Specific targeting of IL-1β activity to CD8+ T cells allows for safe use as a vaccine adjuvant

Abstract

Annual administration and reformulation of influenza vaccines is required for protection against seasonal infections. However, the induction of strong and long-lasting T cells is critical to reach broad and potentially lifelong antiviral immunity. The NLRP3 inflammasome and its product interleukin-1β (IL-1β) are pivotal mediators of cellular immune responses to influenza, yet, overactivation of these systems leads to side effects, which hamper clinical applications. Here, we present a bypass around these toxicities by targeting the activity of IL-1β to CD8 + T cells. Using this approach, we demonstrate safe inclusion of IL-1β as an adjuvant in vaccination strategies, leading to full protection of mice against a high influenza virus challenge dose by raising potent T cell responses. In conclusion, this paper proposes a class of IL-1β-based vaccine adjuvants and also provides further insight in the mechanics of cellular immune responses driven by IL-1β.

Interleukin-1 as Innate Mediator of T Cell Immunity

“…Recently, we developed an AcTakine molecule that delivers IL-1β activity to CD8 + T cells and safely promotes T cell activation, proliferation and memory differentiation. Inclusion of this AcTakine in an experimental prime/boost IAV vaccine established protection against a high influenza challenge dose, which correlated with the formation of a potent and durable IAV-specific cellular immune response ( 297 ). The use of this strategy could be expanded to other models, for instance to evaluate antitumor CD8 + T cell activation by IL-1β.…”

Selective IL-1 activity on CD8+ T cells empowers antitumor immunity and synergizes with neovasculature-targeted TNF for full tumor eradication

“…25 Previously, we reported on the development of an AcTakine that targets activity of the IL-1β Q148G mutant to CD8 + T cells (CD8α AcTaleukin-1/ALN-1) in an influenza A model. 26 Here, we demonstrate that CD8α ALN-1 drives antitumor CD8 + T cell responses in subcutaneous (s.c.) melanoma (B16) and Lewis lung carcinoma (LLC) models. The potent cellular adjuvant effect of CD8α ALN-1 empowers epitope spreading, expansion and effector functionality of endogenous host T cells and enhances the efficacy of ATCT.…”

“…20 Besides improved antitumor action, we noticed a drastic reduction in toxicity on administration of CD8α ALN-1, which is in accordance with data from our earlier work. 26 How cancer vaccines will deal with tumor heterogeneity remains an important concern. As tumors are highly polyclonal, the breadth of the CD8 + T cell response will be an important determinant of clinical efficacy.…”

“… 25 Previously, we reported on the development of an AcTakine that targets activity of the IL-1β Q148G mutant to CD8 + T cells (CD8α AcTaleukin-1/ALN-1) in an influenza A model. 26 …”

ACE2 and Innate Immunity in the Regulation of SARS-CoV-2-Induced Acute Lung Injury: A Review

“…The NLRP3 inflammasome could be activated through the trans-Golgi network (TGN) owing to the stimulation of ion channels in the host cell membrane by viral porins. These viral porins, including the envelope (E) protein of the SARS-CoV2 virus and the M2 protein of the influenza virus, could subsequently activate caspase-1 [ 160 , 161 , 162 ]. NLRP3 activated by viral porins triggered pre-IL-1β and pre-IL-18 hydrolysis by caspase-1, generating excessive IL-1β, IL-18, and TNF-α and recruiting immune cells into the lung, leading to the death of infected cells.…”