Mannose-Capped Lipoarabinomannan from <i>Mycobacterium tuberculosis</i> Induces CD4+ T Cell Anergy via GRAIL

Sande, Obondo J.; Karim, Ahmad Faisal; Li, Qing; Ding, Xuedong; Rojas, R.M.; Boom, W. Henry

doi:10.4049/jimmunol.1500710

Cited by 34 publications

(42 citation statements)

References 55 publications

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“…The medium was changed on days 5 and 7 of culture, and macrophages were used on day 8. CD4 + T cells were isolated from spleens as described previously (27, 29). Spleens were dissociated through a 40-µm screen in 5 ml DMEM, and red blood cells were lysed in ACK lysis buffer (150 mM NH 4 Cl, 10 mM KHCO 3 , 0.1 mM Na 2 EDTA, pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

“…Cells were activated for 24 h with plate bound anti-CD3ε (1 µg/ml) and soluble anti-CD28 (1 µg/ml) in the continued presence of vesicles or LAM; supernatants were harvested, and IL-2 was quantitated by ELISA using the murine IL-2 DuoSet (R&D Systems, Minneapolis, MN). Alternatively, T cells were activated as above for 48 h, and proliferation was measured as described (29) by addition of 1 µCi of [ 3 H]-thymidine/well (Amersham Pharmacia Biotech, Piscataway, NJ) for an additional 16 h. [ 3 H]-thymidine incorporation was measured by liquid scintillation counting. Results were expressed as mean cpm of triplicate values +/− SD.…”

Section: Methodsmentioning

confidence: 99%

“…In this context, LAM inhibits TCR signaling, as manifested by decreases in Lck, LAT and ZAP-70 phosphorylation (27, 28). Importantly, exposure of CD4 + T cells to LAM during T cell activation induces anergy, manifested by decreased T cell responses upon subsequent stimulation and increased expression of anergy markers such as the E3 ubiquitin ligase GRAIL (gene related to anergy in lymphocytes) (29). However, exposure of T cells to BVs and LAM may primarily occur in the lung, and LAM may primarily impact effector T cells as opposed to priming of naïve T cells.…”

Section: Introductionmentioning

confidence: 99%

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Mycobacterium tuberculosis Membrane Vesicles Inhibit T Cell Activation

Athman

Sande

Groft

et al. 2017

The Journal of Immunology

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Mycobacterium tuberculosis utilizes multiple mechanisms to evade host immune responses, and inhibition of effector CD4+ T cell responses by M. tuberculosis may contribute to immune evasion. T cell receptor signaling is inhibited by M. tuberculosis cell envelope lipoglycans, such as lipoarabinomannan and lipomannan, but a mechanism for lipoglycans to traffic from M. tuberculosis within infected macrophages to reach T cells is unknown. In these studies, we found that membrane vesicles produced by M. tuberculosis and released from infected macrophages inhibited the activation of CD4+ T cells, as indicated by reduced production of interleukin-2 and reduced T cell proliferation. Flow cytometry and western blot demonstrated that lipoglycans from M. tuberculosis-derived bacterial vesicles (BVs) are transferred to T cells, where they inhibit T cell responses. Stimulation of CD4+ T cells in the presence of BVs induced expression of GRAIL, a marker of T cell anergy; upon restimulation, these T cells showed reduced ability to proliferate, confirming a state of T cell anergy. Furthermore, lipoarabinomannan was associated with T cells after their incubation with infected macrophages in vitro and when T cells were isolated from lungs of M. tuberculosis-infected mice, confirming the occurrence of lipoarabinomannan trafficking to T cells in vivo. These studies demonstrate a novel mechanism for the direct regulation of CD4+ T cells by M. tuberculosis lipoglycans conveyed by BVs that are produced by M. tuberculosis and released from infected macrophages. These lipoglycans are transferred to T cells to inhibit T cell responses, providing a mechanism that may promote immune evasion.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mycobacterium tuberculosis Membrane Vesicles Inhibit T Cell Activation

Athman

Sande

Groft

et al. 2017

The Journal of Immunology

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“…Thus, extracellular Mtb MVs may traffic to and subsequently impair the antigen presentation capacity of uninfected macrophages in the lung. The second mechanism is based on the observation that purified Mtb LAM inhibits TCR signaling and CD4+ T cell activation (Mahon et al, 2012; Sande et al, 2016) and that extracellular LAM is secreted via MVs from Mtb-infected cells (Athman et al, 2015). Our recent work demonstrates that Mtb MVs are enriched for LAM, inhibit T cell activation more potently than purified LAM, and induce T cell anergy (Athman et al, manuscript in revision).…”

Section: Mycobacterium Tuberculosis Membrane Vesiclesmentioning

confidence: 99%

Interspecies Communication between Pathogens and Immune Cells via Bacterial Membrane Vesicles

Jurkoshek

Wang

Athman

et al. 2016

Front. Cell Dev. Biol.

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The production of extracellular vesicles is a universal mechanism for intercellular communication that is conserved across kingdoms. Prokaryotes secrete 50–250 nm membrane vesicles (MVs) in a manner that is regulated by environmental stress and is thought to promote survival. Since many types of host-derived stress are encountered during infection, this implies an important role for MV secretion in bacterial pathogenesis. Accordingly, MVs produced by gram-positive and gram-negative pathogens contain toxins, virulence factors, and other molecules that promote survival in the host. However, recent studies have also shown that bacterial MVs are enriched for molecules that stimulate innate and adaptive immune responses. As an example, MVs may serve multiple, important roles in regulating the host response to Mycobacterium tuberculosis (Mtb), an intracellular pathogen that infects lung macrophages and resides within modified phagosomes. Previously, we demonstrated that Mtb secretes MVs during infection that may modulate infected and uninfected immune cells. Our present data demonstrates that Mtb MVs inhibit the functions of macrophages and T cells, but promote Major Histocompatibility Complex (MHC) class II antigen presentation by dendritic cells. We conclude that bacterial MVs serve dual and opposing roles in the activation of and defense against host immune responses to Mtb and other bacterial pathogens. We also propose that MV secretion is a central mechanism for interspecies communication between bacteria and host cells during infection.

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“…Earlier studies from his group have shown that Mtb through prolonged activation via TLR2 inhibits MHC-II Ag processing and presentation in macrophages [20]. He discussed more recent studies demonstrating that Mtb lipoarabinomannan (LAM) and lipomannans (LM) are released in bacterial microvesicles from infected macrophages and can directly inhibit proximal TCR signaling, and induce CD4+ T cell anergy [21,22]. These mechanisms most likely occur during the effector phase of the T cell response and may be relevant to the inability of T cells to clear Mtb during primary infection and during latent infection in lung granulomas.…”

Section: Session I: Early Infection Events and The Biological Consmentioning

confidence: 99%

“The Impact of Mycobacterium tuberculosis Immune Evasion on Protective Immunity: Implications for TB Vaccine Design” – Meeting report

Boggiano

Eichelberg

Ramachandra

et al. 2017

Vaccine

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Tuberculosis (TB) is the major cause of death from infectious diseases around the world, particularly in HIV infected individuals. TB vaccine design and development have been focused on improving Bacille Calmette-Guérin (BCG) and evaluating recombinant and viral vector expressed Mycobacterium tuberculosis (Mtb) proteins, for boosting BCG-primed immunity, but these approaches have not yet yielded significant improvements over the modest effects of BCG in protecting against infection or disease. On March 7–8, 2016, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on “The Impact of Mtb Immune Evasion on Protective Immunity: Implications for TB Vaccine Design” with the goal of defining immune mechanisms that could be targeted through novel research approaches, to inform vaccine design and immune therapeutic interventions for prevention of TB. The workshop addressed early infection events, the impact of Mtb evolution on the development and maintenance of an adaptive immune response, and the factors that influence protection against and progression to active disease. Scientific gaps and areas of study to revitalize and accelerate TB vaccine design were discussed and prioritized. These included a comprehensive evaluation of innate and Mtb–specific adaptive immune responses in the lung at different stages of disease; determining the role of B cells and antibodies (Abs) during Mtb infection; development of better assays to measure Mtb burden following exposure, infection, during latency and after treatment, and approaches to improving current animal models to study Mtb immunogenicity, TB disease and transmission.

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Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces CD4+ T Cell Anergy via GRAIL

Cited by 34 publications

References 55 publications

Mycobacterium tuberculosis Membrane Vesicles Inhibit T Cell Activation

Mycobacterium tuberculosis Membrane Vesicles Inhibit T Cell Activation

Interspecies Communication between Pathogens and Immune Cells via Bacterial Membrane Vesicles

“The Impact of Mycobacterium tuberculosis Immune Evasion on Protective Immunity: Implications for TB Vaccine Design” – Meeting report

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