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Science 16 February 1996:
Vol. 271. no. 5251, pp. 984 - 987
DOI: 10.1126/science.271.5251.984
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Reports

Genetic Susceptibility to Leishmania: IL-12 Responsiveness in TH1 Cell Development

Mehmet L. Güler,  James D. Gorham,  Chyi-Song Hsieh,  Aaron J. Mackey,  Robert G. Steen,  William F. Dietrich,  Kenneth M. Murphy (1)

The genetic background of T lymphocytes influences development of the T helper (TH) phenotype, resulting in either resistance or susceptibility of certain mouse strains to pathogens such as Leishmania major. With an in vitro model system, a difference in maintenance of responsiveness of T cells to interleukin-12 (IL-12) was detected between BALB/c and B10.D2 mice. Although naïve T cells from both strains initially responded to IL-12, BALB/c T cells lost IL-12 responsiveness after stimulation with antigen in vitro, even when cocultured with B10.D2 T cells. Thus, susceptibility of BALB/c mice to infection with L. major may derive from the loss of the ability to generate IL-12-induced TH1 responses rather than from an IL-4-induced TH2 response.


M. L. Güler, J. D. Gorham, C.-S. Hsieh, A. J. Mackey, K. M. Murphy, Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
R. G. Steen and W. F. Dietrich, Whitehead Institute Genome Center, Cambridge, MA 02139, USA.
(1) To whom correspondence should be addressed.


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Cutting Edge: Mice Defective in Fas Are Highly Susceptible to Leishmania major Infection Despite Elevated IL-12 Synthesis, Strong Th1 Responses, and Enhanced Nitric Oxide Production.
F.-P. Huang, D. Xu, E.-O Esfandiari, W. Sands, X.-q. Wei, and F. Y. Liew (1998)
J. Immunol. 160, 4143-4147
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Active Wegener's Granulomatosis Is Associated with HLA-DR+ CD4+ T Cells Exhibiting an Unbalanced Th1-Type T Cell Cytokine Pattern: Reversal with IL-10.
B. R. Ludviksson, M. C. Sneller, K. S. Chua, C. Talar-Williams, C. A. Langford, R. O. Ehrhardt, A. S. Fauci, and W. Strober (1998)
J. Immunol. 160, 3602-3609
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IL-1{alpha} and TNF-{alpha} Are Required for IL-12-Induced Development of Th1 Cells Producing High Levels of IFN-{gamma} in BALB/c But Not C57BL/6 Mice.
K. Shibuya, D. Robinson, F. Zonin, S. B. Hartley, S. E. Macatonia, C. Somoza, C. A. Hunter, K. M. Murphy, and A. O'Garra (1998)
J. Immunol. 160, 1708-1716
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Control of Leishmania major by a Monoclonal {alpha}{beta} T Cell Repertoire.
S. L. Reiner, D. J. Fowell, N. H. Moskowitz, K. Swier, D. R. Brown, C. R. Brown, C. W. Turck, P. A. Scott2, N. Killeen, and R. M. Locksley3 (1998)
J. Immunol. 160, 884-889
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IL-18 (IFN-{gamma}-Inducing Factor) Regulates Early Cytokine Production in, and Promotes Resolution of, Bacterial Infection in Mice.
E. Bohn, A. Sing, R. Zumbihl, C. Bielfeldt, H. Okamura, M. Kurimoto, J. Heesemann, and I. B. Autenrieth (1998)
J. Immunol. 160, 299-307
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Interferon (IFN) Consensus Sequence-binding Protein, a Transcription Factor of the IFN Regulatory Factor Family, Regulates Immune Responses In Vivo through Control of Interleukin 12 Expression.
N. A. Giese, L. Gabriele, T. M. Doherty, D. M. Klinman, L. Tadesse-Heath, C. Contursi, S. L. Epstein, and H. C. Morse III (1997)
J. Exp. Med. 186, 1535-1546
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Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses.
Z. Shi, A. E. Wakil, and D. C. Rockey (1997)
PNAS 94, 10663-10668
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Myelin Basic Protein-specific T Helper 2 (Th2) Cells Cause Experimental Autoimmune Encephalomyelitis in Immunodeficient Hosts Rather than Protect Them from the Disease.
J. J. Lafaille, F. V. d. Keere, A. L. Hsu, J. L. Baron, W. Haas, C. S. Raine, and S. Tonegawa (1997)
J. Exp. Med. 186, 307-312
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Interleukin 12 (IL-12) Is Crucial to the Development of Protective Immunity in Mice Intravenously Infected with Mycobacterium tuberculosis.
A. M. Cooper, J. Magram, J. Ferrante, and I. M. Orme (1997)
J. Exp. Med. 186, 39-45
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Chronic Tumor Necrosis Factor Alters T Cell Responses by Attenuating T Cell Receptor Signaling.
A. P. Cope, R. S. Liblau, X.-D. Yang, M. Congia, C. Laudanna, R. D. Schreiber, L. Probert, G. Kollias, and H. O. McDevitt (1997)
J. Exp. Med. 185, 1573-1584
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Regulation of the Interleukin (IL)-12R {beta}2 Subunit Expression in Developing T Helper 1 (Th1) and Th2 Cells.
S. J. Szabo, A. S. Dighe, U. Gubler, and K. M. Murphy (1997)
J. Exp. Med. 185, 817-824
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Induction of Apoptosis and T Helper 2 (Th2) Responses Correlates with Peptide Affinity for the Major Histocompatibility Complex in Self-reactive T Cell Receptor Transgenic Mice.
C.I. Pearson, W. van Ewijk, and H.O. McDevitt (1997)
J. Exp. Med. 185, 583-600
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Novel Genetic Regulation of T Helper 1 (Th1)/Th2 Cytokine Production and Encephalitogenicity in Inbred Mouse Strains.
I. M. Conboy, R. H. DeKruyff, K. M. Tate, Z. A. Cao, T. A. Moore, D. T. Umetsu, and P. P. Jones (1997)
J. Exp. Med. 185, 439-452
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Resistance to Leishmania major Induced by Tolerance to a Single Antigen.
V. Julia, M. Rassoulzadegan, and N. Glaichenhaus (1996)
Science 274, 421-423
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