Immunization with a mycobacterial lipid vaccine improves pulmonary pathology in the guinea pig model of tuberculosis

Dascher, Christopher C.; Hiromatsu, Kenji; Xiong, Xiaowei; Morehouse, Caroline B.; Watts, Gerald F.; Gui, Liu; McMurray, David N.; LeClair, Kenneth; Porcelli, Steven A.; Brenner, Michael B.

doi:10.1093/intimm/dxg091

Cited by 120 publications

(92 citation statements)

References 40 publications

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“…As a source of hydrophobic Ags, we used a chloroform-methanol extract of a virulent M.Tb strain (H37Rv; Dr. J. Belisle, Colorado State University, Ft. Collins, CO) that was originally developed to enrich lysates of ubiquitous mycobacteria for lipopeptides (29,30) and is now used to purify free lipids of M.Tb (28,31) such as glucose monomycolate, mycolic acid, phosphatidylcholine, or phosphatidylinositol (32). The lyophilized preparation was dissolved in chloroform:methanol (2:1) and stored at Ϫ70°C.…”

Section: Ags and Absmentioning

confidence: 99%

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

Bastian¹,

Braun

Bruns³

et al. 2008

The Journal of Immunology

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In searching for immunogenic molecules with the potential to induce protective immune responses against tuberculosis, we developed an ex vivo model to study frequency, phenotype, and effector functions of human T lymphocytes recognizing hydrophobic Ags of Mycobacterium tuberculosis (M.Tb). To obtain unbiased results, we characterized T lymphocytes responding to a crude cell wall extract (chloroform methanol extract of M.Tb (M.Tb-CME)) containing a broad spectrum of mycobacterial glycolipids and lipopeptides. A significant proportion of T lymphocytes recognized M.Tb-CME (290 IFN-γ+ T cells/105 PBMCs) and developed to effector memory cells as determined by the expression of CD45RO and the chemokine receptors CXCR3 and CCR5. Expanded lymphocytes fulfilled all criteria required for an efficient immune response against tuberculosis: 1) release of macrophage-activating Th1 cytokines and chemokines required for the spatial organization of local immune responses, 2) cytolytic activity against Ag-pulsed macrophages, and 3) recognition of infected macrophages and killing of the intracellular bacteria. Phenotypically, M.Tb-CME-expanded cells were CD4+ and MHC class II restricted, challenging current concepts that cytotoxic and antimicrobial effector cells are restricted to the CD8+ T cell subset. Pretreatment of M.Tb-CME with protease or chemical delipidation abrogated the biological activity, suggesting that responses were directed toward mycobacterial lipopeptides. These findings suggest that lipidated peptides are presented by M.Tb-infected macrophages and elicit CD4+ cytolytic and antimicrobial T lymphocytes. Our data support an emerging concept to include hydrophobic microbial Ags in vaccines against tuberculosis.

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Section: Ags and Absmentioning

confidence: 99%

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

Bastian¹,

Braun

Bruns³

et al. 2008

The Journal of Immunology

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“…Although mice are an excellent model for group II CD1 (e.g., CD1d), they can not serve as a model for the study of group 1 CD1-restricted T cells. However, there exist other animal species that have maintained CD1 in their genome and can be used for research on tuberculosis including guinea pigs, rabbits, and cattle (93)(94)(95)(96)(97).…”

Section: B Group I Cd1mentioning

confidence: 99%

“…Five peptides stabilized HLA-A*0201 expression on T2 cells. One of these peptides, 19-kDa [88][89][90][91][92][93][94][95][96][97] , was recognized by CD8 + T cells in the peripheral blood of two PPD + healthy subjects (18). The19-kDa [88][89][90][91][92][93][94][95][96][97] peptide was used to derive CD8 + T cell lines from these individuals and these CD8 + T cell lines had CTL activity that was specific for the 19-kDa [88][89][90][91][92][93][94][95][96][97] peptide, and was blocked by antibodies to class I MHC or to CD8.…”

Section: -Kda Protein-mentioning

confidence: 99%

“…The19-kDa [88][89][90][91][92][93][94][95][96][97] peptide was used to derive CD8 + T cell lines from these individuals and these CD8 + T cell lines had CTL activity that was specific for the 19-kDa [88][89][90][91][92][93][94][95][96][97] peptide, and was blocked by antibodies to class I MHC or to CD8. Similar CD8 + T cell lines specific for the 19-kDa [88][89][90][91][92][93][94][95][96][97] peptide were obtained from patients with active tuberculosis but not from PPD − donors, suggesting that M. tuberculosis infection leads to in vivo priming of CD8 + T cells specific for the 19-kDa protein. Importantly, CD8 + T cell lines derived in vitro using the 19-kDa [88][89][90][91][92][93][94][95][96][97] peptide recognized autologous monocytes infected with M. tuberculosis, establishing that the 19-kDa [88][89][90][91]…”

Section: -Kda Protein-mentioning

confidence: 99%

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Mycobacterium tuberculosis-Specific CD8+ T Cells and Their Role in Immunity

2006

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There are more cases of tuberculosis in the world today than at anytime in history. The global epidemic has generated intense interest into the immunological mechanisms that control infection. While CD4 + T cells play a critical role in host immunity to Mycobacterium tuberculosis, there is considerable interest in understanding the role of other T cell subsets in preventing disease development following infection. CD8 + T cells are required for optimum host defense following M. tuberculosis infection, which has led to investigation of how this protective effect is mediated. A critical review of recent literature regarding the role of CD8 + T cells in protective immunity to M. tuberculosis infection is now required to address the strengths and weaknesses of these studies. In this review, we evaluate the evidence that CD8 + T cells are critical in immunity to M. tuberculosis infection. We discuss the specific mycobacterial proteins that are recognized by CD8 + T cells elicited during infection. Finally, we examine the effector mechanisms of CD8 + T cells generated during infection and synthesize recent studies to consider the protective roles that these T cells serve in vivo.

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“…It would be interesting to see whether oral immunization stimulated responses that are now known to be associated with protective immunity to R. equi -including recognition of microbial lipids, production of IFN-c and induction of MHC class I-unrestricted CTLs. Alternatively, R. equi lipids could be tested directly as immunogens, as done previously with mycobacterial lipids in guinea pigs (Dascher et al, 2003;Hiromatsu et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Identification of Rhodococcus equi lipids recognized by host cytotoxic T lymphocytes

et al. 2010

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Immune adult horses have CD8 + cytotoxic T lymphocytes (CTLs) that recognize and lyse Rhodococcus equi-infected cells in an equine lymphocyte alloantigen (ELA)-A [classical major histocompatibility complex (MHC) class I]-unrestricted fashion. As protein antigens are MHC class I-restricted, the lack of restriction suggests that the bacterial antigens being recognized by the host are not proteins. The goals of this study were to test the hypothesis that these CTLs recognize unique R. equi cell-wall lipids related to mycobacterial lipids. Initial experiments showed that treatment of soluble R. equi antigen with broadly reactive proteases did not significantly diminish the ability of the antigen to stimulate R. equi-specific CTLs. R. equi-specific CTLs were also shown to lyse target cells (equine macrophages) pulsed with an R. equi lipid extract. Analysis of the R. equi lipid by TLC and MS (MALDI-TOF and ES) indicated that the extracted antigen consisted of three primary fractions: trehalose monomycolate (TMM), trehalose dimycolate (TDM) and cardiolipin (CL). ELA-A-mismatched cells pulsed with purified TMM and CL, but not the TDM fraction, were recognized and lysed by R. equi-specific CTLs. Because of their role in immune clearance and pathogenesis, transcription of the cytokines gamma interferon (IFN-c) and interleukin-4 (IL-4) was also measured in response to R. equi lipids by using real-time PCR; elevated IFN-c, but not IL-4, was associated with host clearance of the bacteria. The whole-cell R. equi lipid and all three R. equi lipid fractions resulted in marked increases in IFN-c transcription, but no increase in IL-4 transcription. Together, these data support the hypothesis that immune recognition of unique lipids in the bacterial cell wall is an important component of the protective immune response to R. equi. The results also identify potential lipid antigens not previously shown to be recognized by CTLs in an important, naturally occurring actinomycete bacterial pathogen.

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Immunization with a mycobacterial lipid vaccine improves pulmonary pathology in the guinea pig model of tuberculosis

Cited by 120 publications

References 40 publications

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

Mycobacterium tuberculosis-Specific CD8+ T Cells and Their Role in Immunity

Identification of Rhodococcus equi lipids recognized by host cytotoxic T lymphocytes

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