PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jexpmedHomeEditorsContactInstructions for Authors
 
J Exp Med. 1996 October 1; 184(4): 1295–1304.
PMCID: PMC2192844

Beta 2-microglobulin-dependent NK1.1+ T cells are not essential for T helper cell 2 immune responses

Abstract

A number of investigations have established the critical role of interleukin 4 (IL-4) in mediating the development of T helper (Th)2 effector cells in vitro and in vivo. Despite intensive study, the origin of the IL-4 required for Th2 priming and differentiation remains unclear. Natural killer (NK)1.1+ alpha/beta T cell receptor+ T(NT) cells, a unique lineage of cells capable of producing large amounts of IL-4 after activation in vivo, are important candidates for directing Th2 priming. These cells are selected by the nonpolymorphic major histocompatibility complex (MHC) class I molecule, CD1, and are deficient in beta 2-microglobulin (beta 2m)-null mice. We used beta 2m- deficient mice on both BALB/c and C57BL/6 backgrounds to examine their capacity to mount Th2 immune responses after challenge with a number of well-characterized antigens administered by a variety of routes. As assessed by immunization with protein antigen, infection with Leishmania major, embolization with eggs of Schistosoma mansoni, intestinal infection with Nippostrongylus brasiliensis, or induction of airway hyperreactivity to aerosolized antigen, beta 2m-deficient mice developed functional type 2 immune responses that were not substantially different than those in wild-type mice. Production of IL- 4 and the generation of immunoglobulin E (IgE) and eosinophil responses were preserved as assessed by a variety of assays. Collectively, these results present a comprehensive analysis of type 2 immune responses in beta 2m-deficient mice, and indicate that beta 2m-dependent NT cells are not required for Th2 development in vivo.

Full Text

The Full Text of this article is available as a PDF (1.0M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Kearney ER, Pape KA, Loh DY, Jenkins MK. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity. 1994 Jul;1(4):327–339. [PubMed]
  • Constant S, Pfeiffer C, Woodard A, Pasqualini T, Bottomly K. Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells. J Exp Med. 1995 Nov 1;182(5):1591–1596. [PMC free article] [PubMed]
  • Hosken NA, Shibuya K, Heath AW, Murphy KM, O'Garra A. The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model. J Exp Med. 1995 Nov 1;182(5):1579–1584. [PMC free article] [PubMed]
  • Thompson CB. Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell differentiation? Cell. 1995 Jun 30;81(7):979–982. [PubMed]
  • Murray JS, Madri J, Tite J, Carding SR, Bottomly K. MHC control of CD4+ T cell subset activation. J Exp Med. 1989 Dec 1;170(6):2135–2140. [PMC free article] [PubMed]
  • Pfeiffer C, Stein J, Southwood S, Ketelaar H, Sette A, Bottomly K. Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med. 1995 Apr 1;181(4):1569–1574. [PMC free article] [PubMed]
  • Hsieh CS, Macatonia SE, O'Garra A, Murphy KM. T cell genetic background determines default T helper phenotype development in vitro. J Exp Med. 1995 Feb 1;181(2):713–721. [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]
  • 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]
  • 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]
  • 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]
  • 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]
  • Heinzel FP, Rerko RM, Ahmed F, Pearlman E. Endogenous IL-12 is required for control of Th2 cytokine responses capable of exacerbating leishmaniasis in normally resistant mice. J Immunol. 1995 Jul 15;155(2):730–739. [PubMed]
  • Magram J, Connaughton SE, Warrier RR, Carvajal DM, Wu CY, Ferrante J, Stewart C, Sarmiento U, Faherty DA, Gately MK. IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. Immunity. 1996 May;4(5):471–481. [PubMed]
  • Wang ZE, Reiner SL, Zheng S, Dalton DK, Locksley RM. CD4+ effector cells default to the Th2 pathway in interferon gamma-deficient mice infected with Leishmania major. J Exp Med. 1994 Apr 1;179(4):1367–1371. [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]
  • 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]
  • Kühn R, Rajewsky K, Müller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991 Nov 1;254(5032):707–710. [PubMed]
  • Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T, Akira S. Essential role of Stat6 in IL-4 signalling. Nature. 1996 Apr 18;380(6575):627–630. [PubMed]
  • Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA, et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 1996 Apr 18;380(6575):630–633. [PubMed]
  • Schmitz J, Thiel A, Kühn R, Rajewsky K, Müller W, Assenmacher M, Radbruch A. Induction of interleukin 4 (IL-4) expression in T helper (Th) cells is not dependent on IL-4 from non-Th cells. J Exp Med. 1994 Apr 1;179(4):1349–1353. [PMC free article] [PubMed]
  • Seder RA, Paul WE, Dvorak AM, Sharkis SJ, Kagey-Sobotka A, Niv Y, Finkelman FD, Barbieri SA, Galli SJ, Plaut M. Mouse splenic and bone marrow cell populations that express high-affinity Fc epsilon receptors and produce interleukin 4 are highly enriched in basophils. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2835–2839. [PubMed]
  • Bradding P, Feather IH, Howarth PH, Mueller R, Roberts JA, Britten K, Bews JP, Hunt TC, Okayama Y, Heusser CH, et al. Interleukin 4 is localized to and released by human mast cells. J Exp Med. 1992 Nov 1;176(5):1381–1386. [PMC free article] [PubMed]
  • Moqbel R, Ying S, Barkans J, Newman TM, Kimmitt P, Wakelin M, Taborda-Barata L, Meng Q, Corrigan CJ, Durham SR, et al. Identification of messenger RNA for IL-4 in human eosinophils with granule localization and release of the translated product. J Immunol. 1995 Nov 15;155(10):4939–4947. [PubMed]
  • Yoshimoto T, Paul WE. CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3. J Exp Med. 1994 Apr 1;179(4):1285–1295. [PMC free article] [PubMed]
  • Lantz O, Bendelac A. An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans. J Exp Med. 1994 Sep 1;180(3):1097–1106. [PMC free article] [PubMed]
  • Coles MC, Raulet DH. Class I dependence of the development of CD4+ CD8- NK1.1+ thymocytes. J Exp Med. 1994 Jul 1;180(1):395–399. [PMC free article] [PubMed]
  • Bendelac A. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J Exp Med. 1995 Dec 1;182(6):2091–2096. [PMC free article] [PubMed]
  • Brutkiewicz RR, Bennink JR, Yewdell JW, Bendelac A. TAP-independent, beta 2-microglobulin-dependent surface expression of functional mouse CD1.1. J Exp Med. 1995 Dec 1;182(6):1913–1919. [PMC free article] [PubMed]
  • Bendelac A, Killeen N, Littman DR, Schwartz RH. A subset of CD4+ thymocytes selected by MHC class I molecules. Science. 1994 Mar 25;263(5154):1774–1778. [PubMed]
  • Yoshimoto T, Bendelac A, Watson C, Hu-Li J, Paul WE. Role of NK1.1+ T cells in a TH2 response and in immunoglobulin E production. Science. 1995 Dec 15;270(5243):1845–1847. [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]
  • Wynn TA, Eltoum I, Cheever AW, Lewis FA, Gause WC, Sher A. Analysis of cytokine mRNA expression during primary granuloma formation induced by eggs of Schistosoma mansoni. J Immunol. 1993 Aug 1;151(3):1430–1440. [PubMed]
  • Wynn TA, Eltoum I, Oswald IP, Cheever AW, Sher A. Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology. J Exp Med. 1994 May 1;179(5):1551–1561. [PMC free article] [PubMed]
  • LITT M. Studies in experimental eosinophilia. V. Eosinophils in lynph nodes of guinea pigs following primary antigenic stimulation. Am J Pathol. 1963 May;42:529–549. [PubMed]
  • Corry DB, Folkesson HG, Warnock ML, Erle DJ, Matthay MA, Wiener-Kronish JP, Locksley RM. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J Exp Med. 1996 Jan 1;183(1):109–117. [PMC free article] [PubMed]
  • Peat JK, Unger WR, Combe D. Measuring changes in logarithmic data, with special reference to bronchial responsiveness. J Clin Epidemiol. 1994 Oct;47(10):1099–1108. [PubMed]
  • Katona IM, Urban JF, Jr, Finkelman FD. The role of L3T4+ and Lyt-2+ T cells in the IgE response and immunity to Nippostrongylus brasiliensis. J Immunol. 1988 May 1;140(9):3206–3211. [PubMed]
  • Reiner SL, Zheng S, Corry DB, Locksley RM. Constructing polycompetitor cDNAs for quantitative PCR. J Immunol Methods. 1993 Sep 27;165(1):37–46. [PubMed]
  • Gross A, Ben-Sasson SZ, Paul WE. Anti-IL-4 diminishes in vivo priming for antigen-specific IL-4 production by T cells. J Immunol. 1993 Mar 15;150(6):2112–2120. [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]
  • Urban JF, Jr, Maliszewski CR, Madden KB, Katona IM, Finkelman FD. IL-4 treatment can cure established gastrointestinal nematode infections in immunocompetent and immunodeficient mice. J Immunol. 1995 May 1;154(9):4675–4684. [PubMed]
  • Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong ST, Brenner MB. Recognition of a lipid antigen by CD1-restricted alpha beta+ T cells. Nature. 1994 Dec 15;372(6507):691–694. [PubMed]
  • Sieling PA, Chatterjee D, Porcelli SA, Prigozy TI, Mazzaccaro RJ, Soriano T, Bloom BR, Brenner MB, Kronenberg M, Brennan PJ, et al. CD1-restricted T cell recognition of microbial lipoglycan antigens. Science. 1995 Jul 14;269(5221):227–230. [PubMed]
  • Balk S. MHC evolution. Nature. 1995 Apr 6;374(6522):505–506. [PubMed]
  • Yoshimoto T, Bendelac A, Hu-Li J, Paul WE. Defective IgE production by SJL mice is linked to the absence of CD4+, NK1.1+ T cells that promptly produce interleukin 4. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11931–11934. [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]
  • Cheever AW, Williams ME, Wynn TA, Finkelman FD, Seder RA, Cox TM, Hieny S, Caspar P, Sher A. Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis. J Immunol. 1994 Jul 15;153(2):753–759. [PubMed]
  • Sher A, Coffman RL, Hieny S, Cheever AW. Ablation of eosinophil and IgE responses with anti-IL-5 or anti-IL-4 antibodies fails to affect immunity against Schistosoma mansoni in the mouse. J Immunol. 1990 Dec 1;145(11):3911–3916. [PubMed]
  • Finkelman FD, Holmes J, Katona IM, Urban JF, Jr, Beckmann MP, Park LS, Schooley KA, Coffman RL, Mosmann TR, Paul WE. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8:303–333. [PubMed]
  • Launois P, Ohteki T, Swihart K, MacDonald HR, Louis JA. In susceptible mice, Leishmania major induce very rapid interleukin-4 production by CD4+ T cells which are NK1.1-. Eur J Immunol. 1995 Dec;25(12):3298–3307. [PubMed]
  • Guery JC, Galbiati F, Smiroldo S, Adorini L. Selective development of T helper (Th)2 cells induced by continuous administration of low dose soluble proteins to normal and beta(2)-microglobulin-deficient BALB/c mice. J Exp Med. 1996 Feb 1;183(2):485–497. [PMC free article] [PubMed]
  • Cardell S, Tangri S, Chan S, Kronenberg M, Benoist C, Mathis D. CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice. J Exp Med. 1995 Oct 1;182(4):993–1004. [PMC free article] [PubMed]
  • Balk SP, Burke S, Polischuk JE, Frantz ME, Yang L, Porcelli S, Colgan SP, Blumberg RS. Beta 2-microglobulin-independent MHC class Ib molecule expressed by human intestinal epithelium. Science. 1994 Jul 8;265(5169):259–262. [PubMed]
  • Williams ME, Kullberg MC, Barbieri S, Caspar P, Berzofsky JA, Seder RA, Sher A. Fc epsilon receptor-positive cells are a major source of antigen-induced interleukin-4 in spleens of mice infected with Schistosoma mansoni. Eur J Immunol. 1993 Aug;23(8):1910–1916. [PubMed]
  • Conrad DH, Ben-Sasson SZ, Le Gros G, Finkelman FD, Paul WE. Infection with Nippostrongylus brasiliensis or injection of anti-IgD antibodies markedly enhances Fc-receptor-mediated interleukin 4 production by non-B, non-T cells. J Exp Med. 1990 May 1;171(5):1497–1508. [PMC free article] [PubMed]
  • Sabin EA, Pearce EJ. Early IL-4 production by non-CD4+ cells at the site of antigen deposition predicts the development of a T helper 2 cell response to Schistosoma mansoni eggs. J Immunol. 1995 Nov 15;155(10):4844–4853. [PubMed]
  • Ferrick DA, Schrenzel MD, Mulvania T, Hsieh B, Ferlin WG, Lepper H. Differential production of interferon-gamma and interleukin-4 in response to Th1- and Th2-stimulating pathogens by gamma delta T cells in vivo. Nature. 1995 Jan 19;373(6511):255–257. [PubMed]
  • Wershil BK, Theodos CM, Galli SJ, Titus RG. Mast cells augment lesion size and persistence during experimental Leishmania major infection in the mouse. J Immunol. 1994 May 1;152(9):4563–4571. [PubMed]

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