Characterization of the protective T-cell response generated in CD4-deficient mice by a live attenuated Mycobacterium tuberculosis vaccine

Steven C. Derrick, Teresa H. Evering, Vasan K. Sambandamurthy, Kripa V. Jalapathy, Tsungda Hsu, Bing Chen, Mei Chen, Robert G. Russell, Ana Paula Junqueira-Kipnis, Ian M. Orme, Steven A. Porcelli, William R. Jacobs, Sheldon L. Morris

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)192-206
Number of pages15
JournalImmunology
Volume120
Issue number2
DOIs
StatePublished - Feb 2007

Keywords

  • Cytokines
  • T cells
  • Tuberculosis
  • Vaccine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Derrick, S. C., Evering, T. H., Sambandamurthy, V. K., Jalapathy, K. V., Hsu, T., Chen, B., Chen, M., Russell, R. G., Junqueira-Kipnis, A. P., Orme, I. M., Porcelli, S. A., Jacobs, W. R., & Morris, S. L. (2007). Characterization of the protective T-cell response generated in CD4-deficient mice by a live attenuated Mycobacterium tuberculosis vaccine. Immunology, 120(2), 192-206. https://doi.org/10.1111/j.1365-2567.2006.02491.x