Tripeptidyl peptidase II is dispensable for the generation of both proteasome‐dependent and proteasome‐independent ligands of HLA‐B27 and other class I molecules

Abstract

A significant fraction of the HLA-B27-bound peptide repertoire is resistant to proteasome inhibitors. The possible implication of tripeptidyl peptidase II (TPPII) in generating this subset was analyzed by quantifying the surface re-expression of HLA-B*2705 after acid stripping in the presence of two TPPII inhibitors, butabindide and AlaAla-Phe-chloromethylketone. Neither decreased HLA-B27 re-expression under conditions in which TPPII activity was largely inhibited. This was in contrast to a significant effect of the proteasome inhibitor epoxomicin. The failure of TPPII inhibition to decrease surface re-expression was not limited to HLA-B27, since it was also observed in several HLA-B27-negative cell lines, including Mel JuSo. Actually, HLA class I reexpression in Mel JuSo cells increased as a function of butabindide concentration, which is consistent with an involvement of TPPII in destroying HLA class I ligands. Inhibition of TPPII with small interfering RNA also failed to decrease the surface expression of HLA class I molecules on 143B cells. Our results indicate that TPPII is dispensable for the generation of proteasome-dependent HLA class I ligands and, without excluding its role in producing some individual epitopes, this enzyme is not involved to any quantitatively significant extent, in generating the proteasomeindependent HLA-B27-bound peptide repertoire.See accompanying commentary: http://dx

Processing of Two Latent Membrane Protein 1 MHC Class I Epitopes Requires Tripeptidyl Peptidase II Involvement

“…Work by two independent groups (43,44) found no difference in the overall MHC class I epitope supply when TPPII was blocked by either pharmacological or genetic ablation. Investigations regarding the proteasome-dependent epitope SIINFEKL derived from OVA also did not prove a dependency on TPPII, because siRNA-mediated inhibition did not reduce epitope presentation (44) and TPP Ϫ/Ϫ cells of a knockout mouse were even better in presenting this epitope (45).…”

Cytosolic Aminopeptidases Influence MHC Class I-Mediated Antigen Presentation in an Allele-Dependent Manner

“…A "model Ag," a "model peptide precursor" (i.e., OVA), and a well-known viral epitope have been applied to study the enzymatic activity of cytosolic peptidases (11, 12, 17, 36 -38). However, the function of certain peptidases in the presentation of MHC class I Ags in in vitro and in vivo systems, as well as the model Ags used in each case, have been controversial (8,10,12,36,39,40). Rock and colleagues showed that the trimming of antigenic peptides in LAP-, BH-, or PSA-deficient mice was not reduced and that there was no significant difference in the presentation of OVA8 from N-terminally extended precursors or full-length OVA (11,12,36).…”

Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency

“…15,16 Similar to the murine findings, 16 expression of MHC class I on T and B cells was higher in the patient compared with his HLA-identical healthy heterozygous sister ( Figure 1C) and a group of 10 healthy adult controls. Pretreatment of control T cells with the TPP2 inhibitor butabindide 18,19 enhanced MHC I upregulation upon phytohemagglutinin stimulation ( Figure 1D). Finally, as described in murine cells, fibroblasts of P1 also showed increased staining with b-galactosidase indicating cellular senescence ( Figure 1E).…”