Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy

Abstract

Complex regulation of T cell functions during pregnancy is required to ensure materno‐fetal tolerance. Here we reveal a novel pathway for the temporary suppression of maternal T cell responses in uncomplicated human pregnancies. Our results show that arginase activity is significantly increased in the peripheral blood of pregnant women and remarkably high arginase activities are expressed in term placentae. High enzymatic activity results in high turnover of its substrate L ‐arginine and concomitant reduction of this amino acid in the microenvironment. Amino acid deprivation is emerging as a regulatory pathway of lymphocyte responses and we assessed the consequences of this enhanced arginase activity on T cell responses. Arginase‐mediated L ‐arginine depletion induces down‐regulation of CD3ζ, the main signalling chain of the TCR, and functional T cell hyporesponsiveness. Importantly, this arginase‐mediated T cell suppression was reversible, as inhibition of arginase activity or addition of exogenous L ‐arginine restored CD3ζ chain expression and T cell proliferation. Thus, L ‐arginine metabolism constitutes a novel physiological mechanism contributing to the temporary suppression of the maternal immune response during human pregnancy.

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References 53

1. 1.

   Medawar PB. Some immunological and endocrinological problems raised by the evolultion of viviparity in vertebrates. Symp. Soc. Exp. Biol. 1953;7:320-338.

   Not in our library

2. 2.

   Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and immune tolerance in pregnancy. FASEB J. 2005;19:681-693.

   Not in our library10.1096/fj.04-2078rev

3. 3.

   Petroff MG. Immune interactions at the maternal-fetal interface. J. Reprod. Immunol. 2005;68:1-13.

   Not in our library10.1016/j.jri.2005.08.003

4. 4.

   Tafuri A, Alferink J, Moller P, Hammerling GJ, Arnold B. T cell awareness of paternal alloantigens during pregnancy. Science. 1995;270:630-633.

   Not in our library10.1126/science.270.5236.630

5. 5.

   Guleria I, Khosroshahi A, Ansari MJ, Habicht A, Azuma M, Yagita H, Noelle RJ, et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J. Exp. Med. 2005;202:231-237.

   Not in our library10.1084/jem.20050019

6. 6.

   Fournel S, Aguerre-Girr M, Huc X, Lenfant F, Alam A, Toubert A, Bensussan A, Le Bouteiller P. Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. J. Immunol. 2000;164:6100-6104.

   Not in our library10.4049/jimmunol.164.12.6100

7. 7.

   Hunt JS, Vassmer D, Ferguson TA, Miller L. Fas ligand is positioned in mouse uterus and placenta to prevent trafficking of activated leukocytes between the mother and the conceptus. J. Immunol. 1997;158:4122-4128.

   Not in our library

8. 8.

   Phillips TA, Ni J, Pan G, Ruben SM, Wei YF, Pace JL, Hunt JS. TRAIL (Apo-2L) and TRAIL receptors in human placentas: implications for immune privilege. J. Immunol. 1999;162:6053-6059.

   Not in our library

9. 9.

   Aluvihare VR, Kallikourdis M, Betz AG. Tolerance, suppression and the fetal allograft. J. Mol. Med. 2005;83:88-96.

   Not in our library10.1007/s00109-004-0608-2

10. 10.

    Saito S, Sasaki Y, Sakai M. CD4(+)CD25high regulatory T cells in human pregnancy. J. Reprod. Immunol. 2005;65:111-120.

    Not in our library10.1016/j.jri.2005.01.004

11. 11.

    Heikkinen J, Mottonen M, Komi J, Alanen A, Lassila O. Phenotypic characterization of human decidual macrophages. Clin. Exp. Immunol. 2003;131:498-505.

    Not in our library10.1046/j.1365-2249.2003.02092.x

12. 12.

    Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191-1193.

    Not in our library10.1126/science.281.5380.1191

13. 13.

    Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol. Today. 1999;20:469-473.

    Not in our library10.1016/s0167-5699(99)01520-0

14. 14.

    Mellor AL, Munn D. Policing pregnancy: Tregs help keep the peace. Trends Immunol. 2004;25:563-565.

    Not in our library10.1016/j.it.2004.09.001

15. 15.

    McCracken SA, Gallery E, Morris JM. Pregnancy-specific down-regulation of NF-kappa B expression in T cells in humans is essential for the maintenance of the cytokine profile required for pregnancy success. J. Immunol. 2004;172:4583-4591.

    Not in our library10.4049/jimmunol.172.7.4583

16. 16.

    Schneider E, Dy M. The role of arginase in the immune response. Immunol. Today. 1985;6:136-140.

    Not in our library10.1016/0167-5699(85)90081-7

17. 17.

    Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 2005;65:3044-3048.

    Not in our library10.1158/0008-5472.can-04-4505

18. 18.

    Bronte V, Kasic T, Gri G, Gallana K, Borsellino G, Marigo I, Battistini L, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J. Exp. Med. 2005;201:1257-1268.

    Not in our library10.1084/jem.20042028

19. 19.

    Whiteside TL. Down-regulation of zeta-chain expression in T cells: A biomarker of prognosis in cancer? Cancer Immunol. Immunother. 2004;53:865-878.

    Not in our library10.1007/s00262-004-0521-0

20. 20.

    Bronte V, Zanovello P. Regulation of immune responses by l-arginine metabolism. Nat. Rev. Immunol. 2005;5:641-654.

    Not in our library10.1038/nri1668

21. 21.

    Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa AC. Regulation of T cell receptor CD3ζ chain expression by l-arginine. J. Biol. Chem. 2002;277:21123-21129.

    Not in our library10.1074/jbc.m110675200

22. 22.

    Bansal V, Ochoa JB. Arginine availability, arginase, and the immune response. Curr. Opin. Clin. Nutr. Metab. Care. 2003;6:223-226.

    Not in our library10.1097/00075197-200303000-00012

23. 23.

    Zabaleta J, McGee DJ, Zea AH, Hernandez CP, Rodriguez PC, Sierra RA, Correa P, Ochoa AC. Helicobacter pylori arginase inhibits T cell proliferation and reduces the expression of the TCR zeta-chain (CD3zeta). J. Immunol. 2004;173:586-593.

    Not in our library10.4049/jimmunol.173.1.586

24. 24.

    Kropf P, Fuentes JM, Fahnrich E, Arpa L, Herath S, Weber V, Soler G, et al. Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo. FASEB J. 2005;19:1000-1002.

    Not in our library10.1096/fj.04-3416fje

25. 25.

    Vincendeau P, Gobert AP, Daulouede S, Moynet D, Mossalayi MD. Arginases in parasitic diseases. Trends Parasitol. 2003;19:9-12.

    Not in our library10.1016/s1471-4922(02)00010-7

26. 26.

    Wu G, Jaeger LA, Bazer FW, Rhoads JM. Arginine deficiency in preterm infants: Biochemical mechanisms and nutritional implications. J. Nutr. Biochem. 2004;15:442-451.

    Not in our library10.1016/j.jnutbio.2003.11.010

27. 27.

    Cederbaum SD, Yu H, Grody WW, Kern RM, Yoo P, Iyer RK. Arginases I and II: Do their functions overlap? Mol. Gen. Metabol. 2004;81:S38-S44.

    Not in our library10.1016/j.ymgme.2003.10.012

28. 28.

    Jenkinson CP, Grody WW, Cederbaum SD. Comparative properties of arginases. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 1996;114:107-132.

    Not in our library10.1016/0305-0491(95)02138-8

29. 29.

    Rodriguez PC, Zea AH, DeSalvo J, Culotta KS, Zabaleta JQ,, D.G, Ochoa JB, Ochoa AC. l-Arginine consumption by macrophages modulates the expression of CD3ζ chain in T lymphocytes. J. Immunol. 2003;171:1232-1239.

    Not in our library10.4049/jimmunol.171.3.1232

30. 30.

    Baniyash M. TCR zeta-chain downregulation: Curtailing an excessive inflammatory immune response. Nat. Rev. Immunol. 2004;4:675-687.

    Not in our library10.1038/nri1434

31. 31.

    Porta R, Esposito C, Martin A, Pietra GD. Arginase from human full-term placenta. Biochem. J. 1976;159:579-583.

    Not in our library10.1042/bj1590579

32. 32.

    Custot J, Moali C, Brollo M, Boucher JL, Delaforge M, Mansuy D, Tenu JP, Zimmermann JL. The new a-amino acid Nω-hydroxy-nor-l-arginine: A high affinity inhibitor of arginase well adapted to bind to its manganese cluster. J. Am. Chem. Soc. 1997;199:4086-4807.

    Not in our library

33. 33.

    Munder M, Mollinedo F, Calafat J, Canchado J, Gil-Lamaignere C, Fuentes JM, Luckner C, et al. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood. 2005;105:2549-2556.

    Not in our library10.1182/blood-2004-07-2521

34. 34.

    Munder M, Schneider H, Luckner C, Giese T, Langhans CD, Fuentes J, Kropf P, et al. Suppression of T cell functions by human granulocyte arginase. Blood. 2006;108:1627-1634.

    Not in our library10.1182/blood-2006-11-010389

35. 35.

    Kindzelskii AL, Huang JB, Chaiworapongsa T, Fahmy RM, Kim YM, Romero R, Petty HR. Pregnancy alters glucose-6-phosphate dehydrogenase trafficking, cell metabolism, and oxidant release of maternal neutrophils. J. Clin. Invest. 2002;110:1801-1811.

    Not in our library10.1172/jci200215973

36. 36.

    Kindzelskii AL, Clark AJ, Espinoza J, Maeda N, Aratani Y, Romero R, Petty HR. Myeloperoxidase accumulates at the neutrophil surface and enhances cell metabolism and oxidant release during pregnancy. Eur. J. Immunol. 2006;36:1619-1628.

    Not in our library10.1002/eji.200535391

37. 37.

    Petty HR, Kindzelskii AL, Espinoza J, Romero R. Trophoblast contact deactivates human neutrophils. J. Immunol. 2006;176:3205-3214.

    Not in our library10.4049/jimmunol.176.5.3205

38. 38.

    Tsukimori K, Fukushima K, Tsushima A, Nakano H. Generation of reactive oxygen species by neutrophils and endothelial cell injury in normal and preeclamptic pregnancies. Hypertension. 2005;46:696-700.

    Not in our library10.1161/01.hyp.0000184197.11226.71

39. 39.

    Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308:1592-1594.

    Not in our library10.1126/science.1111726

40. 40.

    Zea AH, Culotta KS, Ali J, Mason C, Park HJ, Zabaleta J, Garcia LF, Ochoa AC. Decreased expression of CD3 zeta and nuclear transcription factor kappa B in patients with pulmonary tuberculosis: Potential mechanisms and reversibility with treatment. J. Infect. Dis. 2006;194:1385-1393.

    Not in our library10.1086/508200

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