The presence of CD25 on bovine WC1+ γδ T cells is positively correlated with their production of IL-10 and TGF-β, but not IFN-γ
WC1+ cells in cattle exhibit both regulatory and effector activities. However, it has not been elucidated whether they are so plastic that both activities co-exist in one cell or there are separate subpopulations of effector and regulatory cells. Since the production of IFN-γ and IL-10 seems to be related to WC1+ cells' effector and regulatory function, respectively, the main aim of this study was to determine whether those cytokines are produced by separate subpopulations of WC1+, or are co-produced by the same cells. Due to increasingly frequent emphasised role of consumption of IL-2 in the mechanism of suppressor action of mouse CD25+CD4+ T regulatory cells, expression of the receptor's α chain for interleukin 2 (CD25) on WC1+ lymphocytes has been evaluated. An average of 5.21% of WC1+ cells obtained from PBMCs of 12-month-old heifers show constitutive expression of the CD25 molecule, with CD25highWC1+ and CD25lowWC1+ cells accounting for 1.05% and 4.10% of WC1+ lymphocytes, respectively. For detection of intracellular cytokine production, PBMCs were stimulated with concanavalin A. Both IFN-γ- and IL-10-producing cells within the CD25-WC1+ and CD25+WC1+ subpopulations were mainly separate subpopulations. The average percentage of IFN-γ+IL-10-, IFN-γ-IL-10+ and IFN-γ+IL-10+ cells among CD25-WC1+ lymphocytes was 4.03%, 2.67% and 0.51%, respectively. A positive correlation was observed between the presence of the CD25 molecule on WC1+ lymphocytes and production of IL-10 and TGF-β, because the average percentage of IFN-γ-IL-10+ and IFN-γ+IL-10+ among CD25+WC1+ lymphocytes was 3 and 4.5 times higher as compared to the corresponding cells in the CD25-WC1+ subpopulation, whereas the percentage of IFN-γ+IL-10- cells in both the subpopulations was not significantly different. The percentage of TGF-β+ cells within the CD25+WC1+ subpopulation was 2.72 times as high as that of CD25-WC1+ lymphocytes. Therefore, with respect to the production of IFN-γ, IL-10 and TGF-β, CD25+WC1+ lymphocytes turn out to have a more suppressor profile than CD25-WC1+.
Amadori M, Archetti IL, Verardi R, Berneri C (1995) Role of a distinct population of bovine γδ T cells in the immune response to viral agents. Viral Immunol 8: 81-91.
Brown WC, Davis WC, Choi SH, Dobbelaere DA, Splitter GA (1994) Functional and phenotypic characterization of WC1+ γδ T-cells isolated from Babesia bovis-stimulated T cell lines. Cell Immunol 153: 9-27.
Bucy RP, Chen CL, Cooper MD (1989) Tissue localization and CD8 accessory molecule expression of T γδ cells in humans. J Immunol 142: 3045-3049.
Collins RA, Sopp P, Gelder KI, Morrison WI, Howard CJ (1996) Bovine γδ TcR+ T lymphocytes are stimulated to proliferate by autologous Theileria annulata-infected cells in the presence of interleukin-2. Scand J Immunol 44: 444-452.
Collins RA, Werling D, Duggan SE, Bland AP, Parsons KR, Howard CJ (1998) γδ T cells present antigen to CD4+ αβ T cells. J Leukoc Biol 63: 707-714.
Fikri Y, Denis O, Pastoret P, Nyabenda J (2001) Purified bovine WC1+ γδ T lymphocytes are activated by staphylococcal enterotoxins and toxic shock syndrome toxin-1 superantigens: proliferation response, TCR Vγ profile and cytokines expression. Immunol Lett 77: 87-95.
Hanby-Flarida MD, Trask OJ, Yang TJ, Baldwin CL (1996) Modulation of WC1, a lineage-specific cell surface molecule of γδ T cells augments cellular proliferation. Immunology 88: 116-123.
Hedges JF, Cockrell D, Jackiw L, Meissner N, Jutila MA (2003) Differential mRNA expression in circulating γδ T lymphocyte subsets defines unique tissue-specific functions. J Leukoc Biol 73: 306-314.
Hoek A, Rutten VP, Kool J, Arkesteijn GJ, Bouwstra RJ, Van Rhijn I, Koets AP (2009) Subpopulations of bovine WC1+ γδ T cells rather than CD4+CD25highFoxp3+ T cells act as immune regulatory cells ex vivo. Vet Res 40: 06.
Itohara S, Nakanishi N, Kanagawa O, Kubo R, Tonegawa S (1989) Monoclonal antibodies specific to native murine T-cell receptor γδ: analysis of γδ T cells during thymic ontogeny and in peripheral lymphoid organs. Proc Natl Acad Sci USA 86: 5094-5098.
Kemp K, Kemp M, Kharazmi A, Ismail A, Kurtzhals JA, Hviid L, Theander TG (1999) Leishmania specific T cells expressing interferon-gamma (IFN-γ) and IL-10 upon activation are expanded in individuals cured of visceral leishmaniasis. Clin Exp Immunol 116: 500-504.
Lahmers KK, Norimine J, Abrahamsen MS, Palmer GH, Brown WC (2005) The CD4+ T cell immunodominant Anaplasma marginale major surface protein 2 stimulates γδ T cell clones that express unique T cell receptors. J Leukoc Biol 77: 199-208.
Meissner N, Radke J, Hedges JF, White M, Behnke M, Bertolino S, Abrahamsen M, Jutila MA (2003) Serial analysis of gene expression in circulating γδ T cell subsets defines distinct immunoregulatory phenotypes and unexpected gene expression profiles. J Immunol 170: 356-364.
Maślanka T (2010) CD4+ regulatory cells. Med Weter 66: 827-832.
Maślanka T (2011) CD8+ regulatory cells. Med Weter 67: 91-96.
Maślanka T, Jaroszewski JJ (2011) In vitro effects of dexamethasone on bovine CD25+CD4+ and CD25-CD4+ cells. Res Vet Sci doi: 10.1016/j.rvsc.2012.01.018.
McNally A, Hill GR, Sparwasser T, Thomas R, Steptoe RJ (2011) CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis. Proc Natl Acad Sci USA 108: 7529-7534.
Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ (2007) CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 8: 1353-1362.
Pollock JM, Welsh MD (2002) The WC1+ γδ T-cell population in cattle: a possible role in resistance to intracellular infection. Vet Immunol Immunopathol 89: 105-114.
Price SJ, Sopp P, Howard CJ, Hope JC (2007) Workshop cluster 1+ γδ T-cell receptor+ T cells from calves express high levels of interferon-γ in response to stimulation with interleukin-12 and -18. Immunology 120: 57-65.
Rogers AN, VanBuren DG, Hedblom EE, Tilahun ME, Telfer JC, Baldwin CL (2005a) γδ T cell function varies with the expressed WC1 coreceptor. J Immunol 174: 3386-3393.
Rogers AN, VanBuren DG, Hedblom EE, Tilahun ME, Telfer JC, Baldwin CL (2005b) Function of ruminant γδ T cells is defined by WC1.1 or WC1.2 isoform expression. Vet Immunol Immunopathol 108: 211-217.
Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK (2001) Type 1 T regulatory cells. Immunol Rev 182: 68-79.
Sandbulte MR, Roth JA (2002) T-cell populations responsive to bovine respiratory syncytial virus in seronegative calves. Vet Immunol Immunopathol 84: 111-123.
Sawitzki B, Kingsley CI, Oliveira V, Karim M, Herber M, Wood KJ (2005) IFN-γ production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med 201: 1925-1935.
Smyth AJ, Welsh MD, Girvin RM, Pollock JM (2001) In vitro responsiveness of γδ T cells from Mycobacterium bovis-infected cattle to mycobacterial antigens: predominant involvement of WC1+ cells. Infect Immun 69: 89-96.
Takamatsu HH, Kirkham PA, Parkhouse RM (1997) A γδ T cell specific surface receptor (WC1) signaling G0/G1 cell cycle arrest. Eur J Immunol 27: 105-110.
Tang Q, Bluestone JA (2008) The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol 9: 239-244.
Toka FN, Kenney MA, Golde WT (2011) Rapid and transient activation of γδ T cells to IFN-γ production, NK cell-like killing, and antigen processing during acute virus infection. J Immunol 186: 4853-4861.
Welsh MD, Kennedy HE, Smyth AJ, Girvin RM, Andersen P, Pollock JM (2002) Responses of bovine WC1+ γδ T cells to protein and nonprotein antigens of Mycobacterium bovis. Infect Immun 70: 6114-6120.
White AM, Blumerman S, Naiman B, Baldwin CL (2002) Expression of the bovine high affinity IL-12 receptor β2. Vet Immunol Immunopathol 84: 127-142.
Wilson RA, Zolnai A, Rudas P, Frenyo LV (1996) T-cell subsets in blood and lymphoid tissues obtained from fetal calves, maturing calves, and adult bovine. Vet Immunol Immunopathol 53: 49-60.
Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DA (2009) The development and function of regulatory T cells. Cell Mol Life Sci 66: 2603-2622.
Wyatt CR, Madruga C, Cluff C, Parish S, Hamilton MJ, Goff W, Davis WC (1994) Differential distribution of γδ T-cell receptor lymphocyte subpopulations in blood and spleen of young and adult cattle. Vet Immunol Immunopathol 40: 187-199.