Using Endogenous Peptides to Increase Sensitivity

Abstract

How can a T cell detect a single foreign peptide presented in the context of the major histocompatibility complex (MHC)? One model suggests that endogenous peptides may aid in recognition and activation of T cells by foreign peptides. Krogsgaard et al . tested this model using T cells that respond to moth cytochrome c (MCC) peptides bound to the MHCII molecule I-E k . I-E k also interacts with several self-peptides. Upon exposure to antigen-presenting cells (APCs) displaying the agonist peptides K5 or MCC, multiple endogenous peptides--in addition to these agonist peptides--were also found to accumulate in the immunological synapse that forms at the site of APC-T cell contact. T cells exposed to soluble covalently linked heterodimers of a subset of endogenous peptides and the agonist K5 peptide stimulated T cells, as measured by increased intracellular calcium concentration, activation of phosphoinositide 3-kinase (PI3K), and interleukin-2 (IL-2) production. To recapitulate a more native exposure to the antigens, T cell responsiveness to lipid bilayers or engineered APCs that displayed MCC in addition to increasing concentrations of endogenous peptides bound to I-E k was measured. These assays showed that, in the presence of endogenous peptides, T cells were stimulated by concentrations of MCC that were not stimulatory in the absence of endogenous peptides. This effect was specific to a subset of endogenous peptides. The role of the CD4 costimulatory receptor in this process was verified by testing I-E k containing a mutation in the CD4 binding domain. In this case, if in the MHC dimer, the mutant I-E k was presenting the agonist peptide, then responsiveness was lost, but if the endogenous peptide was presented, then activation was comparable to that observed with wild-type I-E k dimers presenting agonist and endogenous peptide. Through a CD4-mediated process, T cells can be stimulated by MHC heterodimers containing one agonist peptide and one endogenous peptide, thus increasing the sensitivity for detecting foreign antigens. M. Krogsgaard, Q.-J. Ling, C. Sumen, J. B. Huppa, M. Huse, M. M. Davis, Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature 434 , 238-243 (2005). [PubMed]