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

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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 fromMycobacterium tuberculosisare 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-γ) 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. tuberculosischallenge in reconstituted mice led to the extravasation of IFN-γ-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 challengeM. tuberculosisinfection. 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.