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Infection and Immunity, July 2000, p. 4264-4273, Vol. 68, No. 7
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Ineffective Cellular Immune Response Associated with T-Cell Apoptosis in Susceptible Mycobacterium bovis BCG-Infected Mice

Laurent Kremer,1,dagger Jérôme Estaquier,2,* Isabelle Wolowczuk,3 Franck Biet,1 Jean-Claude Ameisen,2 and Camille Locht1

INSERM U4471 and CNRS UMR 8527,3 Institut de Biologie de Lille, Institut Pasteur de Lille, Lille, and INSERM E9922, Groupe Hospitalier Bichat-Claude Bernard, Paris,2 France

Received 13 September 1999/Returned for modification 1 November 1999/Accepted 7 March 2000

It has previously been reported that inhibition of delayed-type hypersensitivity-mediating functions of T cells during mycobacterial infection in mice is haplotype dependent. In the present study, we show that Mycobacterium bovis BCG infection induced, in susceptible C57BL/6 and BALB/c mice but not in resistant C3H/HeJ and DBA/2 mice, an important splenomegaly. An in vitro defect in T-cell proliferation in response to T-cell receptor (TCR) stimulation with mitogens or anti-CD3 antibodies was associated with enhanced levels of CD4+ and CD8+ T-cell apoptosis in susceptible but not in resistant mice 2 weeks after infection. Further investigations of C57BL/6 and C3H/HeJ mice revealed that in vivo splenomegaly was associated with destruction of the lymphoid tissue architecture, liver cellular infiltrates, and increased numbers of apoptotic cells in both spleen and liver tissue sections. Infection of C57BL/6 mice but not of C3H/HeJ mice induced massive production of tumor necrosis factor alpha (TNF-alpha ) in serum, as well as an increase in Fas and Fas ligand (FasL) expression in T cells. In vitro addition of neutralizing anti-TNF-alpha antibodies led to a significant reduction in CD3-induced T-cell apoptosis of both CD4+ and CD8+ T cells of C57BL/6 mice, while the blockade of Fas-FasL interactions reduced apoptosis only in CD4+ but not in CD8+ T cells. Together, these results suggest that TNF-alpha and Fas-FasL interactions play a role in the activation-induced cell death (AICD) process associated with a defect in T-cell proliferation of the susceptible C57BL/6 mice. T-cell death by apoptosis may represent one of the important components of the ineffective immune response against mycobacterium-induced immunopathology in susceptible hosts.

* Corresponding author. Mailing address: INSERM E9922, Groupe Hospitalier Bichat-Claude Bernard, 16 rue Henri Huchard, 75018 Paris, France. Phone: (33) 1 44 85 62 88. Fax: (33) 1 44 85 62 88. E-mail: estaquie{at}bichat.inserm.fr.

dagger Present address: Department of Microbiology and Immunology, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom.

Infection and Immunity, July 2000, p. 4264-4273, Vol. 68, No. 7
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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