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Martin, Constance

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Martin

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Constance

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Martin, Constance

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2012 - 20152

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Author's Publications: search.filters.isAuthorOfPublication.67160cff-144e-4b3b-a1c7-3b066f28187f

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    Efferocytosis is an Innate Antibacterial Mechanism of Mycobacterium tuberculosis Control
    (2012-12-13) Martin, Constance; Behar, Samuel M.; Horng, Tiffany; Fortune, Sarah; Kornfeld, Hardy; Wessling-Resnick, Marianne
    One third of the world’s population is infected with Mycobacterium tuberculosis, causing two million deaths annually. The bacteria avoid immune clearance by persisting within macrophages by subverting normal phagosome maturation and acidification. In order to spread, the bacteria induce necrotic death of its host macrophage, broadcasting the infection into neighboring cells. However, it has long been appreciated that the apoptotic, rather than necrotic death of an infected macrophage results in bacterial growth suppression, improved adaptive immune response and survival. The mechanism for apoptosis-mediated bacterial suppression has hitherto remained unknown. In this dissertation we report that apoptosis itself is not intrinsically bactericidal. We find that following apoptosis, the M. tuberculosis-infected macrophage is engulfed by bystander macrophages through the process of efferocytosis. Efferocytosis, or apoptotic cell clearance, is a critical function of macrophages; however, little is known regarding efferocytosis of infected apoptotic cells. We find that M. tuberculosis-infected macrophages die by apoptosis more commonly than found previously. By confocal microscopy we observed that apoptotic macrophages are rapidly engulfed by uninfected macrophages. Efferocytosis of M. tuberculosisinfected macrophages occurs in vitro with all macrophage types tested and in vivo- specifically in the lung, indicating that efferocytosis could play an important role during infection. We developed an uninfected macrophage co-culture system in which we observe efferocytosis and define conditions in which it occurs. Using this co-culture system we observe a suppression of bacterial growth. By blocking efferocytosis, we have found that the engulfment of infected cells is required for M. tuberculosis control in the macrophage co-culture system, demonstrating that efferocytosis is a novel antibacterial mechanism. We then demonstrated using transmission electron microscopy that the M. tuberculosis-containing efferocytic phagosome is structurally distinct from the traditional M. tuberculosis phagosome. Bacteria from within the efferocytic phagosome are unable to halt its maturation, and as such are delivered to lysosomes. Furthermore, we find that following efferocytosis, M. tuberculosis are killed. While efferocytosis is recognized as a constitutive housekeeping function of macrophages, our work indicates that is should also be viewed as an antimicrobial effector mechanism.
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    Human and Murine Clonal CD8+ T Cell Expansions Arise during Tuberculosis Because of TCR Selection
    (Public Library of Science, 2015) Nunes-Alves, Cláudio; Booty, Matthew G.; Carpenter, Stephen M.; Rothchild, Alissa C.; Martin, Constance; Desjardins, Danielle; Steblenko, Katherine; Kløverpris, Henrik N.; Madansein, Rajhmun; Ramsuran, Duran; Leslie, Alasdair; Correia-Neves, Margarida; Behar, Samuel M.
    The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRβ bias. Using a retrogenic model of TB10.44-11-specific CD8+ T cells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-γ production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity.