{Reference Type}: Journal Article
{Title}: Therapeutic potential of co-signaling receptor modulation in hepatitis B.
{Author}: Andreata F;Laura C;Ravà M;Krueger CC;Ficht X;Kawashima K;Beccaria CG;Moalli F;Partini B;Fumagalli V;Nosetto G;Di Lucia P;Montali I;Garcia-Manteiga JM;Bono EB;Giustini L;Perucchini C;Venzin V;Ranucci S;Inverso D;De Giovanni M;Genua M;Ostuni R;Lugli E;Isogawa M;Ferrari C;Boni C;Fisicaro P;Guidotti LG;Iannacone M;
{Journal}: Cell
{Volume}: 187
{Issue}: 15
{Year}: 2024 Jul 25
{Factor}: 66.85
{DOI}: 10.1016/j.cell.2024.05.038
{Abstract}: 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 (TSL) cells and two distinct dysfunctional tissue-resident memory (TRM) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to TSL. 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.