Cognate Peptide–MHC Complexes Are Expressed as Tightly Apposed Nanoclusters in Virus-Infected Cells To Allow TCR Crosslinking

Abstract

Antigenic T cell stimulation requires interaction between the TCR of the T cell and cognate peptide–MHC molecules presented by the APC. Although studies with TCR-specific Abs and soluble peptide–MHC ligands have shown that the TCR needs to be crosslinked by two or more ligands to induce T cell stimulation, it is not understood how several MHC molecules loaded with the cognate antigenic peptide can produce crosslinking under physiological conditions. We show at the molecular level that large clusters of cognate peptide–MHC are formed at the surface of murine professional and nonprofessional APCs upon virus infection and that these clusters impinge on the stimulatory capacity of the APC. These clusters are formed by tight apposition of cognate peptide–MHC complexes in a configuration that is compatible with simultaneous engagement of two or more TCRs. This suggests that physiological expression of Ag allows formation of multivalent ligands for the TCR that permit TCR crosslinking and T cell activation.

Organizing MHC Class II Presentation

“…Superantigen staphylococcal enterotoxin A, which can activate T cells in an antigen-independent manner, has been shown to induce clusters of MHC II molecules (11). This suggests that the clustered state of MHC II may regulate the sensitivity of antigen presentation as we and others have reported for MHC I (3, 12). …”

“…Do DCs regulate MHC class II organization in responses to maturation or inflammation? Can pathogens target organization to modify antigen presentation as they seem to do for MHC class I molecules (12)? By modulating MHC II organization, we should be able to better control T cell activation to generate more effective anti-tumor responses and long-lived immunological memory in the future.…”

Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors

“…Peptide-specific clusters are stable for hours on the cell surface, and clusters are associated with increased T cell sensitivity, presumably by increasing interaction with clustered TCRs at the immune synapse. Cluster formation also occurs in VV-infected DCs and is associated with increased T cell sensitivity [123]. Class II molecules also present processed peptides in clusters [124], pointing to a possible common mechanism for enhancing immunosurveillance.…”

“…The trickle of papers regarding the role of ribosomes in monitoring and regulating stress, energy metabolism, or cellular proliferation [141] precedes an incipient flood of information regarding the function of ribosomes in myriad cellular processes, not the least of which is generation of class I-and class II [123]-restricted antigens.…”

Linking form to function: Biophysical aspects of artificial antigen presenting cell design

“…Near-field scanning techniques have resolved protein-rich “patches” of MHC with radii between 70 and 600 nm on the surface of resting APC [127], containing approximately 25–125 MHC each. During antigen processing, MHC bearing peptides derived from a given pathogen are deposited as a cluster on the APC membrane [128–130], generating peptide-specific clusters that facilitate interaction with peptide-specific TCR. Subsequently, during T cell activation, MHC move in concert with their binding partners to form clusters in the cSMAC zone of the APC, with adhesion molecules such as ICAM-1 migrating to the pSMAC.…”