Introduction: Toward an Engaged Feminist Heritage Praxis

We advocate a feminist approach to archaeological heritage work in order to transform heritage practice and the production of archaeological knowledge. We use an engaged feminist standpoint and situate intersubjectivity and intersectionality as critical components of this practice. An engaged feminist approach to heritage work allows the discipline to consider women’s, men’s, and gender non-conforming persons’ positions in the field, to reveal their contributions, to develop critical pedagogical approaches, and to rethink forms of representation. Throughout, we emphasize the intellectual labor of women of color, queer and gender non-conforming persons, and early white feminists in archaeology

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases

Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah−/− mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease

Rapid interferon independent expression of IFITM3 following T cell activation protects cells from influenza virus infection

<div><p>Interferon-induced transmembrane protein 3 (IFITM3) is a potent antiviral protein that enhances cellular resistance to a variety of pathogens, including influenza virus. Classically defined as an interferon-stimulated gene, expression of IFITM3 on cells is rapidly up-regulated in response to type I and II interferon. Here we found that IFITM3 is rapidly up-regulated by T cells following their activation and this occurred independently of type I and II interferon and the interferon regulatory factors 3 and 7. Up-regulation of IFITM3 on effector T cells protected these cells from virus infection and imparted a survival advantage at sites of virus infection. Our results show that IFITM3 expression on effector T cells is crucial for these cells to mediate their effector function and highlights an interferon independent pathway for the induction of IFITM3 which, if targeted, could be an effective approach to harness the activity of IFITM3 for infection prevention.</p></div

Activation-induced up-regulation of IFITM3 expression by T cells is not driven by a secreted factor and occurs independently of the transcription factors IRF3 and IRF7.

(A) Supernatants from CD8+ T cell cultures, before (0) and 2–3 days after in vitro activation with anti-CD3/28 were recovered and the level of inflammatory cytokines was measured using a cytometric bead array. Data pooled from 3 independent experiments. Bars represent the mean + SEM. (B-C) TCR transgenic OT-I CD8+ T cells and B6 CD8+ T cells were mixed 1:1 and co-cultured in the presence of SIINFEKL peptide for 3 days. After co-culture, OT-I and B6 cells were sort purified and levels of IFITM3 expression were determined by western blot. (B) Schematic of the experimental procedure. (C) Western blot depicting levels of IFITM3 expression. Data are representative of 3 experiments. Actin was included as a loading control throughout. (D) CFSE-labelled naïve CD8+ T cells purified from WT, IRF3 KO, IRF7 KO, or IRF3/7 KO were activated in vitro with anti-CD3/28 and cultured for 3 days. Representative flow cytometry profiles of CFSE expression confirm division of CD8+ T cells. Grey histograms represent unstimulated cells. (E) Western blot analysis of IFITM3 expression by WT (B6), IRF3 KO, IRF7 KO, or IRF3/7 KO CD8+ T cells before (0) and 2–3 days after in vitro activation with anti-CD3/28. Data are representative of three independent experiments.</p

Activation induced up-regulation of IFITM3 on T cells occurs independently of type I and type II interferons.

(A) Western blot analysis of IFITM3 expression by CD8+ T cells before (0) and after in vitro activation with anti-CD3/28 and 1–5 days in culture. Actin was included as a loading control throughout. (B) Western blot analysis of IFITM3 expression by CD4+ and CD8+ T cells from WT or IFNAR-/- before (0) and 3 days after in vitro activation with anti-CD3/28. Data are representative of three independent experiments. (C) Western blot analysis of IFITM3 expression by WT IFNγ -/- CD4+ and CD8+ T cells before (0) and 3 days after in vitro activation with anti-CD3/28. Data are representative of three independent experiments. (D) Western blot analysis of IFITM3 expression by WT or IFNγR x IFNAR KO CD8+ T cells before (-) and 18 hrs after exposure to IFNα and IFNγ. Data are representative of three independent experiments. (E-F) Western blot analysis of IFITM3 expression by WT or IFNγR x IFNAR KO naïve (E) CD4+ and (F) CD8+ T cells before (0) and 3 days after in vitro activation with anti-CD3/28. Data are representative of three independent experiments. (G-H) Intracellular staining for influenza A virus nuclear protein (Flu-NP) in naïve CD8+ T cells isolated from WT B6 and (G) IFNAR KO or (H) IFNγ KO mice infected in vitro with influenza virus strain X31 (multiplicity of infection, moi = 1) and cultured for 24 and 48 hrs. Data are pooled from 3 independent experiments. Symbols represent the mean ± SEM. (I-J) Western blot analysis of IFITM3 expression by WT B6 CD8+ T cells and (I) IFNγ KO CD8+ T cells or (J) IFNAR KO CD8+ T cells before (0) and 1 and 2 days after infection with influenza virus strain X-31 (moi = 1). Data are pooled from 3 independent experiments.</p