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Significance: Chagas disease (CD) affects several million people in Latin America and is spreading beyond its classical boundaries due to the migration of infected host and insect vectors, HIV co-infection, and blood transfusion. The current therapy is not adequate for treatment of the chronic phase of CD, and new drugs are warranted. Recent Advances: Trypanosoma cruzi is equipped with a specialized and complex network of antioxidant enzymes that are located at different subcellular compartments which defend the parasite against host oxidative assaults. Recently, strong evidence has emerged which indicates that enzyme components of the T. cruzi antioxidant network (cytosolic and mitochondrial peroxiredoxins and trypanothione synthetase) in naturally occurring strains act as a virulence factor for CD. This precept is recapitulated with the observed increased resistance of T. cruzi peroxirredoxins overexpressers to in vivo or in vitro nitroxidative stress conditions. In addition, the modulation of mitochondrial superoxide radical levels by iron superoxide dismutase (FeSODA) influences parasite programmed cell death, underscoring the role of this enzyme in parasite survival. Critical Issues: The unraveling of the biological significance of FeSODs in T. cruzi programmed cell death in the context of chronic infection in CD is still under examination. Future Directions: The role of the antioxidant enzymes in the pathogenesis of CD, including parasite virulence and persistence, and their feasibility as pharmacological targets justifies further investigation. Antioxid. Redox Signal. 19, 723-734.

A modified version of the Trier Social Stress Test (TSST) was employed to determine whether exposure to a virtual audience using virtual reality (VR) technology would prompt an increase of neuroendocrine activity comparable to that prompted by a real audience. Following an anticipatory period, participants completed a speech or a speech-plus-math challenge in front of either a virtual audience, a panel of judges they were led to believe was behind a one-way mirror, or an audience comprised of confederates. An additional group that had prepared a speech was simply directed to observe the virtual audience but did not deliver the speech. Finally, a control group completed questionnaires for the duration of the experiment. Cortisol samples were obtained upon arrival to the laboratory, just before the challenge, and 15 and 30 minutes after the task. Participants also completed a measure assessing stressor appraisals of the task before and after the challenge. Anticipation of the task was associated with a modest increase of cortisol levels, and a further rise of cortisol was evident in response to the challenge. The neuroendocrine changes evoked by the virtual audience were comparable to those elicited by the imagined audience (behind the one-way mirror) but less than changes evoked by the panel of confederates. Stressor appraisals were higher post-challenge compared to those reported prior to the task; however, appraisals were similar across each group. These data suggest that VR technology may be amenable to evaluating the impact of psychosocial stressors such as the TSST.

Tumor antigen–specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1 hi CD39 + CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.

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