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

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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

Fingerprint

Tuberculosis Vaccines
Mycobacterium tuberculosis
T-Lymphocytes
Tuberculosis
Major Histocompatibility Complex
Vaccination
Lung
T-Cell Antigen Receptor
Aerosols
Interferons
Interleukin-2
Acquired Immunodeficiency Syndrome
Vaccines

Keywords

  • Cytokines
  • T cells
  • Tuberculosis
  • Vaccine

ASJC Scopus subject areas

  • Immunology

Cite this

Characterization of the protective T-cell response generated in CD4-deficient mice by a live attenuated Mycobacterium tuberculosis vaccine. / Derrick, Steven C.; Evering, Teresa H.; Sambandamurthy, Vasan K.; Jalapathy, Kripa V.; Hsu, Tsungda; Chen, Bing; Chen, Mei; Russell, Robert G.; Junqueira-Kipnis, Ana Paula; Orme, Ian M.; Porcelli, Steven A.; Jacobs, William R.; Morris, Sheldon L.

In: Immunology, Vol. 120, No. 2, 02.2007, p. 192-206.

Research output: Contribution to journalArticle

Derrick, SC, Evering, TH, Sambandamurthy, VK, Jalapathy, KV, Hsu, T, Chen, B, Chen, M, Russell, RG, Junqueira-Kipnis, AP, Orme, IM, Porcelli, SA, Jacobs, WR & Morris, SL 2007, 'Characterization of the protective T-cell response generated in CD4-deficient mice by a live attenuated Mycobacterium tuberculosis vaccine', Immunology, vol. 120, no. 2, pp. 192-206. https://doi.org/10.1111/j.1365-2567.2006.02491.x
Derrick, Steven C. ; Evering, Teresa H. ; Sambandamurthy, Vasan K. ; Jalapathy, Kripa V. ; Hsu, Tsungda ; Chen, Bing ; Chen, Mei ; Russell, Robert G. ; Junqueira-Kipnis, Ana Paula ; Orme, Ian M. ; Porcelli, Steven A. ; Jacobs, William R. ; Morris, Sheldon L. / Characterization of the protective T-cell response generated in CD4-deficient mice by a live attenuated Mycobacterium tuberculosis vaccine. In: Immunology. 2007 ; Vol. 120, No. 2. pp. 192-206.
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