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Therapeutic potential of co-signaling receptor modulation in hepatitis B

Francesco Andreata1, Chiara Laura2, Micol Ravà1

  • 1Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

Cell
|June 19, 2024
PubMed

Insights

Reversing CD8+ T cell dysfunction in chronic hepatitis B (HBV) infection is key. Activating 4-1BB and OX40 co-signaling receptors can restore antiviral functions, offering a promising therapeutic strategy.

Area of Science:

  • Immunology
  • Hepatology
  • Virology

Background:

  • CD8+ T cell dysfunction impairs control of chronic hepatitis B virus (HBV) infection.
  • Specific molecular targets for reversing this dysfunction remain elusive.

Purpose of the Study:

  • To analyze co-signaling receptor expression on dysfunctional HBV-specific CD8+ T cells.
  • To investigate the potential of co-signaling receptor modulation to restore antiviral function.

Main Methods:

  • Analysis of co-signaling receptor expression (PD-1, CTLA-4, LAG-3, OX40, 4-1BB, ICOS) on HBV-specific CD8+ T cells.
  • In vitro stimulation assays involving blocking co-inhibitory receptors and activating co-stimulatory receptors (4-1BB, OX40).
  • Characterization of T cell populations (T_SL, T_RM) using transcriptional profiling.

Main Results:

  • Dysfunctional CD8+ T cells upregulate multiple co-signaling receptors.
  • Activation of 4-1BB and OX40, but not blockade of co-inhibitory receptors, restored antiviral effector functions.
  • Prolonged stimulation generated a heterogeneous T cell population including stem-like (T_SL) and tissue-resident memory (T_RM) cells.
  • 4-1BB stimulation was effective in chronic settings and in HBeAg+ patients, showing potential for T cell rejuvenation.

Conclusions:

  • Targeting co-signaling pathways, particularly 4-1BB activation, can reverse CD8+ T cell dysfunction in chronic HBV.
  • Restoring antiviral activity in both stem-like and effector memory T cell populations is crucial for effective therapy.
  • Modulating 4-1BB offers a promising therapeutic avenue for chronic hepatitis B patients.
Keywords:
4-1BBCD8(+) T cellsOX40T cell dysfunctionchronic viral infectionhepatitis B virusimmunotherapyliver

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