| First Author | Andreata F | Year | 2024 |
| Journal | Cell | Volume | 187 |
| Issue | 15 | Pages | 4078-4094.e21 |
| PubMed ID | 38897196 | Mgi Jnum | J:352545 |
| Mgi Id | MGI:7665901 | Doi | 10.1016/j.cell.2024.05.038 |
| Citation | Andreata F, et al. (2024) Therapeutic potential of co-signaling receptor modulation in hepatitis B. Cell |
| abstractText | 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. |
