DM, but not cathepsin L, is required to control an aerosol infection with<i>Mycobacterium tuberculosis</i>

Nepal, Rajeev M.; Vesosky, Bridget; Turner, Joanne; Bryant, Paula Wolf

doi:10.1189/jlb.1207852

Cited by 12 publications

(10 citation statements)

References 45 publications

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“…Our data ascribe a substantial portion of snapc1b phenotypes to cathepsin L1 deficiency though we cannot rule out a minor role for cathepsin B deficiency. Prior findings that cathepsin L knockout mice are not hypersusceptible to M. tuberculosis ( Nepal et al., 2008 ) may reflect functional redundancies present in the mouse but not the zebrafish.…”

Section: Resultsmentioning

confidence: 99%

Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration

Berg

Levitte

O’Sullivan

et al. 2016

Cell

115

129

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SummaryA zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers’ susceptibility to tuberculosis.

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Section: Resultsmentioning

confidence: 99%

Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration

Berg

Levitte

O’Sullivan

et al. 2016

Cell

115

129

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“…These results led us to re-examine the evidence that CD8 + T cells recognize infected cells. In our evaluation of the literature, among the best evidence is: (1) direct ex vivo recognition of Mtb-infected macrophages and DC by CD4 + and CD8 + T cells [ 45 – 48 ]; (2) murine T cells’ cytolytic activity (CTL) of MTb-infected cells [ 49 – 51 ]; (3) human CD8 + T cells that recognize Mtb-infected DC [ 52 – 54 ]. However, these data have limitations.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis-specific CD4+ and CD8+ T cells differ in their capacity to recognize infected macrophages

et al. 2018

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Containment of Mycobacterium tuberculosis (Mtb) infection requires T cell recognition of infected macrophages. Mtb has evolved to tolerate, evade, and subvert host immunity. Despite a vigorous and sustained CD8+ T cell response during Mtb infection, CD8+ T cells make limited contribution to protection. Here, we ask whether the ability of Mtb-specific T cells to restrict Mtb growth is related to their capacity to recognize Mtb-infected macrophages. We derived CD8+ T cell lines that recognized the Mtb immunodominant epitope TB10.44−11 and compared them to CD4+ T cell lines that recognized Ag85b240-254 or ESAT63-17. While the CD4+ T cells recognized Mtb-infected macrophages and inhibited Mtb growth in vitro, the TB10.4-specific CD8+ T cells neither recognized Mtb-infected macrophages nor restricted Mtb growth. TB10.4-specific CD8+ T cells recognized macrophages infected with Listeria monocytogenes expressing TB10.4. However, over-expression of TB10.4 in Mtb did not confer recognition by TB10.4-specific CD8+ T cells. CD8+ T cells recognized macrophages pulsed with irradiated Mtb, indicating that macrophages can efficiently cross-present the TB10.4 protein and raising the possibility that viable bacilli might suppress cross-presentation. Importantly, polyclonal CD8+ T cells specific for Mtb antigens other than TB10.4 recognized Mtb-infected macrophages in a MHC-restricted manner. As TB10.4 elicits a dominant CD8+ T cell response that poorly recognizes Mtb-infected macrophages, we propose that TB10.4 acts as a decoy antigen. Moreover, it appears that this response overshadows subdominant CD8+ T cell response that can recognize Mtb-infected macrophages. The ability of Mtb to subvert the CD8+ T cell response may explain why CD8+ T cells make a disproportionately small contribution to host defense compared to CD4+ T cells. The selection of Mtb antigens for vaccines has focused on antigens that generate immunodominant responses. We propose that establishing whether vaccine-elicited, Mtb-specific T cells recognize Mtb-infected macrophages could be a useful criterion for preclinical vaccine development.

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“…In dendritic cells, processing in DM-dependent or DM-independent pathways can be regulated by TLR ligands and type I interferon [97,98]. Different epitopes are targeted in DM-deficient and DM-sufficient mice [64,99,100], although DM can be required for pathogen clearance [101]. Thus, MHC II peptide loading can occur in many scenarios in the absence of DM, and a lack of DM expression should not be considered to rule out MHC II presentation.…”

Section: Dm-dependent and Dm-independent Loadingmentioning

confidence: 99%

The melting pot of the MHC II peptidome

Stern

Santambrogio

2016

Current Opinion in Immunology

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Recent advances in mass spectrometry technology have facilitated detailed examination of MHC-II immunopeptidomes, i.e. the repertoires of peptides bound to MHC-II molecules expressed in antigen presenting cells. These studies have deepened our view of MHC-II presentation. Other studies have broadened our view of pathways leading up to peptide loading. Here we review these recent studies in the context of earlier work on conventional and non-conventional MHC-II processing. The message that emerges is that sources of antigen beyond conventional endosomal processing of endocytosed proteins are important for generation of cellular immune responses to pathogens and maintenance of central and peripheral tolerance. The multiplicity of pathways results in a broad MHC II immunopeptidome that conveys the sampled environment to patrolling T cells.

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DM, but not cathepsin L, is required to control an aerosol infection withMycobacterium tuberculosis

Cited by 12 publications

References 45 publications

Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration

Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration

Mycobacterium tuberculosis-specific CD4+ and CD8+ T cells differ in their capacity to recognize infected macrophages

The melting pot of the MHC II peptidome

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