ORCID Profile
0000-0003-4429-0110
Current Organisation
McGill University and Genome Québec Innovation Centre
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Publications
Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents
Publisher: American Society for Clinical Investigation
Date: 09-2021
DOI: 10.1172/JCI150143
Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria
Publisher: Cold Spring Harbor Laboratory
Date: 31-08-2020
DOI: 10.1101/2020.08.31.274589
Abstract: Inborn errors of human IFN-γ immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, including IFNG , by altering chromatin accessibility and DNA methylation in CD4 + T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2 + γδ T lymphocytes, and of non-mycobacterial-reactive classic T H 1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-γ. Other IFN-γ-producing lymphocyte subsets however develop normally, but with low levels of IFN-γ production, with exception of Vδ2 − γδ T lymphocytes, which produce normal amounts of IFN-γ in response to non-mycobacterial stimulation, and non-classic T H 1 (T H 1*) lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-γ production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2 + γδ T cells), with mycobacterial-specific, IFN-γ-producing, purely adaptive αβ T H 1* cells unable to compensate for this deficit.
Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria
Publisher: Elsevier BV
Date: 12-2020
Novel Effects of Chromosome Y on Cardiac Regulation, Chromatin Remodeling, and Neonatal Programming in Male Mice
Publisher: The Endocrine Society
Date: 12-2013
DOI: 10.1210/EN.2013-1699
Abstract: Little is known about the functions of chromosome Y (chrY) genes beyond their effects on sex and reproduction. In hearts, postpubertal testosterone affects the size of cells and the expression of genes differently in male C57BL/6J than in their C57.Y(A) counterparts, where the original chrY has been substituted with that from A/J mice. We further compared the 2 strains to better understand how chrY polymorphisms may affect cardiac properties, the latter being sexually dimorphic but unrelated to sex and reproduction. Genomic regions showing occupancy with androgen receptors (ARs) were identified in adult male hearts from both strains by chromatin immunoprecipitation. AR chromatin immunoprecipitation peaks (showing significant enrichment for consensus AR binding sites) were mostly strain specific. Measurements of anogenital distances in male pups showed that the biologic effects of perinatal androgens were greater in C57BL/6J than in C57.Y(A). Although perinatal endocrine manipulations showed that these differences contributed to the strain-specific differences in the response of adult cardiac cells to testosterone, the amounts of androgens produced by fetal testes were not different in each strain. Nonetheless, chrY polymorphisms associated in newborn pups' hearts with strain-specific differences in genomic regions showing either AR occupancy, accessible chromatin sites, or trimethylation of histone H3 Lysine 4 marks, as well as with differential expression of 2 chrY-encoded histone demethylases. In conclusion, the effects of chrY on adult cardiac phenotypes appeared to result from an interaction of this chromosome with the organizational programming effects exerted by the neonatal testosterone surge and show several characteristics of being mediated by an epigenetic remodeling of chromatin.
Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria
Publisher: Elsevier BV
Date: 02-2023
Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
Publisher: Public Library of Science (PLoS)
Date: 03-11-2022
DOI: 10.1371/JOURNAL.PGEN.1010367
Abstract: Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10 -7 ). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
Transcriptional mechanisms that control expression of the macrophage colony-stimulating factor receptor locus
Publisher: Portland Press Ltd.
Date: 31-07-2017
DOI: 10.1042/CS20170238
Abstract: The proliferation, differentiation, and survival of cells of the macrophage lineage depends upon signals from the macrophage colony-stimulating factor (CSF) receptor (CSF1R). CSF1R is expressed by embryonic macrophages and induced early in adult hematopoiesis, upon commitment of multipotent progenitors to the myeloid lineage. Transcriptional activation of CSF1R requires interaction between members of the E26 transformation-specific family of transcription factors (Ets) (notably PU.1), C/EBP, RUNX, AP-1/ATF, interferon regulatory factor (IRF), STAT, KLF, REL, FUS/TLS (fused in sarcoma/ranslocated in liposarcoma) families, and conserved regulatory elements within the mouse and human CSF1R locus. One element, the Fms-intronic regulatory element (FIRE), within intron 2, is conserved functionally across all the amniotes. Lineage commitment in multipotent progenitors also requires down-regulation of specific transcription factors such as MYB, FLI1, basic leucine zipper transcriptional factor ATF-like (BATF3), GATA-1, and PAX5 that contribute to differentiation of alternative lineages and repress CSF1R transcription. Many of these transcription factors regulate each other, interact at the protein level, and are themselves downstream targets of CSF1R signaling. Control of CSF1R transcription involves feed–forward and feedback signaling in which CSF1R is both a target and a participant and dysregulation of CSF1R expression and/or function is associated with numerous pathological conditions. In this review, we describe the regulatory network behind CSF1R expression during differentiation and development of cells of the mononuclear phagocyte system.
Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency
Publisher: Springer Science and Business Media LLC
Date: 20-08-2018
Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy
Publisher: Elsevier BV
Date: 07-2021
Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child
Publisher: Springer Science and Business Media LLC
Date: 28-06-2021
Related Organisations
McGill University And Genome Québec Innovation Centre
Location: Canada
Related Funding Activities
No related grants have been discovered for David Langlais.