Fig. 2
Related molecular pathways and membrane surface markers. OX40-OX40L, TRAF2/TRAF5/TRAF6 will induce the form of IKKα/β/γ which further leads to NF-κB entering the nucleus. Besides, OX40-OX40L can promote PI3K/Akt pathway and cause STAT5 to enter the nucleus. CD40-CD40L will recruit various downstream molecules. TRAF1, TRAF2, TRAF3, and TRAF5 bind competitively the one CD40 tail site and TRAF6 can bind to another individually. They can promote the Ras/ERK pathway and the non-classical NF-κB pathway, NIK pathway. Besides, it can promote the TAK1 and MKKs/p38 pathways. CD40-CD40L can start the JAK3/STATs pathway. CD28-B7-1/B7-2 also provides the activation signal. After the tyrosine phosphorylation of the YMNM fragment, the subunit p85 of PI3K binds to YMNM. PI3K will recruit PDK1 and PKB/Akt, and PKB can phosphorylate downstream targets such as mTOR, IκB, GSK3β and Bad after PKB is phosphorylated by PDK1 which leads to an increase of the transcriptional activity of NF-κB and NFAT. Besides, CD28 signal will recruit GRB2/GADs and increase NF-κB, NFAT, and AP1 by Vav catalysis. CTLA-4 also binds B7-1/B7-2, but it transmits the suppression signal to downstream. The specific process is through the inhibition of ZAP70 and PI3K/Akt pathway by recruitment of SHP2 and inhibition of PI3K/Akt pathway by PP2A. The combination with PD-1 and PD-L1 leads to the activation of the tyrosine phosphorylation of the ITIM and ITSM at the tail of PD1. SHP-1 or SHP-2 can bind the ITSM and promote the expression of PTEN which can further inhibit the activation of PI3K/Akt pathways and ZAP70. The SHP2 can also promote the BATF to enter the nucleus. It leads to the inhibition of T cell proliferation and inflammatory progression. This inhibitory process may be somewhat similar to the CTLA-4 pathway
