The metalloprotease ADAM10 generates soluble interleukin-2 receptor alpha (sCD25) in vivo

Abstract

The cytokine interleukin-2 (IL-2) plays a critical role in controlling the immune homeostasis by regulating the proliferation and differentiation of immune cells, especially T cells. IL-2 signaling is mediated via the IL-2 receptor (IL-2R) complex, which consists of the IL-2Rα (CD25), the IL-2Rβ, and the IL-2Rγ. While the latter are required for signal transduction, IL-2Rα controls the ligand-binding affinity of the receptor complex. A soluble form of the IL-2Rα (sIL-2Rα) is found constitutively in human serum, though its levels are increased under various pathophysiological conditions. The sIL-2Rα originates partly from activated T cells through proteolytic cleavage, but neither the responsible proteases nor stimuli that lead to IL-2Rα cleavage are known. Here, we show that the metalloproteases ADAM10 and ADAM17 can cleave the IL-2Rα and generate a soluble ectodomain, which functions as a decoy receptor that inhibits IL-2 signaling in T cells. We demonstrate that ADAM10 is mainly responsible for constitutive shedding of the IL-2Rα, while ADAM17 is involved in IL-2Rα cleavage upon T cell activation. In vivo, we found that mice with a CD4-specific deletion of ADAM10, but not ADAM17, show reduced steady-state sIL-2Rα serum levels. We propose that the identification of proteases involved in sIL-2Rα generation will allow for manipulation of IL-2Rα cleavage, especially as constitutive and induced cleavage of IL-2Rα are executed by different proteases, and thus offer a novel opportunity to alter IL-2 function. The cytokine interleukin-2 (IL-2) plays a critical role in controlling the immune homeostasis by regulating the proliferation and differentiation of immune cells, especially T cells. IL-2 signaling is mediated via the IL-2 receptor (IL-2R) complex, which consists of the IL-2Rα (CD25), the IL-2Rβ, and the IL-2Rγ. While the latter are required for signal transduction, IL-2Rα controls the ligand-binding affinity of the receptor complex. A soluble form of the IL-2Rα (sIL-2Rα) is found constitutively in human serum, though its levels are increased under various pathophysiological conditions. The sIL-2Rα originates partly from activated T cells through proteolytic cleavage, but neither the responsible proteases nor stimuli that lead to IL-2Rα cleavage are known. Here, we show that the metalloproteases ADAM10 and ADAM17 can cleave the IL-2Rα and generate a soluble ectodomain, which functions as a decoy receptor that inhibits IL-2 signaling in T cells. We demonstrate that ADAM10 is mainly responsible for constitutive shedding of the IL-2Rα, while ADAM17 is involved in IL-2Rα cleavage upon T cell activation. In vivo, we found that mice with a CD4-specific deletion of ADAM10, but not ADAM17, show reduced steady-state sIL-2Rα serum levels. We propose that the identification of proteases involved in sIL-2Rα generation will allow for manipulation of IL-2Rα cleavage, especially as constitutive and induced cleavage of IL-2Rα are executed by different proteases, and thus offer a novel opportunity to alter IL-2 function. Interleukin-2 (IL-2) is not only one of the earliest discovered cytokines, it is also one of the most important regulators of immune responses. After its initial description as a T cell proliferation factor (1Morgan D.A. Ruscetti F.W. Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows.Science (New York, N.Y.). 1976; 193: 1007-1008Crossref PubMed Scopus (1754) Google Scholar), a variety of other functions of IL-2 have been described, including differentiation of CD4+ T cell subsets, antibody production by B cells, and cytotoxic activity of NK cells (2Leonard W.J. Lin J.X. O'Shea J.J. The gammac family of cytokines: Basic biology to therapeutic ramifications.Immunity. 2019; 50: 832-850Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). However, the most important function is probably the maintenance of the homeostasis of regulatory T cells and, consequently, self-tolerance (3Toomer K.H. Malek T.R. Cytokine signaling in the development and homeostasis of regulatory T cells.Cold Spring Harb. Perspect. Biol. 2018; 10a028597Crossref PubMed Scopus (32) Google Scholar, 4Nelson B.H. IL-2, regulatory T cells, and tolerance.J. Immunol. (Baltimore, Md. : 1950). 2004; 172: 3983-3988Crossref PubMed Scopus (440) Google Scholar). Signal transduction of IL-2 is mediated via different combinations of the receptor subunits IL-2 receptor α (IL-2Rα/CD25/Tac), IL-2Rβ (CD122), and IL-2Rγ (common γ chain/γc/CD132). A heterodimer of IL-2Rβ and γc is required for the induction of intracellular signals via activation of the Janus kinases JAK1 and JAK3. The IL-2Rα is the only one of these receptors that is specific for IL-2. Its extracellular part consists of two sushi domains and a flexible, 54 amino-acid residues long stalk region that connects the extracellular domains with the transmembrane helix. The intracellular region is rather short and lacks interaction sites for kinases. Consequently, the IL-2Rα is not directly involved in signal transduction (5Wang X. Lupardus P. Laporte S.L. Garcia K.C. Structural biology of shared cytokine receptors.Annu. Rev. Immunol. 2009; 27: 29-60Crossref PubMed Scopus (258) Google Scholar). It does, however, bind IL-2 and facilitate binding of the cytokine to the other two receptor subunits, giving the trimeric receptor complex a higher affinity than the dimeric complex. Thus, the expression of the IL-2Rα dictates sensitivity of a cell toward IL-2. Notably, high expression of IL-2Rα is especially found on regulatory T cells and transiently also on CD4+ and CD8+ T cells upon T cell receptor (TCR) stimulation (6Boyman O. Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system.Nat. Rev. Immunol. 2012; 12: 180-190Crossref PubMed Scopus (974) Google Scholar, 7Spolski R. Li P. Leonard W.J. Biology and regulation of IL-2: From molecular mechanisms to human therapy.Nat. Rev. Immunol. 2018; 18: 648-659Crossref PubMed Scopus (175) Google Scholar). In addition to the membrane-bound receptor, also a soluble form of the IL-2Ra has been described. This soluble (s)IL-2Rα is present in the blood of healthy humans (8Bien E. Balcerska soluble receptor in human of and A PubMed Scopus Google and is in from activated T cells R. receptors are from activated human cells in Immunol. (Baltimore, Md. : 1950). Google Scholar). Notably, the of soluble IL-2Rα (sIL-2Rα) is increased in a variety of including different which has to its as a (8Bien E. Balcerska soluble receptor in human of and A PubMed Scopus Google Scholar, J. soluble interleukin-2 receptor levels for for and from other 2019; Google Scholar, of soluble interleukin-2 receptor in J. Google Scholar). However, to the high of that present with increased sIL-2Rα levels and the that it is increased upon T cell the is of soluble interleukin-2 receptor in J. Google Scholar). While the sIL-2Rα the to bind IL-2 The receptor Immunol. (Baltimore, Md. : 1950). Google Scholar), the function of binding is not mechanisms the sIL-2Rα IL-2 signaling have been the complex of IL-2 and sIL-2Rα can bind to membrane-bound a high affinity receptor complex and IL-2 signaling immune and reduced in PubMed Scopus Google Scholar), sIL-2Rα IL-2, binding of the cytokine to the membrane-bound and thus signaling O. Sprent J. to a by binding to soluble PubMed Scopus Google Scholar, T regulatory cells proliferation partly by the of soluble in with PubMed Scopus Google Scholar, IL-2Rα and the development of in 2012; Scopus Google Scholar, D.A. levels in and the of soluble on immune Immunol. (Baltimore, Md. : 1950). 2009; PubMed Scopus Google Scholar), and the sIL-2Rα of IL-2, its of antibody the soluble receptor can the and of PubMed Scopus Google Scholar). of these mechanisms is on the is of soluble interleukin-2 receptor in J. Google Scholar). it is also not the sIL-2Rα is cytokine receptors can from two different of shedding of membrane-bound receptors J. functions and therapeutic of soluble cytokine Rev. PubMed Scopus Google Scholar). of the that to a sIL-2Rα has been The molecular for the generation of the human soluble PubMed Scopus Google Scholar, J. The IL-2 IL-2 receptor in and The role of the soluble IL-2 Immunol. PubMed Scopus Google Scholar). Consequently, the sIL-2Rα is to from proteolytic of the membrane-bound This by the that in sIL-2Rα upon stimulation of T cell is with a of the receptor on the cell immune and reduced in PubMed Scopus Google Scholar). proteases have been to to cleave the IL-2Rα, and the proteases and P. P. J. E. interleukin-2 receptor and expression in and and of Immunol. PubMed Scopus Google Scholar, O. cleavage of the of the human T cell receptor, by a with PubMed Scopus Google Scholar, Selective proteolytic cleavage of IL-2 receptor and receptor binding by proteases of Cytokine : J. Cytokine PubMed Scopus Google Scholar). of are involved in sIL-2Rα generation in is not Notably, sIL-2Rα shedding from blood cells with the P. P. J. E. interleukin-2 receptor and expression in and and of Immunol. PubMed Scopus Google Scholar), that one are responsible for IL-2Rα However, is not responsible for the constitutive shedding of IL-2Rα, as mice in sIL-2Rα serum to mice P. P. J. E. interleukin-2 receptor and expression in and and of Immunol. PubMed Scopus Google Scholar). metalloproteases that have as important are of a and especially ADAM10 and ADAM17 have a of a variety of including different cytokine and the function of immune cells J. A molecular to and Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar, The role of in Rev. Immunol. 2018; 18: PubMed Scopus Google Scholar). ADAM10 and ADAM17 have been to in CD4+ T cells upon in vitro activation O. is by shedding in activated T Immunol. (Baltimore, Md. : 1950). PubMed Scopus Google Scholar). we the role of the metalloproteases ADAM10 and ADAM17 in the generation of sIL-2Rα as as the of the sIL-2Rα on IL-2 signaling in T cells. Cytokine receptors can upon but soluble receptors are also constitutively from cells. constitutive of we transiently cells with expression IL-2Rα and with different of We to to proteases, and and A to and proteases, we the specific for and for ADAM10 and P. R. The ADAM10 is involved in constitutive cleavage of and PubMed Scopus Google Scholar). We the production of sIL-2Rα by the cells with the in cells sIL-2Rα and the cells with the and the In other on sIL-2Rα that constitutive shedding is on activity and ADAM10 the most these we cells which are for ADAM10 ADAM17 proteases We transiently these cell and constitutive production of in cells for ADAM10 ADAM17 of sIL-2Rα as cells. In cells proteases sIL-2Rα than cells, that these proteases are involved in constitutive shedding of that different expression of IL-2Rα the different cell for the in sIL-2Rα we the of IL-2Rα the cell and found in IL-2Rα This that the reduced sIL-2Rα production is by of of ADAM10 and ADAM17 the of sIL-2Rα to to that of cells, but not This that for the of sIL-2Rα but that also one other to sIL-2Rα the by expression of IL-2Rα, we the cell which the IL-2Rα R. of cytokine cytokine receptor and in and Google Scholar). We the with as for cells and sIL-2Rα by and the of metalloproteases and a of other of ADAM10 with the sIL-2Rα shedding to the as the we IL-2Rα signal in the which to the sIL-2Rα This is cells with one of the role in sIL-2Rα with the the as the of We from these that ADAM10 is the responsible for the constitutive shedding of the After constitutive we to activation of ADAM10 ADAM17 the of We transiently the cell with expression IL-2Rα and with the for which is a of ADAM10 P. P. shedding of transmembrane by the and of Immunol. (Baltimore, Md. : 1950). PubMed Scopus Google Scholar). We found that in cells, induced the of sIL-2Rα A and the that ADAM10 is involved in shedding of the the of sIL-2Rα upon stimulation not different in cells ADAM10 The shedding in the cells is most by ADAM17, as it has been for other ADAM10 that ADAM17 can cleave in the of ADAM10 J. of ADAM10 and ADAM17 in and novel role of ADAM10 in receptor Full Text Full Text PDF PubMed Scopus Google Scholar, P. P. and of a shedding for as growth factor and factor Biol. 2009; PubMed Scopus Google Scholar). This is by the that cells of proteases not sIL-2Rα with stimulation A and we the cells with the for which and ADAM17 P. of growth and regulation by and Biol. 18: PubMed Scopus Google Scholar). with ADAM10, we found that activation of ADAM17 in cells in a in sIL-2Rα and This in cells. cells in sIL-2Rα upon stimulation with which however, not different from the probably to increased shedding by ADAM10 cells of proteases sIL-2Rα upon stimulation and that activation of ADAM10 ADAM17 in increased shedding of the IL-2Rα and toward a cleavage by ADAM17 upon stimulation in the of In to the with IL-2Rα we the in cells. We the cells with in to ADAM10 ADAM17, and sIL-2Rα However, and cells, which is most to the high constitutive sIL-2Rα of the cells. It has been that ADAM10 and ADAM17 are the stalk in to the J. A molecular to and Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar). we the stalk region of the IL-2Rα and can by ADAM10 and While and to the cell sIL-2Rα in the of cells the in the cell and that the cleavage is the stalk as deletion of region constitutive In a we deletion we of in the part of the IL-2Rα stalk and and the shedding of these the deletion of the stalk also the deletion of the different not cell expression of the IL-2Rα, it has to that the a expression to IL-2Rα Notably, soluble of of these deletion in the cell by and and It has to however, that the in the cell which is in with the and toward a reduced expression of to the However, these show in to the deletion of the neither of the constitutive shedding of these from cells and This that the cleavage by ADAM10 and ADAM17 is not and that cleavage sites the IL-2Rα stalk It is also that the in the stalk region in a novel cleavage that is in of the cleavage are to a sIL-2Rα is increased in various conditions. the role of T cells in human as as the of IL-2 on T cell we on IL-2Rα shedding from T cells. we the T cell and the cells with and for in to the cells via the We found that in vitro activation increased the of IL-2Rα on the cell which has been for human T cells and cells Interleukin-2 receptor on human to is by the of PubMed Scopus Google Scholar, expression on the of Biol. Scopus Google We the in the of one of the as and sIL-2Rα We found that in vitro activation increased the of sIL-2Rα from cells which is in with R. receptors are from activated human cells in Immunol. (Baltimore, Md. : 1950). Google Scholar). sIL-2Rα the cells with the different Notably, of ADAM10 the as of that ADAM10 is also the responsible for IL-2Rα shedding from activated cells. In to not only on a T cell we to human T cells from We two different stimuli to the cells in we the cells with and and and and of the cell expression of the IL-2Rα that stimuli in increased IL-2Rα and also the T cells of sIL-2Rα upon activation and In with the cells, of metalloproteases sIL-2Rα it not in to cells, of ADAM10 activity on sIL-2Rα from activated cells. A only ADAM10 and ADAM17 with with the show that on activated T cells, ADAM17 is mainly responsible for the cleavage of the IL-2Rα from the cell it that other mechanisms to sIL-2Rα from human T cells. the function of the sIL-2Rα is not we the of sIL-2Rα on IL-2 signaling in T cells. we in human T cells with IL-2 and of in stimulation of cells with IL-2 in in This IL-2 with sIL-2Rα and with Notably, the levels in activated cells higher than in cells, and stimulation with IL-2 in This is most by the that activation to of from T cells, which IL-2 but also other In these show that the sIL-2Rα as for IL-2 signaling in cells. we to ADAM10 shedding is also involved in the steady-state production of sIL-2Rα in We mice for the which is a of ADAM10 and ADAM17, but also a variety of other metalloproteases P. R. extracellular regulators in Rev. PubMed Scopus Google Scholar, The in vitro activity of is by and PubMed Scopus Google Scholar, is by PubMed Scopus Google Scholar). However, the sIL-2Rα in the serum not different and mice that the constitutive sIL-2Rα production in mice is not mediated by a a we to the of ADAM10 and ADAM17 for the steady-state sIL-2Rα serum levels in T cells are the of we the serum of mice which ADAM10 ADAM17 on CD4+ cells. We found that of ADAM10 the sIL-2Rα in the serum to that ADAM10 is also responsible for IL-2Rα shedding in In of ADAM17 in CD4+ cells in increased sIL-2Rα in the serum of these mice The of in sIL-2Rα a of to constitutive IL-2Rα cleavage in mice under normal conditions. The is probably to a of ADAM10 ADAM17 is Notably, a of ADAM17 activity in the of ADAM10 has been in B cells in B cell A and is mediated by in ADAM17 and Immunol. PubMed Scopus Google Scholar). is in with in the cell cells also in constitutive IL-2Rα shedding that is and cell In to the of ADAM10 and ADAM17 in constitutive IL-2Rα we which proteases on CD4+ T cells. Here, we a in sIL-2Rα serum in the to the mice However, to the one in mice only ADAM10 that ADAM17 not but rather that ADAM17 only to cleavage of the IL-2Rα in the of the in that in the ADAM17 is in the the that is by in ADAM10 we which only of the ADAM17 of mice P. J. P. J. O. R. role of the ADAM17 for and in PubMed Scopus Google Scholar). mice normal sIL-2Rα serum levels to that ADAM17 not to the constitutive generation of the sIL-2Rα in mice ADAM10 is that the reduced sIL-2Rα in the serum of mice is by a expression of the we the of IL-2Rα on the cell of T cells. we IL-2Rα on CD4+ cells from mice and the of IL-2Rα cells. in of ADAM10 not the of IL-2Rα cells. it higher in cells than cells. regulatory T cells are the T cell that constitutively IL-2Rα (6Boyman O. Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system.Nat. Rev. Immunol. 2012; 12: 180-190Crossref PubMed Scopus (974) Google Scholar, 7Spolski R. Li P. Leonard W.J. Biology and regulation of IL-2: From molecular mechanisms to human therapy.Nat. Rev. Immunol. 2018; 18: 648-659Crossref PubMed Scopus (175) Google Scholar), we also IL-2Rα on regulatory T cells from these the of IL-2Rα cells higher in the of ADAM10 Thus, the of constitutive shedding of the IL-2Rα by ADAM10 not only lead to reduced sIL-2Rα serum but also the of membrane-bound IL-2Rα on CD4+ cells. show that ADAM10 is responsible for the steady-state sIL-2Rα levels in mice and also controls the expression of However, the CD4-specific of ADAM10 not in a of which is most probably by the that CD4+ T cells are not the only cell from which the constitutive sIL-2Rα IL-2 is one of the regulators of the immune which has functions on various immune cells and is especially important for the function of regulatory T cells (2Leonard W.J. Lin J.X. O'Shea J.J. The gammac family of cytokines: Basic biology to therapeutic ramifications.Immunity. 2019; 50: 832-850Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, K.H. Malek T.R. Cytokine signaling in the development and homeostasis of regulatory T cells.Cold Spring Harb. Perspect. Biol. 2018; 10a028597Crossref PubMed Scopus (32) Google Scholar). While a sIL-2Rα that originates from activated T cells has been in R. receptors are from activated human cells in Immunol. (Baltimore, Md. : 1950). Google Scholar), neither its function in IL-2 biology nor the of its generation are Here, we the role of the metalloproteases ADAM10 and ADAM17 in shedding of the shedding is a form of not only it is the only but also it has It a soluble that has functions and it the cell of the ADAM10 and ADAM17 have as important with a variety of of shared by proteases while are only by one of J. A molecular to and Immunol. Full Text Full Text PDF PubMed Scopus Google Scholar, P. The A therapeutic PubMed Scopus Google Scholar). While the of ADAM10 ADAM17 in which in toward a function in development to cleavage of receptor P. The is for but not for activity in PubMed Google Scholar, J.J. P. role for shedding in (New York, N.Y.). PubMed Scopus Google Scholar), also other functions of the two proteases, in cytokine signaling and immune cell functions The role of in Rev. Immunol. 2018; 18: PubMed Scopus Google Scholar). We have ADAM10 as the involved in the constitutive of ADAM10 is also involved in IL-2Rα shedding upon in vitro T cell which has been to a of However, the of ADAM10 to in human T cells than cell as specific of the on sIL-2Rα levels as to of ADAM10 and Notably, ADAM10 has been to upon T cell activation O. is by shedding in activated T Immunol. (Baltimore, Md. : 1950). PubMed Scopus Google Scholar). the IL-2Rα is also upon activation of T cells, it that the of is responsible for the in sIL-2Rα However, it is also in addition to the increased ADAM10 is also activated upon T cell have been show that activation of ADAM17 also in increased sIL-2Rα production from cells, while plays role in constitutive IL-2Rα sIL-2Rα shedding from activated T cells is mainly on ADAM17 shedding upon T cell activation has also been for other the O. is by shedding in activated T Immunol. (Baltimore, Md. : 1950). PubMed Scopus Google Scholar, J. The role of ADAM17 in the 12: PubMed Scopus Google Scholar). it has been for the that ADAM17 is not involved in steady-state production of but the during J. of ADAM10 and ADAM17 in and novel role of ADAM10 in receptor Full Text Full Text PDF PubMed Scopus Google Scholar, J. P. ADAM17 controls signaling by cleavage of the from the cell of during Biol. PubMed Scopus Google Scholar). show that a role for ADAM17 is also in IL-2Rα the function of the sIL-2Rα is under with as as of soluble interleukin-2 receptor in J. Google Scholar). We show that the sIL-2Rα has functions in IL-2 signaling in T cells. that of sIL-2Rα bind the of the IL-2 and binding of the cytokine to the cells. This is in with a it that sIL-2Rα proliferation of T cells T regulatory cells proliferation partly by the of soluble in with PubMed Scopus Google Scholar). the in are higher than has been in serum However, it in that in the serum are described, sIL-2Rα is the of activation of T cells it is that the of sIL-2Rα is also higher than the serum However, as also functions of the sIL-2Rα immune and reduced in PubMed Scopus Google Scholar), we that functions are The specific of the sIL-2Rα cell on the of membrane-bound IL-2Rα in a will in to the function of the we also show that ADAM10 is responsible for the constitutive shedding of the IL-2Rα in ADAM10 also plays a role in constitutive sIL-2Rα in humans is not However, as in vitro which show the role of ADAM10 in constitutive IL-2Rα with human cells, we it that ADAM10 also controls the sIL-2Rα levels in human This is by the that different that show increased ADAM10 for immune J. X. J. J. Li X. Li ADAM10 expression in with immune 2018; PubMed Scopus Google Scholar, E. P. is by and in Full Text Full Text PDF PubMed Scopus Google Scholar), also increased sIL-2Rα serum levels soluble IL-2 receptor and levels in Full Text PDF PubMed Scopus Google Scholar, E. soluble interleukin-2 receptor levels in with J. PubMed Scopus Google Scholar). The role of the sIL-2Rα is not and different in the complex functions of IL-2 on various immune cell J. The IL-2 IL-2 receptor in and The role of the soluble IL-2 Immunol. PubMed Scopus Google Scholar). In addition to of the role of soluble receptor, it is important to the sIL-2Rα is will allow for in sIL-2Rα We have ADAM10 as a that not only the of sIL-2Rα but controls the of cell IL-2Rα, regulating the sensitivity of a cell toward IL-2. This the to membrane-bound as as sIL-2Rα levels through ADAM10 In to constitutive IL-2Rα shedding from T cells, which is a of to on ADAM17 Notably, ADAM10 as as ADAM17 have been in different P. The A therapeutic PubMed Scopus Google Scholar, The shedding and PubMed Scopus Google Scholar), and it is to that levels of sIL-2Rα partly responsible for the In we show that the sIL-2Rα as for IL-2 signaling in T cells. we ADAM10 and ADAM17 as two novel proteases that can cleave the IL-2Rα, constitutive and induced it is that proteases have different the of the IL-2Rα for the sensitivity of cells toward IL-2, a novel regulatory to the complex biology of IL-2. we ADAM10 as the to responsible for the steady-state levels of sIL-2Rα in cells and cells for ADAM10 ADAM17 proteases have been P. J. J. R. of the soluble human in and a role of Biol. PubMed Scopus Google and in with serum by and cells and cells in with and cells in a and a from and as as the A and from The specific for and by P. R. The ADAM10 is involved in constitutive cleavage of and PubMed Scopus Google Scholar). from and IL-2 from for the of T cells from human blood from the of the of the The with the of the of ADAM17 mice and P. J. P. J. O. R. role of the ADAM17 for and in PubMed Scopus Google Scholar, J. The role of ADAM17 in the 12: PubMed Scopus Google Scholar, J. P. ADAM17 controls signaling by cleavage of the from the cell of during Biol. PubMed Scopus Google Scholar). mice for the ADAM17 and for the mice for the ADAM10 E. J. R. ADAM10 is for the of the PubMed Scopus Google and for the in to in a under specific conditions. from to and serum by of blood for from mice E. in PubMed Scopus Google and by of The of the human IL-2Rα from and via and the stalk via by by of IL-2Rα in cells. shedding of IL-2Rα and cells transiently with expression the IL-2Rα the to constitutive cells with as with the different for in as induced cells with for for in to ADAM10 ADAM17, and cell via of sIL-2Rα the of transiently cells, cells, cells, T cells, the by for and from the cells. the human to of mice the to in to the of the with with and, for of from with of and on for a to After the with and on for a After the the to in of cell by and to with serum for and with After with for After signals the the The for and from from and from blood from healthy by and in cells via cell and the from to cells in with and In to human T cells cells, with antibody the cells the and with antibody for cells activated by addition of and for cells also with the for the of the activation. the of sIL-2Rα on IL-2 human cells from human blood and in vitro activated as of sIL-2Rα with IL-2 in for to allow complex cells with these for and by of activation by the and of the from to cell expression of IL-2Rα and IL-2Rα deletion cells. 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