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Infection and Immunity, May 2006, p. 2751-2759, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2751-2759.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Partial Reconstitution of the CD4+-T-Cell Compartment in CD4 Gene Knockout Mice Restores Responses to Tuberculosis DNA Vaccines

Sushila D'Souza,1* Marta Romano,1 Johanna Korf,1 Xiao-Ming Wang,2 Pierre-Yves Adnet,1 and Kris Huygen1

Laboratory of Mycobacterial Immunology,1 Biochemistry of Macromolecules, Scientific Institute for Public Health—Pasteur Institute of Brussels, 642 Engelandstraat, 1180 Brussels, Belgium2

Received 21 November 2005/ Returned for modification 29 December 2005/ Accepted 7 February 2006

Reactivation tuberculosis (TB) is a serious problem in immunocompromised individuals, especially those with human immunodeficiency virus (HIV) coinfection. The adaptive immune response mediated by CD4+ and CD8+ T cells is known to confer protection against TB. Hence, vaccines against TB are designed to activate these two components of the immune system. Anti-TB DNA vaccines encoding the immunodominant proteins Ag85A, Ag85B, and PstS-3 from Mycobacterium tuberculosis are ineffective in mice lacking CD4+ T cells (CD4–/– mice). In this study, we demonstrate that reconstitution of the T-cell compartment in CD4–/– mice restores vaccine-specific antibody and gamma interferon (IFN-{gamma}) responses to these DNA vaccines. The magnitude of the immune responses correlated with the extent of reconstitution of the CD4+-T-cell compartment. Reconstituted mice vaccinated with DNA encoding PstS-3, known to encode a dominant Db-restricted CD8+-T-cell epitope, displayed CD8+-T-cell responses not observed in CD4–/– mice. M. tuberculosis challenge in reconstituted mice led to the extravasation of IFN-{gamma}-producing CD4+ and CD8+ T cells into lungs, the primary site of bacterial replication. Importantly, a reconstitution of 12 to 15% of the CD4+-T-cell compartment resulted in Ag85B plasmid DNA-mediated protection against a challenge M. tuberculosis infection. Our findings provide evidence that anti-TB DNA vaccines could be effective in immunodeficient individuals after CD4+-T-lymphocyte reconstitution, as may occur following antiretroviral therapy in HIV+ patients.

* Corresponding author. Present address: Laboratory of Toxoplasmosis Research, Pasteur Institute of Brussels, 642 rue Engeland, 1180 Brussels, Belgium. Phone: 32-2-373-3041. Fax: 32-2-373-3367. E-mail: sdsouza{at}pasteur.be.

Editor: J. B. Bliska

Infection and Immunity, May 2006, p. 2751-2759, Vol. 74, No. 5
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.5.2751-2759.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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