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. Copyright © 2013 American Society for Investigative Pathology.

B7h (ICOS-L) maintains tolerance at the fetomaternal interface / L.V. Riella, S. Dada, L. Chabtini, B. Smith, L. Huang, P. Dakle, B. Mfarrej, F. D'Addio, L. Adams, N. Kochupurakkal, A. Vergani, P. Fiorina, A.L. Mellor, A.H. Sharpe, H. Yagita, I. Guleria. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - 182:6(2013), pp. 2204-2213. [10.1016/j.ajpath.2013.02.014]

B7h (ICOS-L) maintains tolerance at the fetomaternal interface

F. D'Addio;P. Fiorina;
2013

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. Copyright © 2013 American Society for Investigative Pathology.
Adoptive Transfer; Animals; Antibodies, Monoclonal; CD8-Positive T-Lymphocytes; CTLA-4 Antigen; Cytokines; Embryo Loss; Female; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inducible T-Cell Co-Stimulator Ligand; Litter Size; Lymph Nodes; Maternal-Fetal Exchange; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Placenta; Pregnancy; Spleen; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; 2734
Settore MED/13 - Endocrinologia
Article (author)
File in questo prodotto:
File Dimensione Formato  
1-s2.0-S0002944013001922-main.pdf

non disponibili

Tipologia: Publisher's version/PDF
Dimensione 1.22 MB
Formato Adobe PDF
1.22 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/499236
Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 25
  • ???jsp.display-item.citation.isi??? 24
social impact