The TCR binding site does move

Multicellular organisms face a large variety of different pathogens that can infect them. To identify and combat these potential invaders efficiently, the adaptive immune system has evolved. Its main components are T and B lymphocytes that constantly screen the body in search of unknown, and hence foreign, structures, an extremely challenging task because these structures (antigens) are unknown to the immune system and can be of diverse shape and chemical nature. Antigen recognition is accomplished by the T and B cell antigen receptors (TCRs and BCRs) that contain variable regions designed for antigen binding. The variability is generated by somatic assembly and mutations of the corresponding genes, so that each lymphocyte expresses a different receptor of random specificity. Autoreactive cells are eliminated by a selection process during the development of lymphocytes. Once the receptor on mature T or B cells has recognized (i.e., bound) an antigen with sufficient affinity, the cell is activated and can trigger an immune response against this antigen. Each single receptor has to recognize a large number of different antigens because the number of T and B cells is not sufficient to cover each potential antigen [e.g., the TCRs have to cope with >10¹³ possible antigens (1)]. Thus, extensive cross-reactivity is an essential characteristic of these receptors (1). Still, the TCRs exhibit a remarkable degree of specificity, capable of distinguishing minor structural differences among their ligands. These features have attracted the attention of immunologists and biophysicists.

The TCR recognizes, in most cases, small peptides that are presented by MHC molecules residing on the surface of cells of its own body. MHC molecules possess a cleft in which the peptide is bound (pMHC). More than two dozen 3D structures of different TCRs and …

*To whom correspondence should be addressed: E-mail: schamel{at}immunbio.mpg.de