Fig. 4

CD40:CD40L stimulatory immune checkpoint (molecular mechanism and biological function). a Forward immune checkpoint. CD40:CD40L stimulation occurs when B7 engages CD28. In TC, CD40:CD40L ligation, via ZAP-70 activation, leads to activating three important signal pathways (MAPK/NF-κB/calcineurin) and promotes gene transactivation and TC activation. b Reverse-immune checkpoint. In APC, CD40:CD40L ligation, via TRAF2/3/5/6 activation and the following STATS, NF-κB, and AP-1 activation, promotes gene expression and APC inflammation. c TC contact-independent immune checkpoint. Metabolic RF increases circulating sCD40L and CD40 in MC. sCD40L:CD40 co-stimulation results in CD40 MC differentiation and inflammation via metabolic sensor and DNA hypomethylation-related mechanisms. Words in red emphasize our new findings and proposed signal. Abbreviations: APC antigen present cell, AP-1 activator protein 1, BC B cell, ERK extracellular signal-regulated kinase, HHcy hyperhomocysteinemia, Ig immunoglobulin, IKK I-κB kinase, I-κBs I-κB proteins, JNK JUN amino-terminal kinase, LAT linker for activation of T cells, MAPK mitogen-activated protein kinase, MØ macrophage, MC monocyte, NKC natural killer cell, NF-κB nuclear factor κB, p phosphorylated, PLCγ1 phospholipase C gamma 1, sCD40L soluble CD40 ligand, SMC smooth muscle cell, STAT3 signal transducers and activator of transcription-3, TC T cell, Treg regulatory T cell, TRAF tumor necrosis factor receptor, ZAP70 zeta chain-associated protein kinase