Trends Immunol. 2025 Jul 23:S1471-4906(25)00168-1. doi: 10.1016/j.it.2025.07.001. Online ahead of print.
ABSTRACT
CD4 T cell tolerance is essential for immune homeostasis but its mechanisms remain unclear. Although regulatory T cells (Tregs) mediate T cell-extrinsic tolerance, this review emphasizes the CD4 T cell-intrinsic pathways – anergy and exhaustion – that are triggered by suboptimal or persistent antigen stimulation. These states share transcriptional and epigenomic features across contexts such as cancer, pregnancy, and transplantation. Instead of being distinct, they form a spectrum of tolerance with potential for therapeutic targeting. CD154 has re-emerged as a promising target, although memory T cell tolerization remains challenging. A deeper understanding of what sustains or reverses CD4 T cell tolerance is key to designing treatments that induce/maintain tolerance in autoimmunity and transplantation, or restore functionality in cancer and chronic infection.
PMID:40707326 | DOI:10.1016/j.it.2025.07.001