Single Receptor reciprocity as message encrypted in CD40-ligand

Interaction between CD40-Ligand (CD40L) and CD40 results in cellular signaling that regulates immune responses against pathogens, autoantigens, tumors and transplantation antigens. The 115–155 amino acids stretch is responsible for CD40L functions and mutations therein results in XIgM syndrome. We hypothesize that each of these amino acids of CD40L encodes specific message. These messages are decoded by CD40 signaling and are expressed as a specific profile of functions. Each single substitution in the XIgM-related amino acids in the 115–155 41-mer peptides in CD40L selectively altered CD40 signaling and effector functions- cytokine productions, HMGCoA reductase, ceramide synthase, inducible nitric oxide synthase and arginase expression, and control of Leishmania infection. There were sets of peptides that triggered reciprocal functions from the same receptor CD40. These results suggest residue-specific encryption of a distinct set of messages. These messages collectively frame CD40L pleiotropy and offer a result-driven ligand manipulation strategy for generating antagonists or superagonists as immunotherapeutics.