The most important aspect of the study is the effect of the CH-π interaction on TCR recognition of the modified peptide. EGP/Db complexes bind better to the cognate TCRs than complexes with WT peptide, providing a double advantage

of the Pro substitution. To gain insight into this effect, Uchtenhagen et al. used high-powered computers to simulate the simultaneous movements of individual atoms of the structure. Such “molecular dynamics” analysis suggests that increased TCR affinity results from increased rigidity of the peptide within the Db cleft. As with all good science, discoveries beget questions. Most pragmatically, Y-27632 cost can the increased pMHC affinity, pMHC stabilization, and TCR recognition afforded by the p3P substitution be generally

extended to other peptide/MHC combinations for enhanced vaccine efficacy? Previous work by Achour and colleagues learn more suggests that p3P altered peptides bind to Db or Kb with increased affinity [23]. Since Y159 is highly conserved among human HLA genes and alleles, this likely applies to human pMHC complexes, particularly for those unusual allomorphs that do not bind with strong p2 anchors (such as B*0801). Can other aromatic residues within the peptide-binding cleft be exploited for CH-π interactions, and if so, will tertiary structure be preserved to maintain TCR recognition? Is increased peptide rigidity generally positive for 4-Aminobutyrate aminotransferase TCR recognition? Does increased binding uniformly extend to endogenous peptides when they are loaded on to class I in the ER by the peptide-loading complex? Although binding of exogenous peptides to class I is generally considered to precisely mimic the binding of endogenous peptides, peptides can bind to class II in multiple conformations, depending on how they are loaded, with major biological consequences [26]. The work of Uchtenhagen et al. [18] beautifully illustrates

the importance of continued research on problems thought to be “solved”. It is essential for young scientists in particular to appreciate that nature’s secrets are boundless, and that the critical information for practical applications often springs from surprising sources that are best accessed by curiosity-driven research. This work was supported by the Division of Intramural Research of the National Institutes of Allergy and Infectious Diseases. The authors declare no financial or commercial conflict of interest. “
“One common way to study human leucocytes and cancer cells in an experimental in vivo situation is to use mice that have been genetically engineered to lack an immune system and prevent human cell rejection. These mice lack CD132 and either RAG2 or the catalytic subunit of the DNA-dependent protein kinase, to make the mice deficient in lymphocytes and natural killer cells.