Therapeutic potential of co-signaling receptor modulation in hepatitis B

被引：18

作者：

Andreata, Francesco ^{[1
,2
]}

Laura, Chiara ^{[1
,2
,3
]}

Rava, Micol ^{[1
,2
]}

Krueger, Caroline C. ^{[1
,2
]}

Ficht, Xenia ^{[1
,2
]}

Kawashima, Keigo ^{[1
]}

Beccaria, Cristian G. ^{[1
,2
]}

Moalli, Federica ^{[1
]}

Partini, Bianca ^{[1
,2
]}

Fumagalli, Valeria ^{[1
,2
]}

Nosetto, Giulia ^{[1
,2
]}

Di Lucia, Pietro ^{[1
,2
]}

Montali, Ilaria ^{[4
]}

Garcia-Manteiga, JoseM. ^{[1
,3
]}

Bono, Elisa B.

Giustini, Leonardo ^{[1
]}

Perucchini, Chiara ^{[1
]}

Venzin, Valentina ^{[1
]}

Ranucci, Serena ^{[1
]}

Inverso, Donato ^{[1
,2
]}

De Giovanni, Marco ^{[1
]}

Genua, Marco ^{[5
]}

Ostuni, Renato ^{[2
,5
]}

Lugli, Enrico ^{[6
]}

Isogawa, Masanori ^{[7
]}

Ferrari, Carlo ^{[4
,8
]}

Boni, Carolina ^{[4
,8
]}

Fisicaro, Paola ^{[4
]}

Guidotti, Luca G. ^{[2
]}

Iannacone, Matteo ^{[1
,2
]}

机构：

[1] IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Milan, Italy

[2] Univ Vita Salute San Raffaele, Milan, Italy

[3] IRCCS San Raffaele Sci Inst, Ctr Om Sci, Milan, Italy

[4] Azienda Osped Univ Parma, Unit Infect Dis & Hepatol, Lab Viral Immunopathol, Parma, Italy

[5] San Raffaele Telethon Inst Gene Therapy SR Tiget, Milan, Italy

[6] IRCSS Humanitas Res Hosp, Rozzano, Italy

[7] Natl Inst Infect Dis, Res Ctr Drug & Vaccine Dev, Tokyo, Japan

[8] Univ Parma, Dept Med & Surg, Parma, Italy

来源：

CELL | 2024年 / 187卷 / 15期

基金：

欧洲研究理事会;

关键词：

CD8(+) T-CELLS; SET ENRICHMENT ANALYSIS; LIVER; IMAGE;

D O I：

10.1016/j.cell.2024.05.038

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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) SL ) cells and two distinct dysfunctional tissue-resident memory (TRM) RM ) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to TSL. 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.

引用

页码：4078 / 4094.e21

页数：39

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