Research
Structural insight into peptide bound MHC stability
Li, X., et al. Protein Cell, 2016 (PDB: 5INC, 5IND, and 5IM7)
The first crystal structure of HLA-B*5801 loaded with an immunodominant antigenic peptide QW9 derived from HIV Gag protein was determined. The unique observation is that the central peptide residue K7 can assume either a buried conformation in peptide-binding groove or an exposed one. This dynamic may affect TCR recognition. This kind of variable conformations in the antigen binding cleft might indicate a relevant stability of a peptide bound HLA for immune activation.
Structural basis of T cell receptor mechanical sensor
The TCRαβ heterodimer is very similar in overall topology to an Ig Fab fragment, consisting of a paired variable module (VαVβ vs. VLVH) linked to a constant domain module (CαCβ vs. CLCH1). Moreover, the overall height and width of these structures are similar. However, there are two striking differences. First, the CαCβ module manifests an obvious asymmetry, exposing residues on the ABD β-sheet of the Cβ domain that are buried in the symmetrical Fab. Second, the size of the VβCβ interface is very different from that of the VHCH1 interface. This more robust VβCβ interface is contributed to by the CβFG loop, a 12-residue-long insertion unique to mammalian αβTCRs and accounting for almost one-third of the buried surface area. The sequence alignment for similar Ig domains show that most Ig domains could not form such a relatively large rigid loop. The structural features of the Cβ FG loop as a focus of single-molecule analysis
Das D. K., Li X. et al. PNAS, 2015
Structural determinant of MHC-II and MHC-I restricted CD4 and CD8 T cells
Li, X. L., et al. Front Immunol, 2013
Although CD4(+) and CD8(+) T cell recognition of peptide antigens is known to be MHC class II- and MHC class I-restricted, respectively, the mechanism of single positive (SP) thymocyte lineage commitment from bipotential double-positive (DP) progenitors is not fully elucidated. Classical models to explain thymic CD4 vs. CD8 fate determination have included a stochastic selection model or instructional models. The latter are based either on strength of signal or duration of signal impacting fate. More recently, differential co-receptor gene imprinting has been shown to be involved in expression of transcription factors impacting cytotoxic T cell development. By surveying 58 MHC class II and 224 MHC class I crystal structures in the Protein Data Bank, it becomes clear that CD4 cannot bind to MHC I molecules, nor can CD8alphabeta or CD8alphaalpha bind to MHC II molecules. Given that the co-receptor delivers Lck to phosphorylate exposed CD3 ITAMs within a peptide/MHC (pMHC)-ligated TCR complex to initiate cell signaling, this strict co-receptor recognition fosters MHC class-restricted SP thymocyte lineage commitment at the DP stage even though both co-receptors are expressed on a single cell.