PuSH - Publikationsserver des Helmholtz Zentrums München: A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection.

Informationen

Hinweise zu Qualitätskriterien von Zeitschriften

Open-Access-Richtlinie der Helmholtz-Gemeinschaft 2016

CC Licencences

Metriken für Publikationen

Navigation

Startseite

English

Recherche

Erweiterte Suche

Durchblättern nach ...

... HMGU-Autoren/Konsortien

... Organisationsstruktur

... Zeitschriften

... Publikationstypen

... Forschungsdaten

... Arbeitsgruppen

... Erscheinungsjahr

Publikationen im Überblick

Statistik

HGF Fortschrittsbericht

OA Publikationen

Eintragen

Neue Publikation eintragen

Neue Publikation holen aus...

...EVA

Fehlende Publikation melden

Highlights

Suche

Hilfe & Kontakt

Ansprechpartner

Hilfe

Datenschutz

Helmholtz Open Science

Bibliometrische Indikatoren

SHERPA/RoMEO

DOAJ

Export:

Text

Endnote (RIS) BIB

BibTeX

Bosch, M.* ; Kallin, N.* ; Donakonda, S.* ; Zhang, J.D.* ; Wintersteller, H.* ; Hegenbarth, S.* ; Heim, K.* ; Ramirez, C.* ; Fürst, A.* ; Lattouf, E.I.* ; Feuerherd, M.* ; Chattopadhyay, S.* ; Kumpesa, N.* ; Griesser, V.* ; Hoflack, J.C.* ; Siebourg-Polster, J.* ; Mogler, C.* ; Swadling, L.* ; Pallett, L.J.* ; Meiser, P.* ; Manske, K.* ; de Almeida, G.P.* ; Kosinska, A. ; Sandu, I.* ; Schneider, A.* ; Steinbacher, V.* ; Teng, Y.* ; Schnabel, J.A. ; Theis, F.* ; Gehring, A.J.* ; Boonstra, A.* ; Janssen, H.L.A.* ; Vandenbosch, M.* ; Cuypers, E.* ; Öllinger, R.* ; Engleitner, T.* ; Rad, R.* ; Steiger, K.* ; Oxenius, A.* ; Lo, W.L.* ; Klepsch, V.* ; Baier, G.* ; Holzmann, B.* ; Maini, M.K.* ; Heeren, R.* ; Murray, P.J.* ; Thimme, R.* ; Herrmann, C.* ; Protzer, U. ; Böttcher, J.P.* ; Zehn, D.* ; Wohlleber, D.* ; Lauer, G.M.* ; Hofmann, M.* ; Luangsay, S.* ; Knolle, P.A.*

A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection.

Nature 631, 867–875 (2024)

Verlagsversion

DOI

PMC

	Open Access Hybrid

Abstract
Metriken
Zusatzinfos

Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide^1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes^3-7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6⁺ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6⁺ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.

Impact Factor

Scopus SNIP

Web of Science
Times Cited

Altmetric

50.500

0.000