Increasing the frequency of T‐cell precursors specific for a cryptic epitope of hen‐egg lysozyme converts it to an immunodominant epitope

Summary Efforts to understand the mechanisms that govern how immunodominant T‐cell epitopes are selected from protein antigens have focused mostly on differences in the efficiency of processing and presentation of peptide/major histocompatibility complex (MHC) complexes by antigen‐presenting cells, while little attention has been directed at the role of the T‐cell repertoire. In this report, the influence of the T‐cell repertoire on immunodominance was investigated using transgenic mice that express the β chain from a T‐cell receptor specific for a cryptic E k restricted epitope of hen‐egg lysozyme, HEL85‐96. In these mice, the frequency of HEL85‐96‐specific T‐cell precursors is increased 10–20‐fold over non‐transgenic mice. Transgenic mice respond as well as non‐transgenic controls to intact HEL, even though they respond poorly or not at all to a variety of other antigens, including the dominant H‐2 k restricted epitopes of HEL. Following immunization with native HEL, the only HEL peptide that could recall a response in vitro in the transgenic mice was HEL85‐96. Therefore, this normally cryptic epitope is the sole immunodominant epitope in the transgenic mice, and this alteration in immune response is due solely to an increase in the frequency of specific T‐cell precursors. An analysis of four additional H‐2 k restricted cryptic epitopes of HEL suggests that three are similarly limited by T‐cell frequency, and that only one is consistent with a defect in efficient antigen presentation. This indicates that there are at least two different types of cryptic epitopes, one in which crypticity is caused by inefficient processing or presentation, and another in which the frequency of specific T‐cell progenitors is limiting.