Trained immunity is regulated by T cell-induced CD40-TRAF6 signaling

Area of Science:

• Immunology
• Cellular and Molecular Immunology

Background:

• Trained immunity, a form of innate immune memory, involves epigenetic and metabolic reprogramming of innate immune cells.
• The role of adaptive immune cells, such as T cells, in modulating trained immunity is not well understood.

Purpose of the Study:

• To investigate the role of T cells in trained immunity.
• To explore the CD40-TRAF6 signaling pathway in T cell-mediated regulation of trained immunity.
• To assess the therapeutic potential of targeting CD40-TRAF6 signaling in transplantation.

Main Methods:

• In vitro studies involving CD40-TRAF6 inhibition.
• Transcriptomic and metabolic analyses.
• In vivo studies using murine heart transplantation models.
• Analysis of single-nucleotide polymorphisms (SNPs) near CD40.

Main Results:

• T cells modulate trained immunity through CD40-TRAF6 signaling.
• Inhibition of CD40-TRAF6 impacts functional, transcriptomic, and metabolic reprogramming associated with trained immunity.
• SNPs near CD40 are associated with trained immunity responses in vivo.
• Combined CD40-TRAF6 inhibition and CTLA4-Ig blockade promote long-term graft acceptance in mice.

Conclusions:

• Trained immunity is regulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells.
• Targeting the CD40-TRAF6 pathway represents a potential therapeutic strategy for modulating immune responses and improving transplant outcomes.