Key epitopes on the secreted ESAT-6 antigen recognized in mice during the recall of protective immunity to Mycobacterium tuberculosis

Brandt, Lise; Oettinger, T; Holm, Arne; Andersen, Andreas; Andersen, Peter

doi:10.1016/s0165-2478(97)86823-x

Cited by 88 publications

(128 citation statements)

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“…Although epitopes have been identified in M.tb proteins other than TB10.4 [12,14,23], a detailed comparison between post immunization and post infection epitopes has not been described.…”

Section: Discussionmentioning

confidence: 99%

“…The ELISPOT technique has been described previously [14]. Briefly, 96-well microtiter plates (Maxisorp; Nunc) were coated with 4 mg of anti-murine IFN-g/well (clone R4-6A2; BD Pharmingen).…”

Section: Ifn-c Elispotmentioning

confidence: 99%

“…Thus, it is likely that different pathogens and vaccine vectors could result in different Ag processing. In the field of tuberculosis vaccine research, there has been considerable focus on identifying infection-driven as well as vaccine-induced epitopes in vaccine candidate Ag [11][12][13][14][15]. Less research has focused on comparing whether the epitopes induced by immunization in fact differ from those recognized following infection with M.tb.…”

mentioning

confidence: 99%

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Difference in TB10.4 T‐cell epitope recognition following immunization with recombinant TB10.4, BCG or infection with Mycobacterium tuberculosis

et al. 2010

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Most novel vaccines against infectious diseases are based on recombinant Ag; however, only few studies have compared Ag-specific immune responses induced by natural infection with that induced by the same Ag in a recombinant form. Here, we studied the epitope recognition pattern of the tuberculosis vaccine Ag, TB10.4, in a recombinant form, or when expressed by the pathogen Mycobacterium tuberculosis (M.tb), or by the current anti-tuberculosis vaccine, Mycobacterium bovis BCG. We showed that BCG and M.tb induced a similar CD4 1 T-cell specific TB10.4 epitope-pattern, which differed completely from that induced by recombinant TB10.4. This difference was not due to post-translational modifications of TB10.4 or because TB10.4 is secreted from BCG and M.tb as a complex with Rv0287. In addition, BCG and TB10.4/CAF01 were both taken up by DC and macrophages in vivo, and in vitro uptake experiments revealed that both TB10.4 and BCG were transported to Lamp 1 -compartments. BCG and TB10.4 however, were directed to different types of Lamp 1 -compartments in the same APC, which may lead to different epitope recognition patterns. In conclusion, we show that different vectors can induce completely different recognition of the same protein.Key words: Epitopes . Intracellular localization . Subdominant . T cells . Vaccine uptake IntroductionThe size, shape and nature of a synthetic recombinant vaccine and its target pathogen differ significantly. For instance, bacteria are typically in the range of 0.5-10 mm in diameter, which exceed the size of most viruses by 10 to 100-fold, and protein based adjuvanted vaccines are even smaller. In addition, compared with vaccines based on recombinant proteins and an adjuvant, pathogens are often taken up by different mechanisms by the cells of the immune system [1]. The different uptake mechanisms could lead to different intracellular processing of Ag, giving rise to different epitopes [1]. Furthermore, live pathogens express a wide range of specific lipids 1342and proteins that bind a variety of pattern-recognition receptors on phagocytes and induce signaling through these receptors, whereas recent evidence suggests subunit vaccines more specifically tend to target DC through activation of toll-like receptors [2]. These differences are likely to lead to different responses with regard to the priming of the early immune response [3]. For instance, the main host cell of the intracellular pathogen Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis in humans, is thought to be macrophages [4]; however, although mycobacteria are mainly taken up by macrophages, mycobacteria can infect a wide range of cells including neutrophils, epithelial cells and other cell types [5,6]. On the other hand, viral vaccine vectors have been shown to be ingested largely by immature DC [1], and soluble Ag formulated in cationic adjuvants such as CAF01 or IC31 are also believed to target DC [7,8]. Different types of APC have different mechanisms of Ag uptake, different pH levels in lysosomal co...

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“…Although epitopes have been identified in M.tb proteins other than TB10.4 [12,14,23], a detailed comparison between post immunization and post infection epitopes has not been described.…”

Section: Discussionmentioning

confidence: 99%

Section: Ifn-c Elispotmentioning

confidence: 99%

mentioning

confidence: 99%

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Difference in TB10.4 T‐cell epitope recognition following immunization with recombinant TB10.4, BCG or infection with Mycobacterium tuberculosis

et al. 2010

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“…tb Ags have been in focus for more than a decade ever since their identification in axenic cultures. Since then, a number of studies document the potential of these Ags in regulating immune responses in animal models and in humans, which among others includes the use of these Ags as potential vaccine candidates in the form of either adjuvants or even DNA (32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Despite these studies, lacunae still exist regarding their physiological roles at sites of infection.…”

Section: Discussionmentioning

confidence: 99%

“…Although both MTSA and ESAT-6 are cotranscribed from the RD1 region of the Mycobacterium genome, they are translated as two separate proteins (31). ESAT-6 has been designated as an important T cell Ag recognized by protective T cells in animal models of infection with M. tb (32). Furthermore, together with MPT64, ESAT-6 has been shown to have potential in the diagnosis of M. tb, as they are recognized by T cells in animal models (33,34) of M. tb.…”

Section: Tb Ags Induce Differentiation Of Dcs From Bm Cellsmentioning

confidence: 99%

Mycobacterium tuberculosisAntigens Induce the Differentiation of Dendritic Cells from Bone Marrow

Latchumanan

Singh

Sharma

et al. 2002

The Journal of Immunology

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We show in this study that incubation of freshly isolated bone marrow cells with Mycobacterium tuberculosis (M. tb) secretory Ag (MTSA), in the absence of any growth or differentiation-inducing factor, differentiates them into dendritic cell (DC)-like APCs. These DCs expressed moderate to high levels of various markers typical of DCs. These included T cell costimulatory molecules CD80, CD86, CD40, and CD54 and high levels of surface MHC class I and II on CD11c+ cells. The levels and the kinetics of up-regulation of these molecules were comparable with those of GM-CSF-differentiated DCs. Furthermore, these DCs exhibited morphology characteristics to DCs like the presence of dendritic processes. These DCs were also potent stimulators of allogeneic T cells and preferentially induced the secretion of IFN-γ over IL-10 from the interacting T cells. Interestingly, the differentiation of bone marrow cells into DC-like APCs was obtained with many other M. tb Ags, including whole cell extract of M. tb. Further characterization of MTSA-differentiated DCs showed that they were immature in nature, as stimulation of these DCs with TNF-α, anti-CD40, or LPS further up-regulated the surface levels of various molecules together with an increase in their T cell stimulatory capacity. The Ag-specific T cell responses of MTSA-differentiated DCs were mainly contributed by the CD4+ subset, indicating that MTSA was largely MHC II restricted. Furthermore, stimulation of bone marrow cells with MTSA induced the nuclear translocation of the transcription factor NF-κB, thereby indicating its role during MTSA-induced differentiation of DCs.

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Efficient protection against Mycobacterium tuberculosis by vaccination with a single subdominant epitope from the ESAT-6 antigen

et al. 2000

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We have investigated the vaccine potential of two peptides derived from the 6‐kDa early secretory antigenic target (ESAT)‐6 antigen in the mouse model of tuberculosis. The peptides were both strongly immunogenic in B6CBAF1 (H‐2b,k) mice and primed recall responses of the same intensity after immunization. However, both tuberculosis infection and immunization with ESAT‐6 resulted in responses focused towards ESAT‐61 – 20. Multiple antigen peptide constructs as well as free peptides were emulsified with dimethyl dioctadecylammonium bromide / monophosphoryl lipid A / IL‐2 and tested as experimental vaccines in an i. v. and aerosol model of tuberculosis in mice. The peptide were highly immunogenic and induced cellular responses of the same magnitude. However, only vaccines based on the subdominant ESAT‐651 – 70 epitope promoted significant levels of protective immunity and the level of protection was equivalent to that achieved with ESAT‐6 and BCG. These findings demonstrate the potential of peptide‐based vaccines against tuberculosis and indicate that there is not direct correlation between the hierarchy of response to naturally processed peptides and their ability to induce protective immunity against Mycobacterium tuberculosis.

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Key epitopes on the secreted ESAT-6 antigen recognized in mice during the recall of protective immunity to Mycobacterium tuberculosis

Cited by 88 publications

References 0 publications

Difference in TB10.4 T‐cell epitope recognition following immunization with recombinant TB10.4, BCG or infection with Mycobacterium tuberculosis

Difference in TB10.4 T‐cell epitope recognition following immunization with recombinant TB10.4, BCG or infection with Mycobacterium tuberculosis

Mycobacterium tuberculosisAntigens Induce the Differentiation of Dendritic Cells from Bone Marrow

Efficient protection against Mycobacterium tuberculosis by vaccination with a single subdominant epitope from the ESAT-6 antigen

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