. Nature. 1996; 383: 722-725Crossref PubMed Scopus (462) Google Scholar). 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Strebhardt K. Hirai H. Wilkinson D.G. Pawson T. Davis S. Yancopoulos G.D. Neuron. 1996; 17: 9-19Abstract Full Text Full Text PDF PubMed Scopus (758) Google Scholar, N. M. T. W. R.R. H. 2004; PubMed Scopus (71) Google Scholar). The receptor of EFNB1 to thymocytes was EFNB1-Fc was as a between the EFNB1 sequence and the human sequence with the receptor as described in G. H. Wu Y. Wu J. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar); revealed the of EFNB1 with the of all of its receptors, are to as on in the of the of cells was in CD8 SP DP and CD4 SP cells In the of cells of as G. H. Wu Y. Wu J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar) was in in in DP, and in CD4 with the of CD8 SP a role of that of receptors in T-cell development. We EFNB1 and expressed in the or cells. in in CD4 SP, CD8 SP, or DP cells, EFNB1 and expression was a with cells EFNB1 cells and cells both. is that we have previously reported that about of CD4 and CD8 cells in the EFNB1 and G. H. Wu Y. Wu J. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Soluble EFNB1 in was to the role of EFNB1 and in thymocyte development in a to a proteins to the We EFNB1-Fc the thymus was in the of EFNB1-Fc for thymocytes and with of the thymocytes positive for and this was with that of thymocytes with EFNB1-Fc This that EFNB1-Fc can the the of EFNBs on was We on as and and in thymocyte in day Thus, all of the of the with or at was in culture, and the CD4 and CD8 expression of cells from was in in with thymocytes from FTOC, was a and of DP to an of CD4 SP to and CD8 SP to the other hand, and the of these for the of this study, was on EFNB1 and was used for The of thymocyte a of factors, as apoptosis, and of CD4 or CD8 expression on DP cells. into the for the ratio in FTOC, we the proliferation of each subpopulation the culture was a significant of cell in to DP to CD4 SP to and CD8 SP to in with that of In cells, cells the cells A. R. A. A.G. T. Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar); of these had significantly increased proliferation in the of in with to for and from to for increased the in these to a with the of and expression in is to be that the thymocytes from to to to DP to SP or SP cells; in cells of a be from their or from proliferation the or both. this clearly demonstrated that soluble EFNB1-Fc enhanced thymocyte is the of the increased proliferation on thymocyte The results revealed that the in or or This that be increased apoptosis in in to the cellularity in the of enhanced thymocyte proliferation soluble EFNB1-Fc EFNB1 and is to the of apoptosis of thymocyte in FTOC, because cells are and and the of this be We an in vitro in the cell was to the of EFNB1 on thymocyte In FTOC, soluble EFNB1 probably the between EFNB1 and its receptors, of on thymocyte This that thymocytes signals through their EFNB1 receptors with solid-phase EFNB1 expressed on thymocytes or cells. this we thymocytes in with EFNB1 or control for in and thymocyte apoptosis was solid-phase for in DP, CD4 SP, and CD8 SP cells in control apoptosis at and culture; in the apoptosis of these cells decreased to and in the of solid-phase This was in eight and clearly demonstrated that when on thymocytes the cells Since thymocyte it that soluble EFNB1-Fc with the between EFNB1 and on the signals to and This was in vitro thymocytes from The cells in the of soluble to apoptosis in DP cells, in CD4 SP cells, and in CD8 SP In the of soluble the of cells was increased in all of the in DP cells, in CD4 SP cells, and in CD8 SP an was and the on solid-phase the we the expression of several antiapoptotic factors, as and R. PubMed Scopus Google Scholar, T. Rev. Immunol. PubMed Scopus Google Scholar), in these cells. DP, CD4 SP, and CD8 SP cells from and in the of solid-phase and as described culture, the cells and their and levels with with solid-phase and used as In the EFNB1-treated CD4 SP cells, of and was in CD8 SP cells, of the molecules was whereas remained This in with the antiapoptotic of these molecules and the of apoptosis in these cells. We that CD4 SP and CD8 SP had levels of and in CD8 cells was solid-phase This of these molecules in the of CD4 SP and CD8 SP cells. The results from DP cells the that these cells protected solid-phase EFNB1-Fc from apoptosis, their and to a this an that the of and antiapoptotic in these cells is with CD4 SP and CD8 SP cells, and antiapoptotic other are for the of DP cells. In this study, we that EFNB1 and expressed on thymocyte in the of soluble EFNB1-Fc had significant subpopulation ratio skew, the of to apoptosis and proliferation of solid-phase EFNB1 signals to the of antiapoptotic and soluble EFNB1 promoted thymocyte results that EFNB1 and its receptors important in thymocyte signaling thymocyte soluble EFNB1-Fc was in FTOC, it caused a of DP cells and an of CD4 and CD8 SP cells. The in the of each the cellularity remained in the We that was enhanced proliferation in all of the and at the we demonstrated that solid-phase EFNB1 promoted thymocyte and soluble EFNB1 enhanced their on these be In the soluble EFNB1 the thymus and the proliferation of thymocyte in a to a thymocytes the between proliferation and apoptosis was as of in we that soluble EFNB1-Fc isolated thymocytes to in or of stimulation Moreover, cells expressed they had significantly increased proliferation in The of this is In the the soluble EFNB1-Fc apoptosis of the of thymocytes in proliferation to cellularity in the The of apoptosis and proliferation results in subpopulation ratio This is because we that in solid-phase EFNB1 DP, CD4 SP, and CD8 SP thymocyte apoptosis, whereas soluble EFNB1-Fc promoted apoptosis of these cells. This that in the soluble EFNB1-Fc the role of cell surface EFNB1 in of thymocytes antiapoptotic This is a study A. N. C. T. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). We demonstrated that CD4 SP, and CD8 SP cells all be or or EFNB1 and at the on an cell we also demonstrated that the of all of these cell was solid-phase and soluble that EFNB1 on a subpopulation of thymocytes is capable of in the subpopulation as well as in on subpopulation to In the thymus, apoptosis in DP cells, have a with of apoptosis to the of positive G. B. D. E. Science. PubMed Scopus Google Scholar). The of DP cells of their apoptosis is it is that at the DP C.D. J. Nature. 1994; PubMed Scopus Google Scholar), Baldwin J.D. Davis M.M. J. Immunol. Google Scholar) reported that it development at DP, and SP This that and SP cells also The of SP cells are in The of cells into and from the is about the The cells at a of R. Immunol. 1995; Full Text PDF PubMed Scopus Google Scholar). this that apoptosis in SP cells, with the of be to a that the soluble EFNB1-Fc can and the in cells a positive at the DP this is in with that the DP was significantly in EFNB1 we that DP had increased their in EFNB1-treated significantly of as of DP in the proliferation of DP and all of its in the and the proliferation in DP in a case in was enhanced proliferation in DP, the of their apoptosis the of their in a of DP The to CD4 SP and CD8 SP cells, and their to be to their subpopulation in We that cells in the of soluble EFNB1-Fc in FTOC, the that they had are for this in cells are from a of cells that are to their percentage, their are in the apoptosis of thymocytes of the of soluble EFNB1-Fc proliferation of cells. We the that in FTOC, to a soluble EFNB1 of CD4 or CD8 expression in DP cells, and this to the DP and SP an it at be the for because it the proliferation of thymocyte Moreover, of DP to SP cells was in isolated thymocyte culture in the of soluble EFNB1 is well that when thymocytes are isolated from their the they This that are in the thymus thymocyte the of been that EFNB1 on thymocytes or cells as of for a We have that thymocyte the other hand, was that with and enhanced signaling the in the We have that in T cells, and to of is in the signaling G. H. Wu Y. Wu J. J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). In the be and enhanced that solid-phase EFNB1 Since thymocytes to be on signaling C. C.A. Rev. Google Scholar, Immunol. PubMed Scopus Google Scholar, H. I. F. L. I. E. F. L. Immunol. Rev. PubMed Scopus Google Scholar), the role of be to signaling to a the of positive at the DP and the of these cells. also the of CD4 SP and CD8 SP cells. these SP cells have already the positive C. C.A. Rev. Google Scholar, Immunol. PubMed Scopus Google Scholar, H. I. F. L. I. E. F. L. Immunol. Rev. PubMed Scopus Google Scholar). Thus, it that also function to from cells to the of SP cells, they probably to in with for an clearly that EFNB1 and its receptors are important in thymocyte and development. We for

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