Original Article
Modulation of T-cell Reactivity During Equine Pregnancy is Antigen Independent
Leela E. Noronha,
Douglas F. Antczak,
Leela E. Noronha
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
Search for more papers by this authorCorresponding Author
Douglas F. Antczak
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
Correspondence
Doug Antczak, Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA. E-mail: [email protected]
Search for more papers by this authorLeela E. Noronha,
Douglas F. Antczak,
Leela E. Noronha
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
Search for more papers by this authorCorresponding Author
Douglas F. Antczak
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
Correspondence
Doug Antczak, Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA. E-mail: [email protected]
Search for more papers by this authorAbstract
Problem
Pregnant mares demonstrate a reduction in cytotoxic T lymphocyte (CTL) reactivity against cells from the breeding stallion. We investigated whether this effect is limited to activity against paternal major histocompatibility complex (MHC) antigens, and whether it occurs during MHC-compatible pregnancy.
Method of Study
Mares were mated to carry MHC-compatible or MHC-incompatible pregnancies. CTL activity of these mares when pregnant and non-pregnant was measured against cells from horses with MHC haplotypes unrelated to the mare or breeding stallion.
Results
While carrying MHC-incompatible pregnancies, mares demonstrated reduced CTL activity against lymphocytes from third-party horses in addition to those from the breeding stallion. This effect was also observed in mares carrying MHC-compatible pregnancies.
Conclusions
The decrease in maternal T-cell reactivity characteristic of normal equine pregnancy is not restricted to paternal alloantigen, and occurs during MHC-matched matings. This suggests that antigen-independent mechanisms may be responsible for this reduction in cell-mediated immune activity.
Supporting Information
| Filename | Description |
|---|---|
| aji1154-sup-0001-FigS1.tifimage/tif, 238.8 KB | Figure S1. CTL activity in non-pregnant mares is robust and specific for the MHC of the stimulator animal. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 Roe R, Bell SC: Humoral immune responses in murine pregnancy. II. Kinetics and nature of the response in females preimmunized against paternal alloantigens. Immunology 1982; 46: 23–30.
- 2 Smith RN, Amsden A, Sudilovsky O, Coleman N, Margolies R: The alloantibody response in the allogeneically pregnant rat. IV. Analysis of the alloantibody specificities with monoclonal antibodies. J Immunol 1986; 136: 4063–4069.
- 3 Antczak DF, Bright SM, Remick LH, Bauman BE: Lymphocyte alloantigens of the horse. I. Serologic and genetic studies. Tissue Antigens 1982; 20: 172–187.
- 4 Antczak DF, Miller JM, Remick LH: Lymphocyte alloantigens of the horse. II. Antibodies to ELA antigens produced during equine pregnancy. J Reprod Immunol 1984; 6: 283–297.
- 5 Van Rood JJ, Eernisse JG, Van Leeuwen A: Leucocyte antibodies in sera from pregnant women. Nature 1958; 181: 1735–1736.
- 6 Robertson SA, Guerin LR, Moldenhauer LM, Hayball JD: Activating T regulatory cells for tolerance in early pregnancy – the contribution of seminal fluid. J Reprod Immunol 2009; 83: 109–116.
- 7 Tilburgs T, Scherjon SA, van der Mast BJ, Haasnoot GW, Versteeg VDV-MM, Roelen DL, van Rood JJ, Claas FH: Fetal-maternal HLA-C mismatch is associated with decidual T cell activation and induction of functional T regulatory cells. J Reprod Immunol 2009; 82: 148–157.
- 8 Zenclussen ML, Thuere C, Ahmad N, Wafula PO, Fest S, Teles A, Leber A, Casalis PA, Bechmann I, Priller J, Volk HD, Zenclussen AC: The persistence of paternal antigens in the maternal body is involved in regulatory T-cell expansion and fetal-maternal tolerance in murine pregnancy. Am J Reprod Immunol 2010; 63: 200–208.
- 9 Seavey MM, Mosmann TR: Paternal antigen-bearing cells transferred during insemination do not stimulate anti-paternal CD8+ T cells: role of estradiol in locally inhibiting CD8+ T cell responses. J Immunol 2006; 177: 7567–7578.
- 10 Smith JL: Foodborne infections during pregnancy. J Food Prot 1999; 62: 818–829.
- 11 van der Klooster JM, Roelofs HJ: Management of Salmonella infections during pregnancy and puerperium. Neth J Med 1997; 51: 83–86.
- 12 Avelino MM, Campos D Jr, do Carmo Barbosa de Parada J, de Castro AM: Pregnancy as a risk factor for acute toxoplasmosis seroconversion. Eur J Obstet Gynecol Reprod Biol 2003; 108: 19–24.
- 13 Krishnan L, Guilbert LJ, Russell AS, Wegmann TG, Mosmann TR, Belosevic M: Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection and causes decreased antigen-specific IFN-gamma response and increased production of T helper 2 cytokines. J Immunol 1996; 156: 644–652.
- 14 Luft BJ, Remington JS: Effect of pregnancy on resistance to Listeria monocytogenes and Toxoplasma gondii infections in mice. Infect Immun 1982; 38: 1164–1171.
- 15 Rowe JH, Ertelt JM, Aguilera MN, Farrar MA, Way SS: Foxp3(+) regulatory T cell expansion required for sustaining pregnancy compromises host defense against prenatal bacterial pathogens. Cell Host Microbe 2011; 10: 54–64.
- 16 Ostensen M, Husby G: A prospective clinical study of the effect of pregnancy on rheumatoid arthritis and ankylosing spondylitis. Arthritis Rheum 1983; 26: 1155–1159.
- 17 Waites GT, Whyte A: Effect of pregnancy on collagen-induced arthritis in mice. Clin Exp Immunol 1987; 67: 467–476.
- 18 Petroff MG: Review: fetal antigens–identity, origins, and influences on the maternal immune system. Placenta 2011; 32(Suppl 2): S176–S181.
- 19 Yamada K: [Analysis on the CTL-p frequency before and after immunotherapy for patients with unexplained habitual abortion]. Nippon Sanka Fujinka Gakkai Zasshi 1993; 45: 527–532.
- 20 Kotlan B, Fulop V, Padanyi A, Szigetvari I, Reti M, Gyodi E, Feher E, Petranyi G: High anti-paternal cytotoxic T-lymphocyte precursor frequencies in women with unexplained recurrent spontaneous abortions. Hum Reprod 2001; 16: 1278–1285.
- 21 Manyonda IT, Pereira RS, Pearce JM, Sharrock CE: Limiting dilution analysis of the allo-MHC anti-paternal cytotoxic T cell response. II: recurrent spontaneous abortion and the effect of immunotherapy. Clin Exp Immunol 1993; 93: 132–137.
- 22 Jiang SP, Vacchio MS: Multiple mechanisms of peripheral T cell tolerance to the fetal “allograft”. J Immunol 1998; 160: 3086–3090.
- 23 Tafuri A, Alferink J, Moller P, Hammerling GJ, Arnold B: T cell awareness of paternal alloantigens during pregnancy. Science 1995; 270: 630–633.
- 24 Erlebacher A, Vencato D, Price KA, Zhang D, Glimcher LH: Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus. J Clin Invest 2007; 117: 1399–1411.
- 25 Parvin M, Isobe K, Goto S, Nakashima I, Tomoda Y: Further evaluation of the pregnancy-linked down-regulation of the paternal antigen-specific splenic cytotoxic T lymphocyte activity in allogeneically pregnant mice. Microbiol Immunol 1992; 36: 757–765.
- 26 Baker JM, Bamford AI, Antczak DF: Modulation of allospecific CTL responses during pregnancy in equids: an immunological barrier to interspecies matings? J Immunol 1999; 162: 4496–4501.
- 27 Clark DA, McDermott MR: Impairment of host vs graft reaction in pregnant mice. I. Suppression of cytotoxic T cell generation in lymph nodes draining the uterus. J Immunol 1978; 121: 1389–1393.
- 28 van Halteren AG, Jankowska-Gan E, Joosten A, Blokland E, Pool J, Brand A, Burlingham WJ, Goulmy E: Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members. Blood 2009; 114: 2263–2272.
- 29 Zhou M, Mellor AL: Expanded cohorts of maternal CD8+ T-cells specific for paternal MHC class I accumulate during pregnancy. J Reprod Immunol 1998; 40: 47–62.
- 30 Nakamura N, Miyazaki K, Kitano Y, Fujisaki S, Okamura H: Suppression of cytotoxic T-lymphocyte activity during human pregnancy. J Reprod Immunol 1993; 23: 119–130.
- 31 Thomas IK, Erickson KL: Gestational immunosuppression is mediated by specific Lyt 2+ T cells. Immunology 1986; 57: 201–206.
- 32 Slapsys RM, Clark DA: Active suppression of host-vs-graft reaction in pregnant mice. IV. Local suppressor cells in decidua and uterine blood. J Reprod Immunol 1982; 4: 355–364.
- 33 Chaouat G, Monnot P, Hoffmann M, Voisin GA: Regulatory T cells in pregnancy. VI. Evidence for T-cell-mediated suppression of CTL generation toward paternal alloantigens. Cell Immunol 1982; 68: 322–331.
- 34 Hamilton MS, Hellstrom I: Altered immune responses in pregnant mice. Transplantation 1977; 23: 423–430.
- 35 Clark DA, McDermott MR, Szewczuk MR: Impairment of host-versus-graft reaction in pregnant mice. II. Selective suppression of cytotoxic T-cell generation correlates with soluble suppressor activity and with successful allogeneic pregnancy. Cell Immunol 1980; 52: 106–118.
- 36 Noronha LE, Antczak DF: Maternal immune responses to trophoblast: the contribution of the horse to pregnancy immunology. Am J Reprod Immunol 2010; 64: 231–244.
- 37 Antczak DF: Lymphocyte alloantigens of the horse. III. ELY-2.1: a lymphocyte alloantigen not coded for by the MHC. Anim Blood Groups Biochem Genet 1984; 15: 103–115.
- 38 Adams AP, Oriol JG, Campbell RE, Oppenheim YC, Allen WR, Antczak DF: The effect of skin allografting on the equine endometrial cup reaction. Theriogenology 2007; 68: 237–247.
- 39 Ellis SA, Bontrop RE, Antczak DF, Ballingall K, Davies CJ, Kaufman J, Kennedy LJ, Robinson J, Smith DM, Stear MJ, Stet RJ, Waller MJ, Walter L, Marsh SG: ISAG/IUIS-VIC Comparative MHC Nomenclature Committee report, 2005. Immunogenetics 2006; 57: 953–958.
- 40 Lazary S, Antczak DF, Bailey E, Bell TK, Bernoco D, Byrns G, McClure JJ: Joint Report of the Fifth International Workshop on Lymphocyte Alloantigens of the Horse, Baton Rouge, Louisiana, 31 October-1 November 1987. Anim Genet 1988; 19: 447–456.
- 41 Tseng CT, Miller D, Cassano J, Bailey E, Antczak DF: Identification of equine major histocompatibility complex haplotypes using polymorphic microsatellites. Anim Genet 2010; 41(Suppl 2): 150–153.
- 42 Wagner B, Hillegas JM, Brinker DR, Horohov DW, Antczak DF: Characterization of monoclonal antibodies to equine interleukin-10 and detection of T regulatory 1 cells in horses. Vet Immunol Immunopathol 2008; 122: 57–64.
- 43 Ellis WA, Bryson DG, O'Brien JJ, Neill SD: Leptospiral infection in aborted equine foetuses. Equine Vet J 1983; 15: 321–324.
- 44 Givens MD, Marley MS: Infectious causes of embryonic and fetal mortality. Theriogenology 2008; 70: 270–285.
- 45 Lunn DP, Davis-Poynter N, Flaminio MJ, Horohov DW, Osterrieder K, Pusterla N, Townsend HG: Equine herpesvirus-1 consensus statement. J Vet Intern Med 2009; 23: 450–461.
- 46 Edington N, Smyth B, Griffiths L: The role of endothelial cell infection in the endometrium, placenta and foetus of equid herpesvirus 1 (EHV-1) abortions. J Comp Pathol 1991; 104: 379–387.
- 47 Paillot R, Daly JM, Luce R, Montesso F, Davis-Poynter N, Hannant D, Kydd JH: Frequency and phenotype of EHV-1 specific, IFN-gamma synthesising lymphocytes in ponies: the effects of age, pregnancy and infection. Dev Comp Immunol 2007; 31: 202–214.
- 48 Lissauer D, Choudhary M, Pachnio A, Goodyear O, Moss PA, Kilby MD: Cytomegalovirus sero positivity dramatically alters the maternal CD8+ T cell repertoire and leads to the accumulation of highly differentiated memory cells during human pregnancy. Hum Reprod 2011; 26: 3355–3365.
- 49 Agricola R, Carvalho H, Barbosa M, Pereira M, Medeiros JA, Ferreira-Dias G: Blood lymphocyte subpopulations, neutrophil phagocytosis and proteinogram during late pregnancy and postpartum in mares. Reprod Domest Anim 2008; 43: 212–217.
- 50 de Mestre A, Noronha L, Wagner B, Antczak DF: Split immunological tolerance to trophoblast. Int J Dev Biol 2010; 54: 445–455.
- 51 Krakowski L, Krawczyk CH, Wrona Z, Dabrowski R, Jarosz L: Levels of selected T lymphocyte subpopulations in peripheral blood of mares which experienced early embryonic death. Anim Reprod Sci 2010; 120: 71–77.
- 52 Beagley KW, Gockel CM: Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunol Med Microbiol 2003; 38: 13–22.
- 53 White HD, Crassi KM, Givan AL, Stern JE, Gonzalez JL, Memoli VA, Green WR, Wira CR: CD3+ CD8+ CTL activity within the human female reproductive tract: influence of stage of the menstrual cycle and menopause. J Immunol 1997; 158: 3017–3027.
- 54 Watson ED, Stokes CR, Bourne FJ: Influence of administration of ovarian steroids on the function of neutrophils isolated from the blood and uterus of ovariectomized mares. J Endocrinol 1987; 112: 443–448.
- 55 Pap E, Pallinger E, Falus A, Kiss AA, Kittel A, Kovacs P, Buzas EI: T lymphocytes are targets for platelet- and trophoblast-derived microvesicles during pregnancy. Placenta 2008; 29: 826–832.
- 56 Morales PJ, Pace JL, Platt JS, Phillips TA, Morgan K, Fazleabas AT, Hunt JS: Placental cell expression of HLA-G2 isoforms is limited to the invasive trophoblast phenotype. J Immunol 2003; 171: 6215–6224.
- 57 Roth TL, White KL, Thompson DL Jr, Rahmanian S, Horohov DW: Involvement of interleukin 2 receptors in conceptus-derived suppression of T and B cell proliferation in horses. J Reprod Fertil 1992; 96: 309–322.
- 58 Lea RG, Bolton AE: The effect of horse placental tissue extracts and equine chorionic gonadotrophin on the proliferation of horse lymphocytes stimulated in vitro. J Reprod Immunol 1991; 19: 13–23.
- 59 Flaminio MJ, Yen A, Antczak DF: The proliferation inhibitory proteins p27(Kip1) and retinoblastoma are involved in the control of equine lymphocyte proliferation. Vet Immunol Immunopathol 2004; 102: 363–377.
- 60 Flaminio MJ, Antczak DF: Inhibition of lymphocyte proliferation and activation: a mechanism used by equine invasive trophoblast to escape the maternal immune response. Placenta 2005; 26: 148–159.
- 61 Watson ED, Zanecosky HG: Regulation of mitogen- and TCGF-induced lymphocyte blastogenesis by prostaglandins and supernatant from equine embryos and endometrium. Res Vet Sci 1991; 51: 61–65.
- 62 Watson ED: Suppression of lymphocyte reactivity by culture supernatant from horse embryos and endometrium. Biol Reprod 1990; 42: 294–300.
- 63 Aluvihare VR, Kallikourdis M, Betz AG: Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 2004; 5: 266–271.
- 64 Leber A, Teles A, Zenclussen AC: Regulatory T cells and their role in pregnancy. Am J Reprod Immunol 2010; 63: 445–459.
- 65 Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF, Offner H: Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol 2004; 173: 2227–2230.
- 66 Prieto GA, Rosenstein Y: Oestradiol potentiates the suppressive function of human CD4 CD25 regulatory T cells by promoting their proliferation. Immunology 2006; 118: 58–65.
- 67 Aung S, Tang YW, Graham BS: Interleukin-4 diminishes CD8(+) respiratory syncytial virus-specific cytotoxic T-lymphocyte activity in vivo. J Virol 1999; 73: 8944–8949.
- 68 Gao Q, Chen N, Rouse TM, Field EH: The role of interleukin-4 in the induction phase of allogeneic neonatal tolerance. Transplantation 1996; 62: 1847–1854.
- 69 Hepworth MR, Hardman MJ, Grencis RK: The role of sex hormones in the development of Th2 immunity in a gender-biased model of Trichuris muris infection. Eur J Immunol 2010; 40: 406–416.
- 70 Druckmann R, Druckmann MA: Progesterone and the immunology of pregnancy. J Steroid Biochem Mol Biol 2005; 97: 389–396.
