Carro, S. | bioRxiv Science

bioRxiv2025

Cutting Edge: An mRNA Platform to Create Isolated, Monospecific Th1 Responses

Helper T cells (TCD4) are lynchpins of adaptive immune responses. Since each TCD4 expresses a single T cell receptor, recognizing an epitope within major histocompatibility complex class II (MHCII), it is often desirable to study a population that responds to the same epitope. We devised a novel method of selective immunization to produce a robust, monospecific TCD4 in mice using a modular mRNA vector. The vector encodes the target epitope attached via flexible linker to MHCII. Immunization with this mRNA selectively elicits TCD4 responses across a range of epitopes and MHCII alleles. These TCD4 show robust, polyfunctional Th1 cytokine release when evaluated in vitro. Additionally, we tested the activity of these TCD4 cells during Salmonella enterica infection, a model of Th1-dependent immune response, and demonstrated their efficacy in vivo in curtailing infection.

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↗