• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. Feb 1, 1995; 181(2): 713–721.
PMCID: PMC2191880

T cell genetic background determines default T helper phenotype development in vitro

Abstract

A host's ability to resist certain pathogens such as Leishmania major can depend upon the phenotype of T helper (Th) subset that develops. Different murine genetic backgrounds are known to significantly alter the direction of Th subset development, although the cellular basis of this influence is poorly understood. To examine the basis of this effect we used an in vitro alpha/beta-T cell receptor (TCR) transgenic system for analysis of Th phenotype development. To control for TCR usage, we derived the DO11.10 alpha/beta-TCR transgene in several genetic backgrounds. Our findings suggest that the effects of genetic background on Th phenotype development reside within the T cell, and not the antigen-presenting cell compartment. Transgenic T cells from both the B10.D2 and BALB/c backgrounds showed development toward either the Th1 or Th2 phenotype under the strong directing influence of interleukin (IL) 12 and IL4, respectively. However, when T cells were activated in vitro under neutral conditions in which exogenous cytokines were not added, B10.D2-derived T cells acquired a significantly stronger Th1 phenotype than T cells from the BALB/c background, correspondent with in vivo Th responses to Leishmania in these strains. Importantly, these cytokine differences resulted in distinct functional properties, because B10.D2- but not BALB/c-derived T cells could induce macrophage production of nitric oxide, an important antimicrobial factor. Thus, the genetically determined default Th phenotype development observed in vitro may correspond to in vivo Th subset responses for pathogens such as Leishmania which do not initiate strong Th phenotype-directing signals.

Full Text

The Full Text of this article is available as a PDF (902K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed]
  • Bottomly K. A functional dichotomy in CD4+ T lymphocytes. Immunol Today. 1988 Sep;9(9):268–274. [PubMed]
  • Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. [PubMed]
  • Scott P, Kaufmann SH. The role of T-cell subsets and cytokines in the regulation of infection. Immunol Today. 1991 Oct;12(10):346–348. [PubMed]
  • Sher A, Coffman RL. Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annu Rev Immunol. 1992;10:385–409. [PubMed]
  • Howard JG. Immunological regulation and control of experimental leishmaniasis. Int Rev Exp Pathol. 1986;28:79–116. [PubMed]
  • Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. [PMC free article] [PubMed]
  • Scott P, Natovitz P, Coffman RL, Pearce E, Sher A. Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. J Exp Med. 1988 Nov 1;168(5):1675–1684. [PMC free article] [PubMed]
  • Locksley RM, Scott P. Helper T-cell subsets in mouse leishmaniasis: induction, expansion and effector function. Immunol Today. 1991 Mar;12(3):A58–A61. [PubMed]
  • Heinzel FP, Schoenhaut DS, Rerko RM, Rosser LE, Gately MK. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. [PMC free article] [PubMed]
  • Sypek JP, Chung CL, Mayor SE, Subramanyam JM, Goldman SJ, Sieburth DS, Wolf SF, Schaub RG. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993 Jun 1;177(6):1797–1802. [PMC free article] [PubMed]
  • Sadick MD, Heinzel FP, Holaday BJ, Pu RT, Dawkins RS, Locksley RM. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990 Jan 1;171(1):115–127. [PMC free article] [PubMed]
  • Belosevic M, Finbloom DS, Van Der Meide PH, Slayter MV, Nacy CA. Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol. 1989 Jul 1;143(1):266–274. [PubMed]
  • Scott P. IFN-gamma modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J Immunol. 1991 Nov 1;147(9):3149–3155. [PubMed]
  • Bretscher PA, Wei G, Menon JN, Bielefeldt-Ohmann H. Establishment of stable, cell-mediated immunity that makes "susceptible" mice resistant to Leishmania major. Science. 1992 Jul 24;257(5069):539–542. [PubMed]
  • Titus RG, Ceredig R, Cerottini JC, Louis JA. Therapeutic effect of anti-L3T4 monoclonal antibody GK1.5 on cutaneous leishmaniasis in genetically-susceptible BALB/c mice. J Immunol. 1985 Sep;135(3):2108–2114. [PubMed]
  • Howard JG, Hale C, Liew FY. Immunological regulation of experimental cutaneous leishmaniasis. IV. Prophylactic effect of sublethal irradiation as a result of abrogation of suppressor T cell generation in mice genetically susceptible to Leishmania tropica. J Exp Med. 1981 Mar 1;153(3):557–568. [PMC free article] [PubMed]
  • Chatelain R, Varkila K, Coffman RL. IL-4 induces a Th2 response in Leishmania major-infected mice. J Immunol. 1992 Feb 15;148(4):1182–1187. [PubMed]
  • Le Gros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990 Sep 1;172(3):921–929. [PMC free article] [PubMed]
  • Swain SL, Weinberg AD, English M, Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990 Dec 1;145(11):3796–3806. [PubMed]
  • Swain SL, Huston G, Tonkonogy S, Weinberg A. Transforming growth factor-beta and IL-4 cause helper T cell precursors to develop into distinct effector helper cells that differ in lymphokine secretion pattern and cell surface phenotype. J Immunol. 1991 Nov 1;147(9):2991–3000. [PubMed]
  • Hsieh CS, Heimberger AB, Gold JS, O'Garra A, Murphy KM. Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6065–6069. [PMC free article] [PubMed]
  • Seder RA, Paul WE, Davis MM, Fazekas de St Groth B. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med. 1992 Oct 1;176(4):1091–1098. [PMC free article] [PubMed]
  • Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. [PubMed]
  • Maggi E, Parronchi P, Manetti R, Simonelli C, Piccinni MP, Rugiu FS, De Carli M, Ricci M, Romagnani S. Reciprocal regulatory effects of IFN-gamma and IL-4 on the in vitro development of human Th1 and Th2 clones. J Immunol. 1992 Apr 1;148(7):2142–2147. [PubMed]
  • Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. [PMC free article] [PubMed]
  • Seder RA, Gazzinelli R, Sher A, Paul WE. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10188–10192. [PMC free article] [PubMed]
  • Reiner SL, Zheng S, Wang ZE, Stowring L, Locksley RM. Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection. J Exp Med. 1994 Feb 1;179(2):447–456. [PMC free article] [PubMed]
  • Scharton TM, Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J Exp Med. 1993 Aug 1;178(2):567–577. [PMC free article] [PubMed]
  • Macatonia SE, Hsieh CS, Murphy KM, O'Garra A. Dendritic cells and macrophages are required for Th1 development of CD4+ T cells from alpha beta TCR transgenic mice: IL-12 substitution for macrophages to stimulate IFN-gamma production is IFN-gamma-dependent. Int Immunol. 1993 Sep;5(9):1119–1128. [PubMed]
  • Tripp CS, Wolf SF, Unanue ER. Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3725–3729. [PMC free article] [PubMed]
  • Murphy KM, Heimberger AB, Loh DY. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science. 1990 Dec 21;250(4988):1720–1723. [PubMed]
  • Marrack P, Shimonkevitz R, Hannum C, Haskins K, Kappler J. The major histocompatibility complex-restricted antigen receptor on T cells. IV. An antiidiotypic antibody predicts both antigen and I-specificity. J Exp Med. 1983 Nov 1;158(5):1635–1646. [PMC free article] [PubMed]
  • Ohara J, Paul WE. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. [PubMed]
  • Wherry JC, Schreiber RD, Unanue ER. Regulation of gamma interferon production by natural killer cells in scid mice: roles of tumor necrosis factor and bacterial stimuli. Infect Immun. 1991 May;59(5):1709–1715. [PMC free article] [PubMed]
  • Gross JA, Callas E, Allison JP. Identification and distribution of the costimulatory receptor CD28 in the mouse. J Immunol. 1992 Jul 15;149(2):380–388. [PubMed]
  • Sarmiento M, Glasebrook AL, Fitch FW. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed]
  • Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982 Oct;126(1):131–138. [PubMed]
  • Hsieh CS, Macatonia SE, O'Garra A, Murphy KM. Pathogen-induced Th1 phenotype development in CD4+ alpha beta-TCR transgenic T cells is macrophage dependent. Int Immunol. 1993 Apr;5(4):371–382. [PubMed]
  • Sha WC, Nelson CA, Newberry RD, Pullen JK, Pease LR, Russell JH, Loh DY. Positive selection of transgenic receptor-bearing thymocytes by Kb antigen is altered by Kb mutations that involve peptide binding. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6186–6190. [PMC free article] [PubMed]
  • Lee NA, Loh DY, Lacy E. CD8 surface levels alter the fate of alpha/beta T cell receptor-expressing thymocytes in transgenic mice. J Exp Med. 1992 Apr 1;175(4):1013–1025. [PMC free article] [PubMed]
  • Mitchell GF. Murine cutaneous leishmaniasis: resistance in reconstituted nude mice and several F1 hybrids infected with Leishmania tropica major. J Immunogenet. 1983 Oct;10(5):395–412. [PubMed]
  • Green SJ, Meltzer MS, Hibbs JB, Jr, Nacy CA. Activated macrophages destroy intracellular Leishmania major amastigotes by an L-arginine-dependent killing mechanism. J Immunol. 1990 Jan 1;144(1):278–283. [PubMed]
  • Liew FY, Millott S, Parkinson C, Palmer RM, Moncada S. Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. J Immunol. 1990 Jun 15;144(12):4794–4797. [PubMed]
  • Sher A, Gazzinelli RT, Oswald IP, Clerici M, Kullberg M, Pearce EJ, Berzofsky JA, Mosmann TR, James SL, Morse HC., 3rd Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. Immunol Rev. 1992 Jun;127:183–204. [PubMed]
  • Murphy EE, Terres G, Macatonia SE, Hsieh CS, Mattson J, Lanier L, Wysocka M, Trinchieri G, Murphy K, O'Garra A. B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation. J Exp Med. 1994 Jul 1;180(1):223–231. [PMC free article] [PubMed]
  • Kubin M, Kamoun M, Trinchieri G. Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J Exp Med. 1994 Jul 1;180(1):211–222. [PMC free article] [PubMed]
  • Scott B, Liblau R, Degermann S, Marconi LA, Ogata L, Caton AJ, McDevitt HO, Lo D. A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity. Immunity. 1994 Apr;1(1):73–83. [PubMed]
  • Else KJ, Finkelman FD, Maliszewski CR, Grencis RK. Cytokine-mediated regulation of chronic intestinal helminth infection. J Exp Med. 1994 Jan 1;179(1):347–351. [PMC free article] [PubMed]
  • Howard JG, Hale C, Chan-Liew WL. Immunological regulation of experimental cutaneous leishmaniasis. 1. Immunogenetic aspects of susceptibility to Leishmania tropica in mice. Parasite Immunol. 1980 Winter;2(4):303–314. [PubMed]
  • Romani L, Mencacci A, Cenci E, Spaccapelo R, Mosci P, Puccetti P, Bistoni F. CD4+ subset expression in murine candidiasis. Th responses correlate directly with genetically determined susceptibility or vaccine-induced resistance. J Immunol. 1993 Feb 1;150(3):925–931. [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...