Chaperones and Catalysts: How Antigen Presentation Pathways Cope With Biological Necessity

Abstract

Immune recognition by T lymphocytes and natural killer (NK) cells is in large part dependent on the identification of cell surface MHC molecules bearing peptides generated from either endogenous (MHC I) or exogenous (MHC II) dependent pathways. This review focuses on MHC I molecules that coordinately fold to bind self or foreign peptides for such surface display. Peptide loading occurs in an antigen presentation pathway that includes either the multimolecular peptide loading complex (PLC) or a single chain chaperone/catalyst, TAP binding protein, related, TAPBPR, that mimics a key component of the PLC, tapasin. Recent structural and dynamic studies of TAPBPR reveal details of its function and reflect on mechanisms common to tapasin. Regions of structural conservation among species suggest that TAPBPR and tapasin have evolved to satisfy functional complexities demanded by the enormous polymorphism of MHC I molecules. Recent studies suggest that these two chaperone/catalysts exploit structural flexibility and dynamics to stabilize MHC molecules and facilitate peptide loading.

Immunotherapy of cytomegalovirus infection by low-dose adoptive transfer of antiviral CD8 T cells relies on substantial post-transfer expansion of central memory cells but not effector-memory cells

“…Some tissue infiltration by CD8 T cells and partial control of mutant virus IE1-L176A might be explained by low-affinity MHC class-I binding of the L176A peptide [60,72], sufficient for presenting the TCR contact site 170-HFMPT-174 [72]. Although the L176A mutation is predicted to also reduce the probability of proteasomal C-terminal cleavage [73–75], trace amounts of the mutated peptide may bind to the presenting MHC class-I molecule L d , catalyzed in the peptide loading complex [76,77]. Such a limited presentation may suffice for sensitization of a fraction of the polyclonal IE1-specific memory CD8 T cells that possess TCRs of particularly high avidity.…”

Xeno interactions between MHC-I proteins and molecular chaperones enable ligand exchange on a broad repertoire of HLA allotypes

“…TAPBPR, a homolog of tapasin, is known for its dual roles as chaperone and peptide exchange catalyst with exquisite HLA allelic specificity ( 32 ). Although predicted structures of TAPBPR from different species are remarkably similar ( 32 ), whether different orthologs can mediate peptide exchange on human MHC-I proteins has not been addressed. Here, we demonstrated novel xeno interactions between a set of HLA allotypes and chTAPBPR distinct from the interaction profile with the human ortholog.…”

“…The orthologous TAPBPR gene was initially identified in mice and humans and later in fish and chickens, strongly suggesting a conserved function ( 31 ). Although structural modeling studies suggest a similar overall protein fold ( 32 ), functional differences among TAPBPR orthologs have not yet been characterized, with most studies concentrating on the human protein.…”

Cancer Immunology: Immune Escape of Tumors—Expression and Regulation of HLA Class I Molecules and Its Role in Immunotherapies

“…Orchestrated by the cofactors calnexin and calreticulin, a stable folding of the MHC class I molecule before the generation of the peptide loading complex comprised of ERp57, tapasin, the TAP-binding protein related that mimics tapasin (TPN), TAP, HC, and β 2 -m is realized. [9][10][11] After peptide binding, the peptide loading complex dissociates and the trimeric HLA class I HC, β 2 -m, and peptide complex are transported through the trans-Golgi to the cell surface and presented to CD8 + T cells. 12 Professional antigen processing cells (APCs) process and present peptides mainly by MHC class II molecules.…”