Biology subjects

Taplitz, R.

Publications and source records attributed to Taplitz, R..

3 recordsLinked to original sources

bioRxiv2022

Peripheral blood T-cell deficiency and hyperinflammatory monocyte responses associate with MAC lung disease

RationaleAlthough nontuberculous mycobacterial (NTM) disease is a growing problem, available treatments are suboptimal and diagnostic tools are inadequate. Immunological mechanisms of susceptibility to NTM disease are poorly understood. ObjectiveTo understand NTM pathogenesis, we evaluated innate and antigen-specific adaptive immune responses to Mycobacterium avium complex (MAC) in individuals with MAC lung disease (MACDZ). MethodsWe synthesized 15mer MAC-, NTM-, or MAC/Mtb-specific peptides and stimulated peripheral blood mononuclear cells (PBMC) with pools of these peptides. We measured T-cell responses by cytokine production, expression of surface markers, and analysis of global gene expression in 27 MACDZ individuals and 32 healthy controls. We also analyzed global gene expression in Mav-infected and uninfected peripheral blood monocytes from 17 MACDZ and 17 healthy controls. Measurements and Main ResultsWe were unable to detect T-cell responses against the peptide libraries or Mav lysate that has increased reactivity in MACDZ subjects compared to controls. T-cell responses to non-mycobacteria derived antigens were preserved. MACDZ individuals had a lower frequency of Th1 and Th1* T-cell populations. By contrast, global gene expression analysis demonstrated upregulation of proinflammatory pathways in uninfected and Mav-infected monocytes derived from MACDZ subjects compared to controls. ConclusionsPeripheral blood T-cell responses to Mycobacterial antigens and the frequency of Th1 and Th1* cell populations are diminished in individuals with MAC disease. In contrast, MACDZ subjects had hyperinflammatory monocyte responses. Together, these data suggest a novel immunologic defect which underlies MAC pathogenesis and includes concurrent innate and adaptive dysregulation.

immunology↗

bioRxiv2021

A novel Mycobacterium tuberculosis-specific subunit vaccine provides synergistic immunity upon co-administration with Bacillus Calmette-Guerin

Tuberculosis (TB) remains a global health crisis. Following encouraging clinical results of subunit vaccination and revaccination with Bacillus Calmette-Guerin (BCG), it has been suggested to combine BCG and subunit vaccines for increased efficacy. Current subunit vaccines are almost exclusively designed as BCG boosters. The goal of this study was to design a subunit vaccine that does not share antigens with BCG and explore the advantages of a BCG+subunit vaccine co-administration strategy, where the two vaccines do not cross-react. Eight protective antigens were selected to create a Mycobacterium tuberculosis (Mtb)-specific subunit vaccine, named H107. Whereas subunit vaccines with BCG-shared antigens displayed cross-reactivity to BCG in vivo in both mice and humans, H107 showed no cross-reactivity and did not inhibit BCG colonization in mice. Encouragingly, co-administering H107 with BCG (BCG+H107) led to increased adaptive immune responses against both H107 and BCG leading to improved BCG-mediated immunity. In contrast to subunit vaccines with BCG-shared antigens, boosting BCG with H107 led to substantial expansion of clonal diversity in the T cell repertoire, and BCG+H107 co-administration conferred significantly increased Th17 responses and less differentiated CD4 T cells. CD4 T cells induced by BCG+H107 maintained functional superiority after Mtb infection, and BCG+H107 provided significantly increased long-term protection compared to both BCG and H107 alone, as well as, BCG co-administered with a subunit vaccine composed of antigens shared with BCG. Overall, we identify several advantages of combining an Mtb-specific subunit vaccine with BCG and introduce H107 as a BCG-complementing vaccine with distinctive value for co-administration with BCG.

immunology↗

bioRxiv2018

No cell is an island: circulating T cell:monocyte complexes are markers of immune perturbations

Our results highlight for the first time that a significant proportion of cell doublets in flow cytometry, previously believed to be the result of technical artefacts and thus ignored in data acquisition and analysis, are the result of true biological interaction between immune cells. In particular, we show that cell:cell doublets pairing a T cell and a monocyte can be directly isolated from human blood, and high resolution microscopy shows polarized distribution of LFA1/ICAM1 in many doublets, suggesting in vivo formation. Intriguingly, T cell:monocyte complex frequency and phenotype fluctuate with the onset of immune perturbations such as infection or immunization, reflecting expected polarization of immune responses. Overall these data suggest that cell doublets reflecting T cell-monocyte in vivo immune interactions can be detected in human blood and that the common approach in flow cytometry to avoid studying cell:cell complexes should be revisited.

immunology↗