High Frequency of CD4<sup>+</sup>T Cells Specific for the TB10.4 Protein Correlates with Protection against<i>Mycobacterium tuberculosis</i>Infection

Hervás-Stubbs, Sandra; Majlessi, Laleh; Simsova, Marcela; Morová, Jana; Rojas, Marie-Jésus; Nouzé, Clémence; Brodin, Priscille; Šebo, Peter; Leclerc, Claude

doi:10.1128/iai.02086-05

Cited by 87 publications

(92 citation statements)

References 47 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: 56%

“…It is thus possible that the sequence context in the TB fusion protein facilitates efficient processing of otherwise silent epitopes, thus expanding the range of reactive epitopes. Using an epitope mapping approach with 15-mer peptides, we did not detect the CD4 epitopes in BALB/c mice that have been reported previously (9,13,18). This might be due to the apparent lower robustness of the ICS in detecting CD4-specific T cells in mice.…”

Section: Discussionmentioning

confidence: 75%

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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: 56%

Section: Discussionmentioning

confidence: 75%

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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“…However, our esxH-specific CD4 and CD8 cytokine secreting T cells was equivalent to or exceeded those of the other vaccine approaches, even without the inclusion of adjuvants or heterologous primeboosting regimens. 24,25,45 Similarly, esxS, esxR, and esxH were the only dominant esx antigens that induced strong Th1 responses in BCG vaccinated mice. Interestingly, these 5 immunogenic esx antigens are categorized as part of the same esx Mtb locus family cluster (Esx3), 43 therefore, likely underlying the importance of this unique esx subfamily members as essential immunogenic esx antigens elicited by BCG and perhaps emphasizes their vital role in the efficacy of BCG.…”

Section: Discussionmentioning

confidence: 99%

Multivalent TB vaccines targeting the esx gene family generate potent and broad cell-mediated immune responses superior to BCG

Villarreal¹,

Walters

Laddy

et al. 2014

Human Vaccines & Immunotherapeutics

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“…The response to infection with M. tuberculosis is characterized by a strong inflammatory cell-mediated immune response, with elevated expression of both and . These two cytokines are essential for controlling mycobacterial infections [11][12][13] but in most cases, M. tuberculosis survives to establish a latent infection -which can rapidly reactivate if TNF-a production is blocked [14]. The precise mechanisms involved in this process are still only poorly known.…”

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confidence: 99%

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

et al. 2009

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Mycobacterium tuberculosis remains one of the world's deadliest pathogens in part because of its ability to persist in the face of an active immune response. It has been suggested that apoptosis of infected macrophages is one way in which the host deals with intracellular pathogens and that M. tuberculosis can inhibit this process. To assess the relevance of this process for human disease, we compared the expression of multiple genes involved in the activation of the extrinsic (''death receptor initiated'') pathway of apoptosis in 29 tuberculosis patients, 70 tuberculosis contacts and 27 community controls from Ethiopia. We found that there is a strong upregulation of genes for factors that promote apoptosis in PBMC from individuals with active disease, including TNF-a and its receptors, Fas and FasL and proCaspase 8. The anti-apoptotic factor FLIP, however, was also upregulated. A possible explanation for this dichotomy was given by fractionation of PBMC using CD14, which suggests that macrophage/monocytes may regulate several key molecules differently from non-monocytic cells (especially TNF-a and its receptors, a finding confirmed by protein ELISA) potentially reducing the sensitivity to apoptotic death of monocyte/macrophages -the primary host cell for M. tuberculosis. This may represent an important survival strategy for the pathogen. IntroductionDespite vaccination and drug treatment campaigns, tuberculosis (TB) causes an estimated 8-9 million new cases and mortality of 2-3 million deaths annually [1]. The TB epidemic is largely confined to developing countries, and is particularly serious in Sub-Saharan Africa [2], where it is fanned by the HIV epidemic. Despite the high mortality, most infected people do not immediately develop active disease, but become latently infected -though they may later reactivate their disease, if they become immunocompromised [3]. It is thought that perhaps as much as a third of the world's population is latently infected, [4] Eur. J. Immunol. 2010. 40: 291-301 DOI 10.1002 Clinical immunology 291 complicating control efforts by providing a reservoir from which new cases continually arise. Understanding immunity to Mycobacterium tuberculosis, so that more effective vaccines can be developed, is thus an international priority. The response to infection with M. tuberculosis is characterized by a strong inflammatory cell-mediated immune response, with elevated expression of both and . These two cytokines are essential for controlling mycobacterial infections [11][12][13] but in most cases, M. tuberculosis survives to establish a latent infection -which can rapidly reactivate if TNF-a production is blocked [14]. The precise mechanisms involved in this process are still only poorly known. We and others have previously shown that a bias towards IL-4 expression is associated with elevated risk of disease [15] while a bias towards the IL-4 antagonist IL-4d2, or towards IFN-g, is associated with reduced pathology, a better prognosis after infection, recovery after treatment and with ...

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High Frequency of CD4⁺T Cells Specific for the TB10.4 Protein Correlates with Protection againstMycobacterium tuberculosisInfection

Abstract: TB10.4 is a newly identified antigen of

Cited by 87 publications

References 47 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

Multivalent TB vaccines targeting the esx gene family generate potent and broad cell-mediated immune responses superior to BCG

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

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High Frequency of CD4+T Cells Specific for the TB10.4 Protein Correlates with Protection againstMycobacterium tuberculosisInfection

Abstract: TB10.4 is a newly identified antigen of

Cited by 87 publications

References 47 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

Multivalent TB vaccines targeting the esx gene family generate potent and broad cell-mediated immune responses superior to BCG

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

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High Frequency of CD4⁺T Cells Specific for the TB10.4 Protein Correlates with Protection againstMycobacterium tuberculosisInfection