Browsing by Author "Lewinsohn, Deborah A."

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    CD81 T Cells Provide an Immunologic Signature of Tuberculosis in Young Children
    (American Thoracic Society, 2011) Lancioni, Christina; Nyendak, Mellisa; Sarah Zalwango, Sarah Kiguli; Mori, Tomi; Mayanja-Kizza, Harriet; Balyejusa, Stephen; Null, Megan; Baseke, Joy; Mulindwa, Deo; Byrd, Laura; Swarbrick, Gwendolyn; Scott, Christine; Johnson, Denise F.; Malone, LaShaunda; Mudido-Musoke, Philipa; Boom, Henry; Lewinsohn, David M.; Lewinsohn, Deborah A.
    Mycobacterium tuberculosis (Mtb), the etiology of tuberculosis (TB), causes over 9 million cases of disease and 1.7 million deaths annually (1). The only available vaccine to prevent TB, bacillus Calmette-Gue´ rin, offers little protection against the most common disease manifestations (2) and efforts to develop an improved vaccine are hampered by poor understanding of immunologic events that occur after Mtb exposure. Scientific studies of immunologic responses to initial Mtb infection are difficult because most individuals living in TB-endemic settings have experienced multiple Mtb exposures. Young children, however, suffer disproportionately after exposure to Mtb, because they are at substantial risk for developing TB after primary infection (3–5). Therefore, young children with TB offer a valuable window into the human immune response to primary Mtb infection.
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    Comprehensive definition of human immunodominant CD8 antigens in tuberculosis
    (NPJ vaccines, 2017) Lewinsohn, Deborah A.; Swarbrick, Gwendolyn M.; Park, Byung; Cansler, Meghan E.; Null, Megan D.; Toren, Katelynne G.; Baseke, Joy; Zalwango, Sarah; Mayanja-Kizza, Harriet; Malone, LaShaunda L.; Nyendak, Melissa; Wu, Guanming; Guinn, Kristi; McWeeney, Shannon; Mori, Tomi; Chervenak, Keith A.; Sherman, David R.; Boom, W. Henry; Lewinsohn, David M.
    Despite widespread use of the Bacillus Calmette-Guerin vaccine, tuberculosis, caused by infection with Mycobacterium tuberculosis, remains a leading cause of morbidity and mortality worldwide. As CD8+ T cells are critical to tuberculosis host defense and a phase 2b vaccine trial of modified vaccinia Ankara expressing Ag85a that failed to demonstrate efficacy, also failed to induce a CD8+ T cell response, an effective tuberculosis vaccine may need to induce CD8+ T cells. However, little is known about CD8, as compared to CD4, antigens in tuberculosis. Herein, we report the results of the first ever HLA allele independent genome-wide CD8 antigen discovery program. Using CD8+ T cells derived from humans with latent tuberculosis infection or tuberculosis and an interferon-γ ELISPOT assay, we screened a synthetic peptide library representing 10% of the Mycobacterium tuberculosis proteome, selected to be enriched for Mycobacterium tuberculosis antigens. We defined a set of immunodominant CD8 antigens including part or all of 74 Mycobacterium tuberculosis proteins, only 16 of which are previously known CD8 antigens. Immunogenicity was associated with the degree of expression of mRNA and protein. Immunodominant antigens were enriched in cell wall proteins with preferential recognition of Esx protein family members, and within proteins comprising the Mycobacterium tuberculosis secretome. A validation study of immunodominant antigens demonstrated that these antigens were strongly recognized in Mycobacterium tuberculosisinfected individuals from a tuberculosis endemic region in Africa. The tuberculosis vaccine field will likely benefit from this greatly increased known repertoire of CD8 immunodominant antigens and definition of properties of Mycobacterium tuberculosis proteins important for CD8 antigenicity.
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    Mycobacterium tuberculosis Specific CD8+ T Cells Rapidly Decline with Antituberculosis Treatment
    (PLoS One, 2013) Nyendak, Melissa R.; Park, Byung; Null, Megan D.; Baseke, Joy; Swarbrick, Gwendolyn; Mayanja-Kizza4, Harriet; Nsereko, Mary; Johnson, Denise F.; Gitta, Phineas; Okwera, Alphonse; Goldberg, Stefan; Bozeman, Lorna; Johnson, John L.; Boom, W. Henry; Lewinsohn, Deborah A.; Lewinsohn, David M.; the Tuberculosis Research Unit and the Tuberculosis Trials Consortium
    Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8+ T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment. We sought to determine the relationship of Mtb specific CD4+ T cells and CD8+ T cells with duration of antituberculosis treatment. We performed a prospective cohort study, enrolling between June 2008 and August 2010, of HIV-uninfected Ugandan adults (n = 50) with acid-fast bacillus smear-positive, culture confirmed pulmonary TB at the onset of antituberculosis treatment and the Mtb specific CD4+ and CD8+ T cell responses to ESAT-6 and CFP-10 were measured by IFN-γ ELISPOT at enrollment, week 8 and 24.There was a significant difference in the Mtb specific CD8+ T response, but not the CD4+ T cell response, over 24 weeks of antituberculosis treatment (p<0.0001), with an early difference observed at 8 weeks of therapy (p = 0.023). At 24 weeks, the estimated Mtb specific CD8+ T cell response decreased by 58%. In contrast, there was no significant difference in the Mtb specific CD4+ T cell during the treatment. The Mtb specific CD4+ T cell response, but not the CD8+ response, was negatively impacted by the body mass index.Our data provide evidence that the Mtb specific CD8+ T cell response declines with antituberculosis treatment and could be a surrogate marker of response to therapy. Additional research is needed to determine if the Mtb specific CD8+ T cell response can detect early treatment failure, relapse, or to predict disease progression.
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    Postnatal Expansion, Maturation, and Functionality of MR1T Cells in Humans
    (Frontiers in Immunology, 2020) Swarbrick, Gwendolyn M.; Gela, Anele; Cansler, Meghan E.; Null, Megan D.; Duncan, Rowan B.; Nemes, Elisa; Shey, Muki; Nsereko, Mary; Mayanja-Kizza, Harriet; Kiguli, Sarah; Koh, Jeffrey; Hanekom, Willem A.; Hatherill, Mark; Lancioni, Christina; Lewinsohn, David M.; Scriba, Thomas J.; Lewinsohn, Deborah A.
    MR1-restricted T (MR1T) cells are defined by their recognition of metabolite antigens presented by the monomorphic MHC class 1-related molecule, MR1, the most highly conserved MHC class I related molecule in mammalian species. Mucosal-associated invariant T (MAIT) cells are the predominant subset of MR1T cells expressing an invariant TCR a-chain, TRAV1-2. These cells comprise a T cell subset that recognizes and mediates host immune responses to a broad array of microbial pathogens, including Mycobacterium tuberculosis. Here, we sought to characterize development of circulating human MR1T cells as defined by MR1-5-OP-RU tetramer labeling and of the TRAV1-2+ MAIT cells defined by expression of TRAV1-2 and high expression of CD26 and CD161 (TRAV1-2+CD161++CD26++ cells). We analyzed postnatal expansion, maturation, and functionality of peripheral blood MR1-5-OP-RU tetramer+ MR1T cells in cohorts from three different geographic settings with different tuberculosis (TB) vaccination practices, levels of exposure to and infection with M. tuberculosis. Early after birth, frequencies of MR1-5-OP-RU tetramer+ MR1T cells increased rapidly by several fold. This coincided with the transition from a predominantly CD4+ and TRAV1-2− population in neonates, to a predominantly TRAV1-2+CD161++CD26++ CD8+ population. We also observed that tetramer+ MR1T cells that expressed TNF upon mycobacterial stimulation were very low in neonates, but increased ∼10-fold in the first year of life. These functional MR1T cells in all age groups were MR1-5-OP-RU tetramer+TRAV1-2+ and highly expressed CD161 and CD26, markers that appeared to signal phenotypic and functional maturation of this cell subset. This age-associated maturation was also marked by the loss of naïve T cell markers on tetramer+ TRAV1-2+ MR1T cells more rapidly than tetramer+TRAV1-2− MR1T cells and non-MR1T cells. These data suggest that neonates have infrequent populations of MR1T cells with diverse phenotypic attributes; and that exposure to the environment rapidly and preferentially expands the MR1-5-OP-RU tetramer+TRAV1-2+ population of MR1T cells, which becomes the predominant population of functional MR1T cells early during childhood.
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    Whole Blood Interferon-Gamma Responses to Mycobacterium tuberculosis Antigens in Young Household Contacts of Persons with Tuberculosis in Uganda
    (Plos one, 2008) Lewinsohn, Deborah A.; Zalwango, Sarah.; Stein, Catherine M.; Mayanja-Kizza, Harriet.; Okwera, Alphonse.; Boom, Henry W.; Mugerwa, Roy D.; Whalen, Christopher C.
    Background: Due to immunologic immaturity, IFN-c-producing T cell responses may be decreased in young children compared to adults, thus we hypothesized that IFN-c responses to mycobacterial antigens in household contacts exposed to Mycobacterium tuberculosis (Mtb) would be impaired in young children relative to adults. The objective of this study was to compare whole blood IFN-c production in response to mycobacterial antigens between children and adults in Uganda. Methodology/Principal Findings: We studied household contacts of persons with culture-positive pulmonary tuberculosis (TB) enrolled in a cohort study conducted in Kampala, Uganda. Whole blood IFN-c production in response to Mtb culturefiltrate antigens was measured by ELISA and compared between infants (,2 years old, n = 80), young children (2 ,5 years old, n = 216), older children (5 ,15 years old, n = 443) and adults ($15 years old, n = 528). We evaluated the relationship between IFN-c responses and the tuberculin skin test (TST), and between IFN-c responses and epidemiologic factors that reflect exposure to Mtb, and the effect of prior BCG vaccination on IFN-c responses. Young household contacts demonstrated robust IFN-c responses comparable to those of adults that were associated with TST and known risk factors for infection. There was no effect of prior BCG immunization on the IFN-c response. Conclusions/Significance: Young children in a TB endemic setting can mount robust IFN-c responses generally comparable to those of adults, and as in adults, these responses correlated with the TST and known epidemiologic risk factors forMtb infection.