Nomenclature for factors of the HLA system, update January 2012

Abstract

The antigen-presenting cell–expressed CD40 is implied in the regulation of counteractive immune responses such as induction of pro-inflammatory and anti-inflammatory cytokines interleukin (IL)–12 and IL-10, respectively. The mechanism of this duality in CD40 function remains unknown. Here, we investigated whether such duality depends on ligand binding. Based on CD40 binding, we identifed two dodecameric peptides, peptide-7 and peptide-19, from the phage peptide library. Peptide-7 induces IL-10 and increases Leishmania donovani infection in macrophages, whereas peptide-19 induces IL-12 and reduces L. donovani infection. CD40-peptide interaction analyses by surface plasmon resonance and atomic force microscopy suggest that the functional differences are not associated with the studied interaction parameters. The molecular dynamic simulation of the CD40-peptides interaction suggests that these two peptides bind to two different places on CD40. Thus, we suggest for the first time that differential binding of the ligands imparts functional duality to CD40.

Residue-Specific Message Encoding in CD40-Ligand

“…During leishmanial infection, CD40 signaling is skewed toward the anti-inflammatory pathways involving cRaf, Syk, MEK1/2, ERK1/2, PKCδ, and PKCζ. However, stimulation with CD40L results in the skewing of the signaling toward pro-inflammatory pathway involving Lyn, PI3K, MKK3/6, p38, PKCα, and PKCβII ( Awasthi et al., 2003 ; Khan et al., 2012 , 2014 ; Mathur et al., 2004 ; Murugaiyan et al., 2006 ; Rub et al., 2009 ; Sudan et al., 2012 ). In addition, it was shown that LMP-1, a protein encoded by Epstein-Barr virus signaling like CD40, rescued certain functions—but not the full range—associated with the CD40 in CD40 −/− mice suggesting that there existed CD40L residue-specific signaling and functions ( Uchida et al., 1999 ).…”