Biology subjects

Heath, W.

Publications and source records attributed to Heath, W..

3 recordsLinked to original sources

bioRxiv2021

High expression of CD38 and MHC class II on CD8+ T cells during severe influenza disease reflects bystander activation and trogocytosis

Although co-expression of CD38 and HLA-DR on CD8+ T cells reflects activation during influenza, SARS-CoV-2, Dengue, Ebola and HIV-1 viral infections, high and prolonged CD38+HLA-DR+ expression can be associated with severe and fatal disease outcomes. As the expression of CD38+HLA-DR+ is poorly understood, we used mouse models of influenza A/H7N9, A/H3N2 and A/H1N1 infection to investigate the mechanisms underpinning CD38+MHC-II+ phenotype on CD8+ T-cells. Our analysis of influenza-specific immunodominant DbNP366+CD8+ T-cell responses showed that CD38+MHC-II+ co-expression was detected on both virus-specific and bystander CD8+ T-cells, with increased numbers of both CD38+MHC-II+CD8+ T-cell populations observed in the respiratory tract during severe infection. To understand the mechanisms underlying CD38 and MHC-II expression, we also used adoptively-transferred transgenic OT-I CD8+ T-cells recognising the ovalbumin-derived KbSIINFEKL epitope and A/H1N1-SIINKEKL infection. Strikingly, we found that OT-I cells adoptively-transferred into MHC-II-/- mice did not display MHC-II after influenza virus infection, suggesting that MHC-II was acquired via trogocytosis in wild-type mice. Additionally, detection of CD19 on CD38+MHC II+ OT-I cells further supports that MHC-II was acquired by trogocytosis, at least partially, sourced from B-cells. Our results also revealed that co-expression of CD38+MHC II+ on CD8+ T-cells was needed for the optimal recall ability following secondary viral challenge. Overall, our study provides evidence that both virus-specific and bystander CD38+MHC-II+ CD8+ T-cells are recruited to the site of infection during severe disease, and that MHC-II expression occurs via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38+MHC II+ phenotype for CD8+ T-cell memory establishment and recall. SummaryCo-expression of CD38 and MHC-II on CD8+ T cells is recognized as a classical hallmark of activation during viral infections. High and prolonged CD38+HLA-DR+ expression, however, can be associated with severe disease outcomes and the mechanisms are unclear. Using our established influenza wild-type and transgenic mouse models, we determined how disease severity affected the activation of influenza-specific CD38+MHC-II+CD8+ T cell responses in vivo and the antigenic determinants that drive their activation and expansion. Overall, our study provides evidence that both virus-specific and bystander CD38+MHC-II+ CD8+ T-cells are recruited to the site of infection during severe disease, and that MHC-II expression occurs, at least in part, via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38+MHC II+ phenotype for CD8+ T-cell memory establishment and recall.

immunology↗

bioRxiv2020

C. elegans processes sensory information to choose between freeloading and self-defense strategies

Hydrogen peroxide is the preeminent chemical weapon that organisms use for combat. Individual cells rely on conserved defenses to prevent and repair peroxide-induced damage, but whether similar defenses might be coordinated across cells in animals remains poorly understood. Here, we identify a neuronal circuit in the nematode Caenorhabditis elegans that processes information perceived by two sensory neurons to control the induction of hydrogen-peroxide defenses in the organism. We found that catalases produced by Escherichia coli, the nematodes food source, can deplete hydrogen peroxide from the local environment and thereby protect the nematodes. In the presence of E. coli, the nematodes neurons signal via TGF{beta}-insulin/IGF1 relay to target tissues to repress expression of catalases and other hydrogen-peroxide defenses. This adaptive strategy is the first example of a multicellular organism modulating its defenses when it expects to freeload from the protection provided by molecularly orthologous defenses from another species.

neuroscience↗

bioRxiv2017

Development of a Novel CD4+ TCR Transgenic Line that Reveals a Dominant Role for CD8+ DC and CD40-Signaling in the Generation of Helper and CTL Responses to Blood Stage Malaria

We describe an MHC II (IAb)-restricted T cell receptor (TCR) transgenic mouse line that produces CD4+ T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4+ T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, P. chabaudi AS and P. yoelii 17XNL) and human (P. falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of antibody to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8+ T cell-mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4+ T cells and the previously described PbT-I CD8+ T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8+ DC (a subset of XCR1+ DC) were the major antigen presenting cell (APC) responsible for activation of both T cell subsets, though other DC also contributed to CD4+ T cell responses. Depletion of CD8+ DC at the beginning of infection prevented ECM development and impaired both Th1 and Tfh responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4+ T cell immunity during malaria and provides evidence that CD4+ T cell help, acting via CD40L signalling, can promote immunity or pathology to blood stage malaria largely through antigen presentation by CD8+ DC.

immunology↗