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The global epidemic of tuberculosis, fuelled by acquired immune-deficiency syndrome, necessitates the development of a safe and effective vaccine. We have constructed a ΔRD1ΔpanCD mutant of Mycobacterium tuberculosis (mc26030) that undergoes limited replication and is severely attenuated in immunocompromised mice, yet induces significant protection against tuberculosis in wild-type mice and even in mice that completely lack CD4+ T cells as a result of targeted disruption of their CD4 genes (CD4–/– mice). Ex vivo studies of T cells from mc26030-immunized mice showed that these immune cells responded to protein antigens of M. tuberculosis in a major histocompatibility complex (MHC) class II-restricted manner. Antibody depletion experiments showed that antituberculosis protective responses in the lung were not diminished by removal of CD8+, T-cell receptor γδ (TCR-γδ+) and NK1.1+ T cells from vaccinated CD4–/– mice before challenge, implying that the observed recall and immune effector functions resulting from vaccination of CD4–/– mice with mc26030 were attributable to a population of CD4– CD8– (double-negative) TCR-αβ+, TCR-γδ–, NK1.1– T cells. Transfer of highly enriched double-negative TCR-αβ+ T cells from mc26030-immunized CD4–/– mice into naive CD4–/– mice resulted in significant protection against an aerosol tuberculosis challenge. Enriched pulmonary double-negative T cells transcribed significantly more interferon-γ and interleukin-2 mRNA than double-negative T cells from naive mice after a tuberculous challenge. These results confirmed previous findings on the potential for a subset of MHC class II-restricted T cells to develop and function without expression of CD4 and suggest novel vaccination strategies to assist in the control of tuberculosis in human immunodeficiency virus-infected humans who have chronic depletion of their CD4+ T cells. [ABSTRACT FROM AUTHOR]