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

Leonardo V. Riella, Shirine Dada, Lola Chabtini, Brian Smith, Lei Huang, Pranal Dakle, Bechara Mfarrej, Francesca D'Addio, La Tonya Adams, Nora Kochupurakkal, Andrea Vergani, Paolo Fiorina, Andrew L. Mellor, Arlene H. Sharpe, Hideo Yagita, Indira Guleria

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2204-2213
Number of pages10
JournalAmerican Journal of Pathology
Volume182
Issue number6
DOIs
StatePublished - Jun 1 2013

Fingerprint

Regulatory T-Lymphocytes
Knockout Mice
Pregnancy
Fetus
Fetal Resorption
Monoclonal Antibodies
Mothers
T-Lymphocytes
Granzymes
Immunomodulation
Adoptive Transfer
Placenta
Immune System
Cytokines
Therapeutics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Riella, L. V., Dada, S., Chabtini, L., Smith, B., Huang, L., Dakle, P., ... Guleria, I. (2013). B7h (ICOS-L) maintains tolerance at the fetomaternal interface. American Journal of Pathology, 182(6), 2204-2213. https://doi.org/10.1016/j.ajpath.2013.02.014

B7h (ICOS-L) maintains tolerance at the fetomaternal interface. / Riella, Leonardo V.; Dada, Shirine; Chabtini, Lola; Smith, Brian; Huang, Lei; Dakle, Pranal; Mfarrej, Bechara; D'Addio, Francesca; Adams, La Tonya; Kochupurakkal, Nora; Vergani, Andrea; Fiorina, Paolo; Mellor, Andrew L.; Sharpe, Arlene H.; Yagita, Hideo; Guleria, Indira.

In: American Journal of Pathology, Vol. 182, No. 6, 01.06.2013, p. 2204-2213.

Research output: Contribution to journalArticle

Riella, LV, Dada, S, Chabtini, L, Smith, B, Huang, L, Dakle, P, Mfarrej, B, D'Addio, F, Adams, LT, Kochupurakkal, N, Vergani, A, Fiorina, P, Mellor, AL, Sharpe, AH, Yagita, H & Guleria, I 2013, 'B7h (ICOS-L) maintains tolerance at the fetomaternal interface', American Journal of Pathology, vol. 182, no. 6, pp. 2204-2213. https://doi.org/10.1016/j.ajpath.2013.02.014
Riella LV, Dada S, Chabtini L, Smith B, Huang L, Dakle P et al. B7h (ICOS-L) maintains tolerance at the fetomaternal interface. American Journal of Pathology. 2013 Jun 1;182(6):2204-2213. https://doi.org/10.1016/j.ajpath.2013.02.014
Riella, Leonardo V. ; Dada, Shirine ; Chabtini, Lola ; Smith, Brian ; Huang, Lei ; Dakle, Pranal ; Mfarrej, Bechara ; D'Addio, Francesca ; Adams, La Tonya ; Kochupurakkal, Nora ; Vergani, Andrea ; Fiorina, Paolo ; Mellor, Andrew L. ; Sharpe, Arlene H. ; Yagita, Hideo ; Guleria, Indira. / B7h (ICOS-L) maintains tolerance at the fetomaternal interface. In: American Journal of Pathology. 2013 ; Vol. 182, No. 6. pp. 2204-2213.
@article{f615f76d838b461a8a06c610d2a70e04,
title = "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.",
author = "Riella, {Leonardo V.} and Shirine Dada and Lola Chabtini and Brian Smith and Lei Huang and Pranal Dakle and Bechara Mfarrej and Francesca D'Addio and Adams, {La Tonya} and Nora Kochupurakkal and Andrea Vergani and Paolo Fiorina and Mellor, {Andrew L.} and Sharpe, {Arlene H.} and Hideo Yagita and Indira Guleria",
year = "2013",
month = "6",
day = "1",
doi = "10.1016/j.ajpath.2013.02.014",
language = "English (US)",
volume = "182",
pages = "2204--2213",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - B7h (ICOS-L) maintains tolerance at the fetomaternal interface

AU - Riella, Leonardo V.

AU - Dada, Shirine

AU - Chabtini, Lola

AU - Smith, Brian

AU - Huang, Lei

AU - Dakle, Pranal

AU - Mfarrej, Bechara

AU - D'Addio, Francesca

AU - Adams, La Tonya

AU - Kochupurakkal, Nora

AU - Vergani, Andrea

AU - Fiorina, Paolo

AU - Mellor, Andrew L.

AU - Sharpe, Arlene H.

AU - Yagita, Hideo

AU - Guleria, Indira

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84878228726&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878228726&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2013.02.014

DO - 10.1016/j.ajpath.2013.02.014

M3 - Article

C2 - 23578385

AN - SCOPUS:84878228726

VL - 182

SP - 2204

EP - 2213

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 6

ER -