Biology subjects

Canna, S. W.

Publications and source records attributed to Canna, S. W..

4 recordsLinked to original sources

bioRxiv2026

The innate cytokine IL-18 inhibits CNS autoimmunity through preferential activation of protective CD8 T-cells

Chronic innate immune activation is widely thought to challenge self-tolerance. IL-18 is an inflammasome-activated cytokine and potent amplifier of T-cell activation whose excess is associated with certain autoinflammatory, but not autoimmune, diseases. We tested how excess IL-18 affected susceptibility to experimental autoimmune encephalomyelitis (EAE), a model of CNS autoimmunity driven by IL-18 responsive, myelin-autoreactive CD4 T-cells (CD4Tauto). We hypothesized that IL-18 would exacerbate immunopathology in EAE. Instead, excess IL-18 was profoundly protective. IL-18 did not impair CD4Tauto priming or early expansion. Rather, it selectively restricted later accumulation of highly activated, splenic CD4Tauto bearing CNS-homing integrins. Despite high IL-18 receptor expression on CD4Tauto and Foxp3+ CD4Treg, excess IL-18 acted specifically through mature CD8 T-cells to promote a highly activated CD8Teffector phenotype and IFN{gamma}-dependent protection from EAE. Therapeutic administration of a "decoy-resistant" IL-18 agonist (DR-18) to wild-type mice, even after CD4Tauto expansion, nevertheless engaged CD8 T-cells to diminish CD4Tauto abundance, prevent CNS infiltration, and block immunopathology. Together, these findings demonstrate IL-18s unexpected, dominant ability to mobilize protective CD8 T-cells against highly activated CD4Tauto and protect from CNS autoimmune pathology; illustrating a potential therapeutically relevant mechanism by which autoinflammation actively opposes autoimmunity.

immunology↗

bioRxiv2025

Multimodal induction of fulminant HLH by IL-18 includes virus-specific NK immunodeficiency

Macrophage Activation Syndrome (MAS) is a cytokine storm syndrome associated with Stills Disease, XIAP deficiency, and elevation of both total and free IL-18. Modeling excess IL-18 using Il18tg mice, we found mild NK-cytopenia and cytotoxic T lymphocyte (CTL) activation in resting mice reminiscent of Stills patients. Infection with Lymphocytic Choriomeningitis Virus (LCMV) triggered MAS via and IFN{gamma}, despite normal viral clearance. Il18tg NK cell transcriptomes showed replicative activity, but few changes in canonical NK function or maturation pathways. LCMV clearance is NK-independent, so we challenged Il18tg mice with mousepox in which NK cells are critical early orchestrators of clearance. Il18tg mices NK cells failed to activate or expand, but mousepox further activated their CTL and early viral control was normal. Il18tg mice soon developed "MAS" including hepatosplenic necrosis, but (contrasting with LCMV) they showed poor virus-specific CTL expansion and viral clearance. Though more normal at rest, Il18bpKO mices NK cells were similarly inert upon mousepox infection, and the mice succumbed to viremic MAS like Il18tg. Rescue of Il18tg mice, and mousepox-specific CTL responses, by NK cell transfer required in vitro NK pre-activation. Thus, IL-18 can induce both hyperinflammation (CTL hyperactivation) and immunodeficiency (NK cell hypoactivation) depending on the nature of the infectious trigger.

immunology↗

bioRxiv2024

Altered Purinergic Signaling and CD8+ T Cell Dysregulation in STAT3 GOF Syndrome

Signal transduction downstream of activating stimuli controls CD8+ T cell biology, however these external inputs can become uncoupled from transcriptional regulation in Primary Immune Regulatory Disorders (PIRD). Gain-of-function (GOF) variants in STAT3 amplify cytokine signaling and cause a severe PIRD characterized by early onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity. The molecular mechanisms by which STAT3 GOF variants drive this pathology remain unclear. We found that naive CD8+ T cells have an increased capacity for IFN-{gamma} and TNF- secretion. Given this dysregulation of CD8+ T cell function, we evaluated changes in immunoregulatory pathways and found evidence of dysregulated purinergic signaling via high dimensional immune profiling, single-cell RNA sequencing, and functional assessment. Specifically, while expression of CD39, which transforms ATP to AMP, was increased on CD8+ T cells from patients with STAT3 GOF, downstream purinergic family members, CD73 and the adenosine receptor, A2AR, were downregulated, impairing the potential to produce or sense inhibitory adenosine. Patients with STAT3 GOF can be clinically treated with JAK inhibitors and this partially normalized naive CD8+ T cell dysregulation, including aberrant cytokine production. The extent of normalization of cytokine secretion scaled with normalization of CD73 and A2AR. This suggests that a dysregulated purinergic signaling axis plays an important role in CD8+ T cell dysregulation in STAT3 GOF, which may have implications for other inflammatory disorders with amplified STAT signaling. One Sentence SummaryAmplified STAT3 signaling in CD8+ T cells from STAT3 GOF patients alters purinergic signaling and dysregulates CD8+ T cell function.

immunology↗

bioRxiv2021

Causal inference using deep-learning variable selection identifies and incorporates direct and indirect causalities in complex biological systems

In complex diseases, causal structure learning across biological variables is critical to identify modifiable triggers or potential therapeutic agents. A limitation of existing causal learning methods is that they cannot identify indirect causal relations, those that would interact through latent mediating variables. We developed the first computational method that identifies both direct and indirect causalities, causal inference using deep-learning variable-selection (causalDeepVASE). To accurately identify indirect causalities and incorporate them with direct causalities, causalDeepVASE develops a deep neural network approach and extends a flexible causal inference method. In simulated and biological data of various contexts, causalDeepVASE outperforms existing methods in identifying expected or validated causal relations. Further, causalDeepVASE facilitates a systematic understanding of complex diseases. For example, causalDeepVASE uniquely identified a possible causal relation between IFN{gamma} and creatinine suggested in a polymicrobial sepsis model. In future biomedical studies, causalDeepVASE can facilitate the identification of driver genes and therapeutic agents.

bioinformatics↗