B7h (ICOS-L) Maintains Tolerance at the Fetomaternal Interface

Abstract

In a successful pregnancy, the semiallogeneic fetus is not rejected by the maternal immune system, which implies tolerance mechanisms protecting fetal tissues from maternal immune attack. Here we report that the ICOS-B7h costimulatory pathway plays a critical role in maintaining the equilibrium at the fetomaternal interface. Blockade of this pathway increased fetal resorption and decreased fetal survival in an allogeneic pregnancy model (CBA female × B6 male). Locally in the placenta, levels of regulatory markers such as IDO and TGF-β1 were reduced after anti-B7h monoclonal antibody treatment, whereas levels of effector cytokines (eg, IFN-γ) were significantly increased. In secondary lymphoid organs, enhanced IFN-γ and granzyme B production (predominantly by CD8+ T cells) was observed in the anti-B7h–treated group. The deleterious effect of B7h blockade in pregnancy was maintained only in CD4 knockout mice, not in CD8 knockout mice, which suggests a role for CD8+ T cells in immune regulation by the ICOS-B7h pathway. In accord, regulatory CD8+ T cells (in particular, CD8+CD103+ cells) were significantly decreased after anti-B7h monoclonal antibody treatment, and adoptive transfer of this subset abrogated the deleterious effect of B7h blockade in fetomaternal tolerance. Taken together, these data support the hypothesis that B7h blockade abrogates tolerance at the fetomaternal interface by enhancing CD8+ effector response and reducing local immunomodulation mediated by CD8+ regulatory T cells. In a successful pregnancy, the semiallogeneic fetus is not rejected by the maternal immune system, which implies tolerance mechanisms protecting fetal tissues from maternal immune attack. Here we report that the ICOS-B7h costimulatory pathway plays a critical role in maintaining the equilibrium at the fetomaternal interface. Blockade of this pathway increased fetal resorption and decreased fetal survival in an allogeneic pregnancy model (CBA female × B6 male). Locally in the placenta, levels of regulatory markers such as IDO and TGF-β1 were reduced after anti-B7h monoclonal antibody treatment, whereas levels of effector cytokines (eg, IFN-γ) were significantly increased. In secondary lymphoid organs, enhanced IFN-γ and granzyme B production (predominantly by CD8+ T cells) was observed in the anti-B7h–treated group. The deleterious effect of B7h blockade in pregnancy was maintained only in CD4 knockout mice, not in CD8 knockout mice, which suggests a role for CD8+ T cells in immune regulation by the ICOS-B7h pathway. In accord, regulatory CD8+ T cells (in particular, CD8+CD103+ cells) were significantly decreased after anti-B7h monoclonal antibody treatment, and adoptive transfer of this subset abrogated the deleterious effect of B7h blockade in fetomaternal tolerance. Taken together, these data support the hypothesis that B7h blockade abrogates tolerance at the fetomaternal interface by enhancing CD8+ effector response and reducing local immunomodulation mediated by CD8+ regulatory T cells. More than 50 years ago, Medawar and colleagues1Billingham R.E. Brent L. Medawar P.B. ‘Actively acquired tolerance’ of foreign cells.Nature. 1953; 172 ([Republished in J Immunol 2010, 184:5–8]): 603-606Crossref PubMed Scopus (2207) Google Scholar proposed that immunological tolerance should be present during pregnancy, to protect the fetus against an aggressive maternal alloimmune response directed at the paternal antigens expressed by the fetus. Since that initial hypothesis, several mechanisms have been proposed to function actively in the protection of the fetus from the maternal immune system.2Guleria I. Sayegh M.H. Maternal acceptance of the fetus: true human tolerance.J Immunol. 2007; 178: 3345-3351PubMed Google Scholar Among them, the presence of regulatory T cells3Aluvihare V.R. Kallikourdis M. Betz A.G. Regulatory T cells mediate maternal tolerance to the fetus.Nat Immunol. 2004; 5: 266-271Crossref PubMed Scopus (1263) Google Scholar, 4Zenclussen A.C. Gerlof K. Zenclussen M.L. Sollwedel A. Bertoja A.Z. Ritter T. Kotsch K. Leber J. Volk H.D. Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model.Am J Pathol. 2005; 166: 811-822Abstract Full Text Full Text PDF PubMed Scopus (436) Google Scholar, 5Sasaki Y. Sakai M. Miyazaki S. Higuma S. Shiozaki A. Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases.Mol Hum Reprod. 2004; 10: 347-353Crossref PubMed Scopus (602) Google Scholar, 6Somerset D.A. Zheng Y. Kilby M.D. Sansom D.M. Drayson M.T. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset.Immunology. 2004; 112: 38-43Crossref PubMed Scopus (629) Google Scholar, 7Terness P. Kallikourdis M. Betz A.G. Rabinovich G.A. Saito S. Clark D.A. Tolerance signaling molecules and pregnancy: IDO, galectins, and the renaissance of regulatory T cells.Am J Reprod Immunol. 2007; 58: 238-254Crossref PubMed Scopus (90) Google Scholar and the expression of immune regulatory molecules in the fetal–maternal interface have been identified as crucial factors for fetomaternal tolerance.8Ishitani A. Sageshima N. Lee N. Dorofeeva N. Hatake K. Marquardt H. Geraghty D.E. Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition.J Immunol. 2003; 171: 1376-1384PubMed Google Scholar, 9King A. Burrows T.D. Hiby S.E. Bowen J.M. Joseph S. Verma S. Lim P.B. Gardner L. Le Bouteiller P. Ziegler A. Uchanska-Ziegler B. Loke Y.W. Surface expression of HLA-C antigen by human extravillous trophoblast.Placenta. 2000; 21: 376-387Abstract Full Text PDF PubMed Scopus (217) Google Scholar, 10Munn D.H. Zhou M. Attwood J.T. Bondarev I. Conway S.J. Marshall B. Brown C. Mellor A.L. Prevention of allogeneic fetal rejection by tryptophan catabolism.Science. 1998; 281: 1191-1193Crossref PubMed Scopus (2120) Google Scholar, 11Guleria I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. Noelle R.J. Coyle A. Mellor A.L. Khoury S.J. Sayegh M.H. A critical role for the programmed death ligand 1 in fetomaternal tolerance.J Exp Med. 2005; 202: 231-237Crossref PubMed Scopus (319) Google Scholar, 12Jin L.P. Fan D.X. Li D.J. Regulation of costimulatory signal in maternal-fetal immune tolerance.Am J Reprod Immunol. 2011; 66: 76-83Crossref PubMed Scopus (20) Google Scholar T cells play a major role in coordinating immune response. Although T-cell activation depends on the initial antigen-specific signal provided to T-cell receptors via the antigen-loaded major histocompatibility complex, additional signals provided by costimulatory molecules fine-tune this response, determining its strength, nature, and duration. Some costimulatory pathways activate effector T cells, but others inhibit T-cell activation and/or promote regulatory T cells. One of these inhibitory molecules is PD-L1, the expression of which is prevalent at the uteroplacental interface.11Guleria I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. Noelle R.J. Coyle A. Mellor A.L. Khoury S.J. Sayegh M.H. A critical role for the programmed death ligand 1 in fetomaternal tolerance.J Exp Med. 2005; 202: 231-237Crossref PubMed Scopus (319) Google Scholar Moreover, placental PD-L1 has been shown to protect murine allogeneic conceptus from maternal T-cell–mediated attack.11Guleria I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. Noelle R.J. Coyle A. Mellor A.L. Khoury S.J. Sayegh M.H. A critical role for the programmed death ligand 1 in fetomaternal tolerance.J Exp Med. 2005; 202: 231-237Crossref PubMed Scopus (319) Google Scholar, 13D'Addio F. Riella L.V. Mfarrej B.G. Chabtini L. Adams L.T. Yeung M. Yagita H. Azuma M. Sayegh M.H. Guleria I. The link between the PDL1 costimulatory pathway and in fetomaternal tolerance.J Immunol. 2011; PubMed Scopus Google Scholar of with a monoclonal antibody in of allogeneic but not a in the of spontaneous fetal resorption and a in fetal I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. Noelle R.J. Coyle A. Mellor A.L. Khoury S.J. Sayegh M.H. A critical role for the programmed death ligand 1 in fetomaternal tolerance.J Exp Med. 2005; 202: 231-237Crossref PubMed Scopus (319) Google Scholar PD-L1 effect on fetomaternal tolerance was on CD4+ regulatory T A. S. M. Yagita H. Azuma M. Sayegh M.H. Guleria I. A link between PDL1 and T regulatory cells in fetomaternal tolerance.J Immunol. 2007; PubMed Scopus Google Scholar costimulatory and its ligand costimulatory molecules that T-cell activation and D.M. Sayegh M.H. pathways in and PubMed Scopus Google Scholar In particular, have been shown to promote regulation in a model and to protect against in a C. CD4+CD25+ T regulatory cells on promote regulation of effector cells in the Exp Med. 2004; PubMed Scopus Google Scholar, I. N. M. J. regulatory T-cell response and enhanced in the of costimulatory PubMed Scopus Google Scholar ICOS-B7h is for fetomaternal tolerance to be In the present we the role of the ICOS-B7h pathway in the at the fetomaternal interface and its role in immune to the fetus. and were from the in the 1 have been Mellor of B. P. Marshall B. D.H. Mellor A.L. expression is to fetal cells during murine and is maternal Reprod Immunol. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar from of have been A.G. Regulatory T by the 2005; Full Text Full Text PDF PubMed Scopus Google Scholar and to of were with to of were for and the a was observed was as of were the of was were at and after for of the of and The of resorption was by the of at were at and with B7h at a of and and and was with a and were for and were in and were in was on with to B7h were in in in in in with and with antibody at were with antibody for at by with with The were with was by a as I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. Noelle R.J. Coyle A. Mellor A.L. Khoury S.J. Sayegh M.H. A critical role for the programmed death ligand 1 in fetomaternal tolerance.J Exp Med. 2005; 202: 231-237Crossref PubMed Scopus (319) Google Scholar were as was with antibody to the of B7h to cells. from with anti-B7h were as and as cells. from and were as The was to cells IFN-γ and as I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. Noelle R.J. Coyle A. Mellor A.L. Khoury S.J. Sayegh M.H. A critical role for the programmed death ligand 1 in fetomaternal tolerance.J Exp Med. 2005; 202: 231-237Crossref PubMed Scopus (319) Google Scholar and were from at of after were and were were in and in and for 1 were were equilibrium between the and and The cells were and the of and cells the placenta, was with and in the of and with and for cells the IFN-γ and were a cells were with and for in the at and were for IFN-γ for and for were from were on a from of were with and were with of anti-B7h monoclonal antibody to the were from and of at and and were in with fetal in at a of × The cells were from with and to the at a of × The was for at in a we the of TGF-β1 and in at and to the A with was to the were in that the were in to the (in which the is in the were with and were for with were at of pregnancy and of anti-B7h to the and and were and were to from and were and CD8+ T cells were a CD8+ T-cell to the CD8+ T cells were cells and cells with a the regulatory function of CD8+CD103+ T cells in a was in which T cells from of were with B6 and CD8+CD103+ T cells at for were with for the of and of was with a The regulatory function of CD8+CD103+ T cells was by the suppressive effect on the of effector T cells. T cells were by with a T-cell and CD8+CD103+ cells were after with for CD8 and than a as CD8+CD103+ cells were to cells) after and fetal resorption was at in the and the and cells were in and was to the was with and of was to of of of of and of and were The were for for by of for and for 1 was during the The were B7h IDO PD-L1 IFN-γ granzyme B and TGF-β1 was as of by of the The was for of was we expression of B7h in the were at and from with of B7h was by on of at expression of B7h in the maternal of and not the these the expression from that observed for PD-L1, in which expression was in the I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. Noelle R.J. Coyle A. Mellor A.L. Khoury S.J. Sayegh M.H. A critical role for the programmed death ligand 1 in fetomaternal tolerance.J Exp Med. 2005; 202: 231-237Crossref PubMed Scopus (319) Google Scholar B7h is not expressed on cells, as from with antibody not B7h was not expressed in placental from of this expression is by of expression of B7h in a on B6 the binding of the of expression was by in from A expression of was observed in CD8+CD103+ T cells and cells with and cells the role of B7h in fetomaternal we a model of allogeneic pregnancy, with The of spontaneous resorption in this model is D.H. Zhou M. Attwood J.T. Bondarev I. Conway S.J. Marshall B. Brown C. Mellor A.L. Prevention of allogeneic fetal rejection by tryptophan catabolism.Science. 1998; 281: 1191-1193Crossref PubMed Scopus (2120) Google Scholar, A.L. J. P. K. H. D.H. Prevention of T activation and by tryptophan during Immunol. PubMed Scopus Google Scholar the of resorption and after B7h with a monoclonal The resorption increased from in the to in the anti-B7h by the of from this allogeneic a of with in the The effect of anti-B7h antibody was was in resorption in after with this antibody not The is the in immune regulation during pregnancy, maternal and fetal cells in I. Sayegh M.H. Maternal acceptance of the fetus: true human tolerance.J Immunol. 2007; 178: 3345-3351PubMed Google Scholar the role of B7h in fetomaternal we effector and regulatory markers in the we from the and observed a in the of after in the anti-B7h–treated mice, with we regulatory markers in the by B7h blockade significantly decreased of the regulatory molecules IDO, and a but this not the PD-L1 is crucial for fetal I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. Noelle R.J. Coyle A. Mellor A.L. Khoury S.J. Sayegh M.H. A critical role for the programmed death ligand 1 in fetomaternal tolerance.J Exp Med. 2005; 202: 231-237Crossref PubMed Scopus (319) Google Scholar PD-L1 expression was but was to be in not In B7h blockade significantly at the fetomaternal interface. expression of IDO and was in the of the anti-B7h we to these regulatory for the enhanced fetal observed on B7h with anti-B7h not a in the of fetal with a antibody against in allogeneic pregnancy model we observed that of abrogated the enhanced fetal observed with anti-B7h to data that the increased of fetal resorption after B7h blockade is in mediated by regulatory signals (eg, IDO and the effect of B7h blockade on the we by the of CD4+ and CD8+ effector T cells in the and of and at and observed a in the of CD4+ effector T cells in the anti-B7h–treated at whereas the of CD8+ effector T cells was the between CD4+ and CD8+ T-cell were in in not we in to the alloimmune response. these from with anti-B7h were at and were in the presence of from was for determining the of cells. were and a observed an in IFN-γ production by from the anti-B7h–treated 1 for the levels were and production not significantly between not In was a TGF-β1 levels in the anti-B7h–treated with after to of after we that the major of IFN-γ in the were CD8+ T cells and that the of CD8+ T cells was significantly in the and of anti-B7h–treated mice, with for data suggest that B7h blockade to enhanced in pregnancy, with a in CD8+ cells. the roles of CD4+ and CD8+ T cells in fetomaternal we CD4+ and CD8+ of anti-B7h CD4+ in a in whereas of anti-B7h for CD8+ T cells abrogated this deleterious effect on in CD8+ suggest a critical role for CD8+ cells in the of B7h blockade on tolerance at the fetomaternal interface. the role of regulatory T cells in we by the of CD4+ regulatory T cells in and by in the of cells was observed between female with anti-B7h a in of CD8+ regulatory T cells by expression of these regulatory T-cell we a this model the of and cells from the and of The of cells after was after from than to the between IFN-γ expression on cells was between the anti-B7h–treated and whereas expression of and was not of the subset by a in granzyme B expression and a in IFN-γ expression in cells from anti-B7h–treated with in with in the and in In we IFN-γ production by the subset of regulatory CD8+ cells CD8+CD103+ cells a production of IFN-γ by after in with cells CD8+CD103+ T cells were to T-cell in the of a regulatory role for this B. is a for regulatory CD8+ T Immunol. Google Scholar of adoptive transfer of CD8+CD103+ cells to abrogated the increased fetal resorption by B7h blockade Taken together, these suggest that is for the of regulatory CD8+ cells and that blockade of B7h significantly immune regulation at the placental interface. The is a costimulatory pathway that actively in the of T-cell and of PubMed Scopus Google Scholar, H. M. A. S.E. T. H. Yagita H. Sayegh M.H. The role of the ICOS-B7h T costimulatory pathway in 2003; 112: PubMed Scopus Google Scholar In to its role in effector T cells, this pathway to be for immune ICOS-B7h signaling was shown to be critical for the of regulatory T cells, of in a model of regulatory T cells via the pathway and inhibit Med. PubMed Scopus Google Scholar was shown to be for tolerance in a model in which the peptide is for protection against K. C. L. The plays a crucial role in the of tolerance.J Immunol. 2005; Google Scholar blockade in mice, and this effect was on regulatory T C. 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Scopus Google Scholar In the present we not in production after B7h in the at the fetomaternal interface. Moreover, has been only in levels at the fetomaternal interface in S. A. T. M. and regulatory T-cell in J Reprod Immunol. PubMed Scopus Google Scholar, A. M. S. Shiozaki A. T. Saito S. and levels in J Reprod Immunol. PubMed Scopus Google Scholar cells play a deleterious role in fetomaternal tolerance to be Regulatory T cells critical for the of tolerance at the fetomaternal V.R. Kallikourdis M. Betz A.G. Regulatory T cells mediate maternal tolerance to the fetus.Nat Immunol. 2004; 5: 266-271Crossref PubMed Scopus (1263) Google Scholar, A.C. Gerlof K. Zenclussen M.L. S. Bertoja A. S. S. S. K. Leber J. Volk H.D. Regulatory T cells a at the J Immunol. PubMed Scopus Google Scholar and in regulatory T cells at the and in peripheral blood have been in spontaneous with Y. Sakai M. Miyazaki S. Higuma S. Shiozaki A. Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases.Mol Hum Reprod. 2004; 10: 347-353Crossref PubMed Scopus (602) Google Scholar of the in pregnancy have shown a role for CD4+ regulatory T cells. L. L. of CD8+ regulatory T cells by human placental Immunol. 2005; Google Scholar that placental to a of regulatory CD8+ cells that In was identified as a of regulatory CD8+ T cells, and CD8+CD103+ T cells were shown to have function with and B. is a for regulatory CD8+ T Immunol. Google Scholar with these in the present we observed a in regulatory CD8+ T cells as a of B7h of regulatory CD8+ T cells were identified by the of The effect on the was observed to be with anti-B7h not the enhanced fetal that the deleterious effect of ICOS-B7h blockade is on CD8+ cells. The adoptive transfer of CD8+ regulatory T cells abrogated the increased fetal resorption in anti-B7h–treated the role of this subset in fetomaternal tolerance In with T. D.J. The regulation of T-cell production by at the human fetomaternal 2011; PubMed Scopus Google Scholar, L. The and expressed in the human J Pathol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar expression was on placental T cells and B7h was present in placental by the expression of by the CD8+CD103+ T-cell subset and B7h in the maternal In B7h expression is present in the L. The and expressed in the human J Pathol. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar Although has been shown to be for regulatory T-cell with a reduced of regulatory T Y. T. A.C. Coyle A. the of and regulatory T Immunol. in J Immunol Google Scholar the of role of in the of regulatory CD8+ cells to be on the expression of on CD8+CD103+ cells and the of this subset on B7h ICOS-B7h signaling be for the of this CD8+ regulatory T-cell on CD4+ regulatory T cells that of regulatory CD4+ cells were by signaling this is true for CD8+ regulatory T cells T. S. K. L. M. functional of regulatory T cells in human and Full Text Full Text PDF PubMed Scopus Google Scholar Regulatory T cells suppressive effect of inhibitory cytokines (eg, and (eg, granzyme as as via inhibitory receptors (eg, have shown that the pathway plays a critical role in tolerance at the fetomaternal interface and that this effect is on regulatory T I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. Noelle R.J. Coyle A. Mellor A.L. Khoury S.J. Sayegh M.H. A critical role for the programmed death ligand 1 in fetomaternal tolerance.J Exp Med. 2005; 202: 231-237Crossref PubMed Scopus (319) Google Scholar, 13D'Addio F. Riella L.V. Mfarrej B.G. Chabtini L. Adams L.T. Yeung M. Yagita H. Azuma M. Sayegh M.H. Guleria I. The link between the PDL1 costimulatory pathway and in fetomaternal tolerance.J Immunol. 2011; PubMed Scopus Google Scholar, A. S. M. Yagita H. Azuma M. Sayegh M.H. Guleria I. A link between PDL1 and T regulatory cells in fetomaternal tolerance.J Immunol. 2007; PubMed Scopus Google Scholar In the present we not a of PD-L1 expression in the of anti-B7h–treated mice, that the deleterious effect of B7h blockade is of PD-L1 IDO has been shown to play an role in tolerance at the fetomaternal D.H. Zhou M. Attwood J.T. Bondarev I. Conway S.J. Marshall B. Brown C. Mellor A.L. Prevention of allogeneic fetal rejection by tryptophan catabolism.Science. 1998; 281: 1191-1193Crossref PubMed Scopus (2120) Google Scholar and of IDO was shown to in increased fetal rejection associated with T-cell and at the uteroplacental A.L. J. P. K. H. D.H. Prevention of T activation and by tryptophan during Immunol. PubMed Scopus Google Scholar In the present blockade of the ICOS-B7h pathway in of IDO, and at the fetomaternal interface. TGF-β1 is an of tolerance during pregnancy and via J.M. M. M. G.A. P. B. I. F. J. Rabinovich G.A. A role for in fetomaternal Med. 2007; in PubMed Scopus Google Scholar, S. Clark D.A. The molecules to successful pregnancy and J Reprod Immunol. PubMed Scopus Google Scholar, A.C. of the CD4+CD25+ T regulatory and tolerance to paternal in Reprod. PubMed Scopus Google Scholar of with the costimulatory expressed on the cells the of D.H. M.D. Mellor A.L. of by human CD4+ T cells in Immunol. 2004; Google Scholar expressed on regulatory T cells has been shown to IDO expression on and peripheral blood cells, and in spontaneous abortion the expression of on regulatory T cells was N. S. Miyazaki S. S. Y. Sakai M. Saito S. IDO expression on and peripheral blood cells and after with in pregnancy but in spontaneous Hum Reprod. 2005; PubMed Scopus Google Scholar be to the between and IDO, and B7h blockade the of CD8+ regulatory T cells. with and with in with anti-B7h suggest that In the present that the ICOS-B7h pathway plays a critical role in the regulation of fetomaternal tolerance by enhancing IFN-γ CD8+ effector response and by reducing local immunomodulation mediated by CD8+ regulatory T cells. should to the function of ICOS-B7h in CD8+ regulatory T-cell and the with and IDO pathways in with of B7h in of and for B7h on placental at in on placental of with of of is for with in in with in an allogeneic pregnancy female were with and with anti-B7h with was at antibody was to female mice, and was between with of CD4+ regulatory T cells in the anti-B7h–treated group. expression was by in from of female with anti-B7h with mice, at The of CD4+CD25+ T cells not between the shown on the