Cell-intrinsic CD4 T cell tolerance: a new frontier in therapy?

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.