title: Characterization of the protective T-cell response generated in CD4-deficient mice by a live attenuated Mycobacterium tuberculosis vaccine.
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 DeltaRD1DeltapanCD mutant of Mycobacterium tuberculosis (mc(2)6030) 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 mc(2)6030-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 gammadelta (TCR-gammadelta(+)) 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 mc(2)6030 were attributable to a population of CD4(-) CD8(-) (double-negative) TCR-alphabeta(+), TCR-gammadelta(-), NK1.1(-) T cells. Transfer of highly enriched double-negative TCR-alphabeta(+) T cells from mc(2)6030-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-gamma 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.
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA. steven.derrick@fda.hhs.gov
authors.forename: Steven C
authors.initials: SC
authors.lastname: Derrick
authors.forename: Teresa H
authors.initials: TH
authors.lastname: Evering
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.forename: Kripa V
authors.initials: KV
authors.lastname: Jalapathy
authors.forename: Tsungda
authors.initials: T
authors.lastname: Hsu
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: Robert G
authors.initials: RG
authors.lastname: Russell
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Junqueira-Kipnis
authors.forename: Ian M
authors.initials: IM
authors.lastname: Orme
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: Sheldon L
authors.initials: SL
authors.lastname: Morris
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000276:immunology; D007111:Immunity, Cellular; D016867:Immunocompromised Host; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014611:Vaccination / Q000379:methods; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D007376:Interleukin-2; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D032581:Tuberculosis Vaccines; D014613:Vaccines, Attenuated; D007371:Interferon-gamma