Role of CD8+ T lymphocytes in control of Mycobacterium tuberculosis infection

Grotzke, Jeff E.; Lewinsohn, David

doi:10.1016/j.micinf.2005.03.001

Cited by 100 publications

(82 citation statements)

References 113 publications

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“…FACS analysis confirmed this finding and revealed that CD4-positive T cells were the primary cell type to have been boosted. This was important to determine, as CD4-positive T cells play a crucial role in controlling TB infection (19). The observed correlation between IFN-␥-secreting cells recruited to the lungs and the protection against TB is in agreement with recent studies using an intranasal-administered recombinant adenovirus-based TB vaccine expressing Ag85A (35,36).…”

Section: Discussionsupporting

confidence: 83%

The Combined CTA1-DD/ISCOMs Vector Is an Effective Intranasal Adjuvant for Boosting PriorMycobacterium bovisBCG Immunity toMycobacterium tuberculosis

et al. 2007

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Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains one of the leading causes of mortality worldwide. The current "gold standard" vaccine Mycobacterium bovis BCG has a limited efficacy that wanes over time. The development of a vaccine to boost BCG-induced immunity is therefore a highly active area of research. Mucosal administration of vaccines is believed to provide better protection against pathogens, such as M. tuberculosis, that invade the host via mucosal surfaces. In this study we demonstrate that an intranasal vaccine, comprising the antigenic fusion protein Ag85B-ESAT-6 and the mucosal combined adjuvant vector CTA1-DD/ISCOMs, strongly promotes a Th1-specific immune response, dominated by gamma interferon-secreting CD4-positive T cells. Mucosal administration of Ag85B-ESAT-6 mixed with CTA1-DD/ISCOMs strongly boosted prior BCG immunity, leading to a highly increased recruitment of antigen-specific cells to the site of infection. Most importantly, we observed a significantly (P < 0.001) reduced bacterial burden in the lung compared to nonboosted control animals. Thus, the results demonstrate the effectiveness of mucosal vaccination with Ag85B-ESAT-6 mixed with CTA1-DD/ISCOMs as adjuvant for stimulating TB-specific protective immunity in the lung.Tuberculosis (TB) remains one of the leading causes of mortality worldwide, accounting for an estimated 2 to 3 million deaths each year (38). Furthermore, infection with Mycobacterium tuberculosis, the causative agent of TB, is a leading cause of mortality for individuals infected with human immunodeficiency virus (http://www.who.int/mediacenter/factsheets/fs104 /en/). When taken together with the spread of multidrug-resistant mycobacterial strains and the reemergence of the disease in the developed world, it becomes clear why TB remains at the forefront of public health awareness campaigns (32).While the Mycobacterium bovis BCG vaccine for TB remains the most extensively used vaccine worldwide and a large proportion of the population of most counties has already been vaccinated with BCG, the vaccine nonetheless has questionable efficacy. Current indications suggest that BCG does not convey life-long immunity and is of limited value in protecting against adult TB (7, 14, 26). Thus, there has recently been a growing interest in (i) the development of a TB vaccine that can effectively boost preexisting immunity generated by prior BCG vaccination and, hence, the discovery of a suitable adjuvant, or (ii) an improved BCG vaccine (8,15,18,27,33).M. tuberculosis is a pathogen which infects the individual via the mucosal tissue of the respiratory tract following inhalation of infectious droplets. While the majority of approaches to the development of a novel TB vaccine have focused on subcutaneous (s.c.) administration, there is evidence to suggest that mucosal vaccination is an efficient route of administration for vaccines against TB (16, 39); however, an efficient intranasal (i.n.) vaccine against TB requires an efficient mucosa...

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Section: Discussionsupporting

confidence: 83%

The Combined CTA1-DD/ISCOMs Vector Is an Effective Intranasal Adjuvant for Boosting PriorMycobacterium bovisBCG Immunity toMycobacterium tuberculosis

et al. 2007

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“…In these experiments a potential role was identified for the contribution of TDM to generating CD4 + T cells that play a role in granuloma development during infection. The importance of the contribution of T cells to M. tuberculosis infection is well established (Caruso et al, 1999;Flynn & Chan, 2001;Grotzke & Lewinsohn, 2005;Muller et al, 1987;Scanga et al, 2000;. These experiments add to those findings by examining the potential function of TDM in generating reactive CD4 + T cells during development of M. tuberculosis-related pathology.…”

Section: Introductionmentioning

confidence: 96%

Mycobacterial glycolipid trehalose 6,6′-dimycolate-induced hypersensitive granulomas: contribution of CD4+ lymphocytes

2007

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The granulomatous response is a characteristic histological feature of Mycobacterium tuberculosis infection responsible for organism containment. The development of cell-mediated immunity is essential for protection against disease, as well as being required for maintenance of the sequestering granulomatous response. Trehalose 6,69-dimycolate (TDM; cord factor), a glycolipid associated with the cell wall of mycobacteria, is implicated as a key immunogenic component in M. tuberculosis infection. Models of TDM-induced hypersensitive granulomatous response have similar pathologies to that of active tuberculosis infection. Prior immunization (sensitization) of mice with TDM results in exacerbated histological damage, inflammation and lymphocytic infiltration upon subsequent TDM challenge. Adoptive transfer experiments were performed to ascertain the cell phenotype governing this response; CD4 + cells were identified as critical for development of related pathology. Mice receiving CD4 + cells from donor TDMimmunized mice demonstrated significantly increased production of Th1-type cytokines IFN-c and IL-12 within the lung upon subsequent TDM challenge. Control groups receiving naïve CD4 + cells, or CD8 + or CD19 + cells isolated from TDM-immunized donors, did not exhibit an exacerbated response. The identified CD4 + cells isolated from TDM-immunized mice produced significant amounts of IFN-c and IL-2 when exposed to TDM-pulsed macrophages in vitro. These experiments provide further evidence for involvement of a cell-mediated response in TDM-induced granuloma formation, which mimics pathological damage elicited during M. tuberculosis infection. INTRODUCTIONTuberculosis is not only a disease of the past; it is a disease of the future. More than 2 million people die each year from Mycobacterium tuberculosis infection, making it the most deadly of all infectious organisms. With nearly 2 billion people infected worldwide, tuberculosis remains a serious health threat (WHO, 2006), so continued research is needed to learn how this organism evades detection and destruction within the host.The cell wall of the M. tuberculosis bacilli is rich in lipids. They constitute more than 50 % of the dry weight of the organism and have been implicated as potential virulence factors (Kolattukudy et al., 1997). More than a half a century ago, Hubert Bloch identified cord factor as a 'toxic substance' that when extracted from virulent organisms caused them to lose their virulence (Bloch, 1950), and when added during infection exacerbated disease (Bloch & Noll, 1955). This substance was later identified as the mycobacterial glycolipid trehalose 6,69-dimycolate or TDM (Noll et al., 1956). TDM has been extensively studied over the years and many unique properties have been attributed to its presence. Removal of TDM from the surface of M. tuberculosis results in enhanced trafficking to acidic vesicles and decreased survival of the organism within macrophages (Indrigo et al., 2002(Indrigo et al., , 2003. Relative to surface-associated TDM, organi...

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“…The recently described crosspriming mechanism of CD8+ T cells in human and murine TB by mycobacterium-induced apoptotic vesicles ("detour pathway") represents a specific host activation alternative for controlling a pathogen that does not readily access the MHC-Iprocessing pathway (22). CD8+ T cells may contribute to the immune response against the tubercle bacilli by at least three mechanisms: IFN-γ secretion (15), lysis of infected cells by Fas/Fas-ligand interaction or mediated by perforin and granzymes (23), and direct mycobactericidal activity. The latter mechanism is mediated by granulysin, an anti-mycobacterial molecule secreted by human CD8+ T cells (23).…”

Section: Immune Factors Controlling Tuberculosis Infectionmentioning

confidence: 99%

“…CD8+ T cells may contribute to the immune response against the tubercle bacilli by at least three mechanisms: IFN-γ secretion (15), lysis of infected cells by Fas/Fas-ligand interaction or mediated by perforin and granzymes (23), and direct mycobactericidal activity. The latter mechanism is mediated by granulysin, an anti-mycobacterial molecule secreted by human CD8+ T cells (23). Granulysin is also found in T cell populations that specifically recognize the lipids and glycolipids of M. tuberculosis.…”

Section: Immune Factors Controlling Tuberculosis Infectionmentioning

confidence: 99%

Immune factors and immunoregulation in tuberculosis

Ferraz

Melo

Albuquerque

et al. 2006

Braz J Med Biol Res

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Pathogens causing tuberculosis and other chronic infectious diseases of major public health importance commonly have complex mechanisms involved in their persistence in the host despite specific and sometimes strong immune responses. These diseases are also associated with the lack of efficient vaccines, difficult therapeutics and a high mortality rate among susceptible individuals. Here, we will review features of the host immune response that contribute to the occurrence of disease. In addition, we propose that the immune responses observed in tuberculosis cannot be interpreted solely on the basis of a Th1-Th2 counter-regulatory paradigm since there is growing evidence that natural regulatory T cells may play an important role in the regulation of host immune responses against Mycobacterium tuberculosis. Thus, the development of more effective vaccines against this bacterial disease should take into account the role of natural regulatory T cells in the progression to severe disease and persistence of infection. Finally, new treatments based on manipulation of regulatory T cells should be investigated.

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Role of CD8+ T lymphocytes in control of Mycobacterium tuberculosis infection

Cited by 100 publications

References 113 publications

The Combined CTA1-DD/ISCOMs Vector Is an Effective Intranasal Adjuvant for Boosting PriorMycobacterium bovisBCG Immunity toMycobacterium tuberculosis

The Combined CTA1-DD/ISCOMs Vector Is an Effective Intranasal Adjuvant for Boosting PriorMycobacterium bovisBCG Immunity toMycobacterium tuberculosis

Mycobacterial glycolipid trehalose 6,6′-dimycolate-induced hypersensitive granulomas: contribution of CD4+ lymphocytes

Immune factors and immunoregulation in tuberculosis

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