Search

Reversing CD8 + T cell dysfunction is crucial in treating chronic hepatitis B virus (HBV) infection, yet specific molecular targets remain unclear. Our study analyzed co-signaling receptors during hepatocellular priming and traced the trajectory and fate of dysfunctional HBV-specific CD8 + T cells. Early on, these cells upregulate PD-1, CTLA-4, LAG-3, OX40, 4-1BB, and ICOS. While blocking co-inhibitory receptors had minimal effect, activating 4-1BB and OX40 converted them into antiviral effectors. Prolonged stimulation led to a self-renewing, long-lived, heterogeneous population with a unique transcriptional profile. This includes dysfunctional progenitor/stem-like (T SL ) cells and two distinct dysfunctional tissue-resident memory (T RM ) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to T SL . In chronic settings, only 4-1BB stimulation conferred antiviral activity. In HBeAg + chronic patients, 4-1BB activation showed the highest potential to rejuvenate dysfunctional CD8 + T cells. Targeting all dysfunctional T cells, rather than only stem-like precursors, holds promise for treating chronic HBV infection., Competing Interests: Declaration of interests M. Iannacone participates in advisory boards/consultantship for Asher Biotherapeutics, GentiBio, BlueJay Therapeutics, and Aligos Therapeutics. L.G.G. participates in boards/consultantship for Genenta Science, Epsilen Bio, Aligos Therapeutics, Medicxi, Chroma Medicine, and Ananda Immunotherapies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Monitoring antigen-specific T cell frequency and function is essential to assess the host immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we present a FluoroSpot assay for concurrently detecting ex vivo antiviral cytokine production by SARS-CoV-2-specific T cells following peptide stimulation. We then detail intracellular cytokine staining by flow cytometry to further validate the FluoroSpot assay results and define the specific T cell subpopulations. For complete details on the use and execution of this protocol, please refer to Tiezzi et al. (2023). 1 ., Competing Interests: Declaration of interests C.F. has received grants from Gilead and AbbVie and is a consultant at Gilead, AbbVie, Vir Biotechnology Inc, Arrowhead, Transgene, and BMS., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Humoral immunity is sensitive to evasion by SARS-CoV-2 mutants, but CD8 T cells seem to be more resistant to mutational inactivation. By a systematic analysis of 30 spike variant peptides containing the most relevant VOC and VOI mutations that have accumulated overtime, we show that in vaccinated and convalescent subjects, mutated epitopes can have not only a neutral or inhibitory effect on CD8 T cell recognition but can also enhance or generate de novo CD8 T cell responses. The emergence of these mutated T cell function enhancing epitopes likely reflects an epiphenomenon of SARS-CoV-2 evolution driven by antibody evasion and increased virus transmissibility. In a subset of individuals with weak and narrowly focused CD8 T cell responses selection of these heteroclitic-like epitopes may bear clinical relevance by improving antiviral protection. The functional enhancing effect of these peptides is also worth of consideration for the future development of new generation, more potent COVID-19 vaccines., Competing Interests: A.T. and D.C. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. C.F.: Grant: Gilead, Abbvie. Consultant: Gilead, Abbvie, Vir Biotechnology Inc, Arrowhead, Transgene, BMS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 The Authors.)