title: Partial reconstitution of the CD4+-T-cell compartment in CD4 gene knockout mice restores responses to tuberculosis DNA vaccines.
abstract: 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 D(b)-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.
authors.affiliation: Laboratory of Mycobacterial Immunology, Scientific Institute for Public Health-Pasteur Institute of Brussels, 642 rue Engeland, 1180 Brussels, Belgium. sdsouza@pasteur.be
authors.forename: Sushila
authors.initials: S
authors.lastname: D'Souza
authors.forename: Marta
authors.initials: M
authors.lastname: Romano
authors.forename: Johanna
authors.initials: J
authors.lastname: Korf
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Wang
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Adnet
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000276:immunology; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D015704:CD4 Antigens; D016207:Cytokines; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA; D007371:Interferon-gamma; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis