MHC CLASS-I MOLECULES COMPETE IN THE ENDOPLASMIC-RETICULUM FOR ACCESSTO TRANSPORTER ASSOCIATED WITH ANTIGEN-PROCESSING

We have used the functionally distinct TAP alleles of the rat in cellu lar transfectants as tools to investigate how newly formed rat class I (RT1.A) molecules with distinct peptide requirements gain access to s uitable peptides in the endoplasmic reticulum (ER), Normal maturation of RT1.A(a) depends on the presence in the ER of peptides with C-termi nal arginine, while restrictive TAP-B allelic group transporters fail to transport such peptides, In this situation, RT1.A(a) is retained in the ER, We show that this retention is accompanied by accumulation of RT1.A(a) in the ER, partly associated with TAP and partly free. In su ch cells, access to TAP of a second allelic product, RT1.A(u), which d oes not require C-terminal arginine peptides, is competitively inhibit ed by the build-up of RT1.A(a). Nevertheless, RT1.A(u) loads and matur es normally, Introduction of a permissive TAP-A allele competent to tr ansport C-terminal arginine peptides releases RT1.A(a) from the ER and restores RT1.A(u) interaction with TAP. Both class I alleles associat e indiscriminately with permissive and restrictive TAP alleles, The da ta support the view that interaction with TAP is not a prerequisite fo r peptide loading by class I molecules, so long as suitable peptides a re available in the ER, They further show that TAP association of a cl ass I molecule depends on a competitive balance in the ER defined by t he extent to which the peptide requirements of other class I molecules present are satisfied and not only by the intrinsic strength of the i nteraction with TAP.