Abstract
The response of splenic CD4 T cells from ovalbumin (OVA)-specific T cell receptor (TCR) transgenic mice after long-term feeding of a diet containing this antigen was examined. These CD4 T cells exhibited a decreased response to OVA peptide stimulation, in terms of proliferation, interleukin-2 secretion, and CD40 ligand expression, compared to those from mice fed a control diet lacking OVA, demonstrating that oral tolerance of T cells had been induced through oral intake of the antigen. We investigated the intracellular signaling pathways, which were Ca/CN cascade and Ras/MAPK cascade, of these tolerant CD4 T cells using phorbol-12-myristate-13-acetate (PMA) and ionomycin, which are known to directly stimulate these pathways. In contrast to the decreased response to TCR stimulation by OVA peptide, it was shown that the response of splenic CD4 T cells to these reagents in the state of oral tolerance was stronger. These results suggest that splenic CD4 T cells in the state of oral tolerance have an impairment in signaling, in which signals are not transmitted from the TCR to downstream signaling pathways, and have impairments in the vicinity of TCR.
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Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C, Liu YJ, Rousset F & Saeland S (1994) The CD40 antigen and its ligand.Ann Rev Immunol 12: 881–922.
Berg LJ, de St Groth BF, Pullen AM & Davis MM (1989) Phenotypic differences between αβ versus β T-cell receptor transgenic mice undergoing negative selection.Nature 340: 559–562.
Castle BE, Kishimoto K, Stearns C, Brown ML & Kehry MR (1993) Regulation of expression of the ligand for CD40 on T helper lymphocytes.J Immunol151: 1777–1778.
Chan AC & Shaw AS (1996)Regulation of antigen receptor signal transduction by protein tyrosine kinases.Curr Opin Immunol8: 394–401.
Crabtree GR (1989) Contingent genetic regulatory events in T lymphocyte activation.Science 243: 355–361.
Downward J, Graves JD, Warne PH, Rayter S & Cantrell DA (1990) Stimulation of p21ras upon T-cell activation.Nature 346:719–723.
Higgins PJ & Weiner HL (1988) Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments.J Immunol140:440–445.
Hirahara K, Hisatsune T, Nishijima K, Kato H, Shiho O & Kaminogawa S (1995) CD4+ T cells anergized by high dose feeding establish oral tolerance to antibody responses when transferred in SCID and nude mice.J Immunol 154:6238–6245.
Hirahara K, Saito S, Serizawa N, Sasaki R, Sakaguchi M, Inouye S, Taniguchi S, Kaminogawa S & Shiraishi A (1998)Oral administration of a dominant T-cell determinant peptide inhibits allergen-specific Th1 and Th2 cell responses in Cry j 2-primed mice.J Allergy Clin Immunol 102:961–967.
Ise W, Totsuka M, Takato R, Hachimura S, Sato T, Ametani A, Kumagai Y, Habu S & Kaminogawa S (2000) Primary response of naive CD4+ T cells to amino acid-substituted analogs of an antigenic peptide can show distinct activation patterns: Th1-and Th2-type cytokine secretion, and helper activity for antibody production without apparent cytokine secretion.FEBS Letters456: 28–33.
Izquierdo M, Downwad J, Graves JD & Cantrell D (1992) Role of protein kinase C in T-cell antigen receptor regulation of p21ras: Evidence that two p21ras regulatory pathways coexist in T cells. Mol Cell Biol 12:3305–3312.
Jaiswal AI, Dubey C, Swain SL & Croft M (1996) Regulation of CD40 ligand expression on naive CD4 T cells: A role for TCR but not co-stimulatory signals.Int Immunol8: 275–285.
Kaminogawa S (1996) Food allergy, oral tolerance and immunomodulation-their molecular and cellular mechanisms.Biosci Biotech Biochem 60:1749–1756.
Kane LP, Lin J & Weiss A (2000) Signal transduction by the TCR for antigen.Curr Opin Immunol12:242–249.
Karin M (1995) The regulation of AP-1 activity by mitogenactivated protein kinases.J Biol Chem 270: 16483–16486.
Kisielow P, Blutzmann H, Staerz UD, Steinmetz M & von Boehmer H (1988) Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes.Nature333:742–746.
Mowat AM (1987) The regulation of immune responses to dietary protein antigens.Immunol Today8:93–98.
Myung PS, Boerthe NJ & Koretzky GA (2000) Adapter proteins in lymphocyte antigen-receptor signaling.Curr Opin Immunol 12: 256–266.
Nagler-Anderson C, Bober LA, Robinson ME, Siskind GW & Thorbecke GJ (1986) Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II antigen. Proc Natl Acad Sci USA83:7443–7446.
Nusslein HG, Frosch K-H, Woith W, Lane P, Kalden JR & Manger B (1996) Increase of intracellular calcium is the essential signal for the expression of CD40 ligand.Eur J Immunol26:846–850.
Nussenblatt RB, Caspi RR, Mahdi R, Chan C-C, Roberge F, Lider O & Weiner HL (1990) Inhibition of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with s-antigen.J Immunol144:1689–1695.
Roy M, Waldschmidt T, Aruffo A, Ledbetter JA & Noelle RJ (1993) The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. J Immunol151:2497–2510.
Roy M, Aruffo A, Ledbetter J, Linsley P, Kehry M & Noelle R (1995) Studies on the interdependence of gp39 and B7 expression and function during antigen-specific immune responses.Eur J Immunol25:596–603.
Sato T, Sasahara T, Nakamura U, Osaki T, Hasegawa T, Tadakuma T, Arata Y, Kumagai Y, Katsuki M & Habu S (1994) Naive T cells can mediate delayed-type hypersensitivity response in T cell receptor transgenic mice.Eur J Immunol24: 1512–1516.
Sayegh MH, Khoury SJ, Hancock WW, Weiner HL & Carpenter CB (1992) Induction of immunity and oral tolerance with polymorphic class II major histocompatibility complex allopeptides in the rat.Proc Natl Acad Sci USA89:7762–7766.
Secrist JP, Karnitz L & Abraham RT (1991) T-cell antigen receptor ligation induces tyrosine phosphorylation of phospholipase c-γ 1. J Biol Chem 266:12135–12139.
Shida K, Hachimura S, Ametani A, Ishimori M, Ling M, Hashiguchi M, Ueda Y, Sato T, Kumagai Y, Takamizawa K, Habu S & Kaminogawa S (2000) Serum IgE response to orally ingested antigen: A novel IgE response model with allergen-specific T-cell receptor transgenic mice.J Allergy Clin Immunol105:788–795.
Taudorf E (1992) Oral immunotherapy of adults with allergic rhinoconjunctivitis: Clinical effects in birch and grass pollinosis.Dan Med Bull39:542–560.
Trentham DE, Dynesius-Trentham RA, Orav EJ, Combitchi D, Lorenzo C, Sewell KL, Hafler DA & Weiner HL (1993) Effects of oral administration of type and collagen on rheumatoid arthritis.Science261:1727–1730.
Tsien RY, Pozzan T & Rink TJ (1982)T-cell mitogens cause early changes in cytoplasmic free Ca2+ and membrane potential in lymphocytes.Nature295:68–73.
Wange RL & Samelson LE (1996)Complex complexes: Signaling at the TCR.Immunity5:197–205.
Weiner HL, Mackin GA, Matsui M, Orav EJ, Khoury SJ, Dawson DM & Hafler DA (1993) Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis.Science259: 1321–1324.
Weiner HL, Friedman A, Miller A, Khoury SJ, Al-Sabbagh A, Santos L, Sayegh M, Nussenblatt RB, Trentham DE & Hafler DA (1994) Oral tolerance: Immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens.Annu Rev Immunol12: 809–837.
Weiner HL (1994) Oral tolerance.Proc Natl Acad Sci USA91: 10762–10765.
Weiss A & Littman DR (1994) Signal transduction by lymphocyte antigen receptors.Cell 76:263–274.
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Asai, K., Hachimura, S., Toraya, T. et al. Orally tolerant CD4 T cells respond poorly to antigenic stimulation but strongly to direct stimulation of intracellular signaling pathways. Cytotechnology 36, 145–153 (2001). https://doi.org/10.1023/A:1014009328207
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DOI: https://doi.org/10.1023/A:1014009328207