Messages in CD40L are encrypted for residue-specific functions

CD40-CD40-ligand (CD40L) interaction plays crucial immunoregulatory roles, as CD40 signals through different signaling intermediates to convert the messages from CD40L to effector functions. Being a TNFα receptor family member, CD40 binds TNFα receptor-associated factors, assembles signalosome complexes and decrypts the messages from CD40L through different signaling modules to result in residue-specific effector functions. The evidence for such a residue-specific message encryption first came from the CD40L mutations resulting in X-linked hyper-IgM syndrome, as the extent of effects varied with the residue mutated. The structural studies on the CD40-CD40L interaction implied differential involvement of the interacting residues on CD40L in influencing the effector functions. Three lines of evidence indicate the previously implied residue-specific message encryption in CD40L: screening of a dodecameric peptide library for CD40 binders identified two peptides with different sequences resulting in counteractive effector functions in macrophages; a series of CD40L mutants identified that the mutations in these residues selectively affected CD40 signaling and macrophage effector functions; and, a panel of 40-mer peptides, representing the CD40-interacting domain of mouse CD40L, with single substitutions resulted in altered CD40 signaling through various signaling intermediates and effector functions in mouse macrophages. We therefore construct the first-ever message encryption-decryption in a biological receptor-ligand system wherein the CD40L residues that interact with CD40 residues have encrypted messages, which are decoded by CD40 signaling to result in residue-specific effector functions. This review presents a novel perspective of receptor-ligand interaction as a system of message transmission, message decoding by signaling, and its transcription to various read-outs. [250 words].