Influence of Protein-Quaternary Structure on Antigen Processing

T cell recognition of the quaternary structure of human chorionic gonadotropin (hCG), resulting from the association between its a (hCG-α) and β (hCG-β) subunits, was analyzed using hCG-α and hCG-β T cell hybridomas produced in BALB/c mice. First, the fine specificity of these T cell hybridomas was determined, enabling us to divide hCG-α-specific T cell hybridomas into two groups. Group I recognized the hCG-α(61-81) region, and group II responded to the hCG-α(50-70) part of the molecule. Two groups of hCG-β-specific T cell hybridomas, designated groups III and IV, were analyzed and found to respond to the C- and the N-terminal parts of the hCG-β(1-22) peptide, respectively. Moreover, we observed that the nature of APC influenced Ag recognition by hCG-β T cell hybridomas from group IV, but not by other selected T cell hybridomas. We then showed that recognition of the hCG α/β dimer by α-specific T cell hybridomas was dramatically reduced compared to both free hCG-α and heat-dissociated hCGα/β molecules. In contrast, hCG-β hybridomas exhibited comparable responses to the free β subunit and the hCG dimer. Experiments using a dimeric molecule assembled from the α-subunit of human follicle-stimulating hormone, which is identical to hCG-α, and the β-subunit of human follicle-stimulating hormone, which is homologous to hCG-β, confirmed that the three-dimensional structure of the complex rather than the primary structure of the β-subunit plays a critical role in the processing pathway. Finally, kinetic experiments showed that the presentation of hCG-α T cell epitopes differed depending upon whether the α-subunit was in its free or combined form. In contrast, the kinetic expression of hCG-β T cell epitopes appeared to be independent of the quaternary structure of hCG. Thus, conformational alterations resulting from the α/β subunit association mainly influenced processing of the α-subunit in its complexed form, rather than processing of the combined β-subunit. The effect of protein-quaternary structure on T cell recognition may represent a new element in our understanding of the processing and presentation of oligomeric molecules. Journal of Immunology, 1993, 150: 782.