CD4+ T cells contain Mycobacterium tuberculosis infection in the absence of CD8+ T cells in mice vaccinated with DNA encoding Ag85A

D’Souza, Sushila; Denis, Olivier; Scorza, Tatiana; Nzabintwali, Fulgence; Verschueren, Hendrik; Huygen, Kris

doi:10.1002/1521-4141(200009)30:9<2455::aid-immu2455>3.3.co;2-u

Cited by 12 publications

(18 citation statements)

References 11 publications

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“…However, this hypothesis remains to be confirmed. Our findings regarding the phenotype of antigen-specific T cells unify somewhat contradicting reports claiming the importance of either CD4 (12,18) or CD8 (10, 47) cells in protection against TB. The finding that protection is achieved in animals of different immunological backgrounds with different types of T cells as the key mediators is promising when considering the vaccination of HLA haplotype-heterogeneous human populations.…”

Section: Discussioncontrasting

confidence: 99%

Protective Immune Responses to a Recombinant Adenovirus Type 35 Tuberculosis Vaccine in Two Mouse Strains: CD4 and CD8 T-Cell Epitope Mapping and Role of Gamma Interferon

et al. 2007

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There is an urgent need for an efficacious vaccine against tuberculosis (TB). Cellular immune responses are key to an effective protective response against TB. Recombinant adenovirus (rAd) vectors are especially suited to the induction of strong T-cell immunity and thus represent promising vaccine vehicles for the prevention of TB. We have previously reported on rAd vector serotype 35, the serotype of choice due to low preexisting immunity worldwide, which expresses a unique fusion protein of Mycobacterium tuberculosis antigens Ag85A, Ag85B, and TB10.4 (Ad35-TBS). Here, we demonstrate that Ad35-TBS confers protection against M. tuberculosis when administered to mice through either an intranasal or an intramuscular route. Histological evaluation of lung tissue corroborated the protection and, in addition, demonstrated differences between two mouse strains, with diffuse inflammation in BALB/c mice and distinct granuloma formation in C57BL/6 mice. Epitope mapping analysis in these mouse strains showed that the major T-cell epitopes are conserved in the artificial fusion protein, while three novel CD8 peptides were discovered. Using a defined set of T-cell epitopes, we reveal differences between the two mouse strains in the type of protective immune response, demonstrating that different antigen-specific gamma interferon (IFN-␥)-producing T cells can provide protection against M. tuberculosis challenge. While in BALB/c (H-2 d ) mice, a dominant CD8 T-cell response was detected, in C57BL/6 (H-2 b ) mice, more balanced CD4/CD8 T-cell responses were observed, with a more pronounced CD4 response in the lungs. These results unify conflicting reports on the relative importance of CD4 versus CD8 T-cell responses in protection and emphasize the key role of IFN-␥. Tuberculosis (TB), an airborne disease caused by Mycobacterium tuberculosis, is responsible for 2 million deaths each year, with more than 90% of cases occurring in developing countries. It has been estimated that one-third of the world population is infected with M. tuberculosis, and about 5 to 10% of the infected individuals will develop TB during their lifetime. The increasing global impact of TB has been linked to growing poverty, increased emigration, deterioration of public health care, the spread of human immunodeficiency virus, and the development of multidrug-resistant strains of M. tuberculosis. Bacille Calmette-Guérin (BCG), a live and attenuated strain of Mycobacterium bovis, is the only available vaccine against TB to date and has been used for the vaccination of newborns for decades. The vaccine is effective in preventing serious complications of childhood TB, but its efficacy wanes over a period of 10 to 15 years, rendering adolescents increasingly susceptible to pulmonary TB. Significant efforts are being made to generate a more effective TB vaccine (3,24,50), and vaccination regimens aimed to improve BCG-induced protection are currently the most favorable approach (4,14,19,21,29,36). The most promising antigens for vaccine generation include protei...

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Section: Discussioncontrasting

confidence: 99%

Protective Immune Responses to a Recombinant Adenovirus Type 35 Tuberculosis Vaccine in Two Mouse Strains: CD4 and CD8 T-Cell Epitope Mapping and Role of Gamma Interferon

et al. 2007

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“…Thus, via cross-priming mechanisms, both secreted fusion proteins expressed from TPA plasmids or peptides released from cells transfected with the Ub constructs could induce both CD4 and CD8 T-cell populations. The importance of CD4 stimulation by TB DNA vaccines was recently demonstrated when CD4 knockout (KO) mice immunized with an antigen 85 TB DNA vaccine could not be protected against tuberculous challenge (14). In the same study, however, CD8 KO mice were protected by DNA vaccination.…”

Section: Discussionmentioning

confidence: 92%

DNA Vaccine Combinations Expressing Either Tissue Plasminogen Activator Signal Sequence Fusion Proteins or Ubiquitin-Conjugated Antigens Induce Sustained Protective Immunity in a Mouse Model of Pulmonary Tuberculosis

et al. 2002

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DNA vaccination has emerged as a powerful approach in the search for a more efficacious vaccine against tuberculosis. In this study, we evaluated the effectiveness of immunizing with combinations of 10 different tuberculosis DNA vaccines that expressed mycobacterial proteins fused at the N terminus to eukaryotic intracellular targeting sequences. In one vaccine combination, the genes were fused to the tissue plasminogen activator signal sequence (TPA), while in a second combination the same 10 genes were expressed as ubiquitin (Ub)-conjugated proteins. In ex vivo studies in which the secretion of gamma interferon was measured, cellular immune responses were detected in mice vaccinated with either the TPA DNA vaccine combination or the Ub DNA vaccine combination at 7 and 14 days following a low-dose Mycobacterium tuberculosis challenge. Moreover, mice vaccinated with the TPA combination, the Ub combination, and Mycobacterium bovis BCG were able to limit the growth of tubercle bacilli in the lung and spleen after a virulent tuberculous aerosol challenge. Histopathological analyses also showed that mice immunized with the DNA vaccine combinations had substantially improved postinfection lung pathology relative to the naïve controls. Finally, in three different long-term experiments, the survival periods following aerogenic challenge were extended as much as sevenfold for vaccinated mice compared to naïve controls. Interestingly, in all three experiments, no significant differences were detected in the mean times to death for mice immunized with the TPA combination or the Ub combination relative to the BCG controls. In conclusion, these studies demonstrate the effectiveness of immunization with DNA vaccine combinations against tuberculosis and suggest that further testing of these plasmid cocktails is warranted.Tuberculosis (TB) is a major global threat to human health, with more than 2 million people dying each year from Mycobacterium tuberculosis infections (39). Although the current TB vaccine (Mycobacterium bovis BCG) has been widely used throughout the world for many decades, its efficacy has been shown to be highly variable in several well-controlled clinical trials (5). Moreover, since BCG is a live attenuated vaccine, its use is contraindicated in human immunodeficiency-infected and other immunocompromised patients, who ironically have the highest risk of developing TB. Clearly, the development of a new, more effective vaccine would greatly facilitate worldwide control of this ancient plague. As a consequence, the search for a new vaccine against TB has greatly intensified over the last decade, with several experimental vaccines already shown to have promise in preclinical testing (30).Since DNA vaccines can induce substantial cellular immunity and evoke both CD4 and CD8 T-cell responses, genetic immunization has become a viable strategy for developing new vaccines against intracellular parasites (18). Several recent studies carried out with animal models of TB have suggested that DNA vaccines against this d...

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“…It has also been postulated that ␥␦ T cells provide a link between innate and acquired immune responses (24,31). Other investigators propose a regulatory role for ␥␦ T cells (14) by immunomodulation of ␣/␤ ϩ T cells in both tuberculosis and paratuberculosis in cattle (8,40). These studies suggest that SOD antigen may be important in the earlier stages of infection by preferentially stimulating ␥␦ T cells (7).…”

Section: Downloaded Frommentioning

confidence: 99%

In Vitro Cellular Immune Responses to Recombinant Antigens ofMycobacterium aviumsubsp.paratuberculosis

Shin

Chang

et al. 2005

Infect Immun

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CD4+ T cells contain Mycobacterium tuberculosis infection in the absence of CD8+ T cells in mice vaccinated with DNA encoding Ag85A

Cited by 12 publications

References 11 publications

Protective Immune Responses to a Recombinant Adenovirus Type 35 Tuberculosis Vaccine in Two Mouse Strains: CD4 and CD8 T-Cell Epitope Mapping and Role of Gamma Interferon

Protective Immune Responses to a Recombinant Adenovirus Type 35 Tuberculosis Vaccine in Two Mouse Strains: CD4 and CD8 T-Cell Epitope Mapping and Role of Gamma Interferon

DNA Vaccine Combinations Expressing Either Tissue Plasminogen Activator Signal Sequence Fusion Proteins or Ubiquitin-Conjugated Antigens Induce Sustained Protective Immunity in a Mouse Model of Pulmonary Tuberculosis

In Vitro Cellular Immune Responses to Recombinant Antigens ofMycobacterium aviumsubsp.paratuberculosis

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