Browsing by Subject "T cell differentiation"

Now showing 1 - 3 of 3
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    Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection
    (Elsevier, 2021) Xu, Wenxi; Snell, Laura M.; Guo, Mengdi; Boukhaled, Giselle; Macleod, Bethany L.; Li, Ming; Tullius, Michael V.; Guidos, Cynthia J.; Tsao, Ming-Sound; Divangahi, Maziar; Horwitz, Marcus A.; Liu, Jun; Brooks, David G.; Microbiology and Immunology, School of Medicine
    Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection. Here, we examined how chronic viral infections alter the pulmonary microenvironment to foster coinfection and worsen disease severity. We developed a coordinated system of chronic virus and Mtb infection that induced central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination, and heightened mortality. These disease states were not due to chronic virus-induced immunosuppression or exhaustion; rather, increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lymph node and subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17 differentiation and increasing pulmonary neutrophilia, which diminished long-term survival. Temporally restoring CD4 T cell induction overcame these diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function, and foster long-term coinfection.
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    Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential
    (Elsevier, 2021-11) Rogers, Dakota; Sood, Aditi; Wang, HanChen; van Beek, Jasper J.P.; Rademaker, Thomas J.; Artusa, Patricio; Schneider, Caitlin; Shen, Connie; Wong, Dylan C.; Bhagrath, Aanya; Lebel, Marie-Ève; Condotta, Stephanie A.; Richer, Martin J.; Martins, Andrew J.; Tsang, John S.; Barreiro, Luis B.; François, Paul; Langlais, David; Melichar, Heather J.; Textor, Johannes; Mandl, Judith N.; Microbiology and Immunology, School of Medicine
    CD4+ T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probe the heterogeneity present among naive CD4+ T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and chromatin landscape differences. Single-cell RNA sequencing shows that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a readout of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naive CD4+ T cells impact follicular helper T (TFH) cell versus non-TFH effector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naive CD4+ T cell chromatin landscapes that ultimately shape their effector potential.
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    Unexpected Help: Follicular Regulatory T Cells in the Germinal Center
    (Frontiers Media, 2018-07-02) Xie, Markus M.; Dent, Alexander L.; Microbiology and Immunology, School of Medicine
    Follicular helper T (Tfh) cells are necessary for germinal center (GC) formation and within the GC, provide key signals to B cells for their differentiation into plasmablasts and plasma cells that secrete high-affinity and isotype-switched antibody (Ab). A specialized subset of Foxp3+ T cells termed T follicular regulatory (Tfr) cells, also regulate the differentiation of Ab-secreting cells from the GC. Tfr-cell function in the GC is not well understood, however, the dominant paradigm currently is that Tfr cells repress excessive Tfh and GC B cell proliferation and help promote stringent selection of high-affinity B cells. A mouse model where the Bcl6 gene is specifically deleted in Foxp3+ T cells (Bcl6FC mice) allows the study of Tfr cell function with more precision than other approaches. Studies with this model have shown that Tfr cells play a key role in maintaining GC B cell proliferation and Ab levels. Part of the mechanism for this positive "helper" effect of Tfr cells on the GC is Tfr cell-derived IL-10, which can promote B cell growth and entry into the dark zone of the GC. Recent studies on Tfr cells support a new paradigm for Tfr cell function in the GC reaction. Here, we review studies on Tfr cell functions and discuss the evidence that Tfr cells can have a major helper role in the GC-dependent Ab response.