THE EXPRESSED T-CELL REPERTOIRE IS HIERARCHICAL - THE PRECISE FOCUS OF LYSOZYME-SPECIFIC T-CELL CLONES IS DEPENDENT UPON THE STRUCTURE OF THE IMMUNOGEN

  • 1 January 1984
    • journal article
    • research article
    • Vol. 1  (6) , 369-379
Abstract
The breadth of the expressed T cell repertoire to antigens under Ir gene regulation is central to the understanding of Ir gene function. While major histocompatibility complex (MHC)-related differences in the elicited T cell repertoire are readily demonstrated, the reasons for the choice of particular determinants are not clear. In is commonly assumed that the Ia molecules as the sole products of Ir genes somehow influence the choice of determinants selected for response. That this choice can be severely restricted in the C57BL/6 mice to hen egg-white lysozyme (HEL) was shown earlier with L2 (amino acids residues 13-105) immunization. L2, as the major CNBr cleavage fragment of HEL represents .apprx. 70% of the whole molecule and contains all the determinants recognized by proliferative T cells induced with HEL in this strain. All clones obtained from L2-immunized B6 mice recognized HEL and determinants available only within the T11 peptide (amino acid residues 74-96), suggesting that the entire T cell repertoire was restricted to determinants within the T11 region for HEL. To test this hypothesis, long-term T cell lines were derived from HEL-immunized B6 mice. Bulk HEL- and L2-induced T cell lines showed similar L2-specific responses. In contrast to clones from the L2-lines, which were all specific for T11, the large majority of clones from the HEL-induced lines were specific for non-T11 determinants. Antigen recognition of all clones was restricted by a similar restriction element on the I-Ab molecule. Thus, T cells directed against non-T11 determinants available on the L2 fragment were not induced by L2 itself but required the whole molecule. Thus, within the T cell repertoire, the selection of clones is dramatically changed by the context in which the determinants are available. In fact, a hierarchy of T cells specific for T11 and non-T11 determinants results. Structural differences between HEL and L2 lead to an inversion of this hierarchy. As both the HEL- and L2-induced lines were maintained and cloned under identical conditions, this appears to reflect the cellular interplay that occurs during the early in vivo selection period, rather than during the later in vitro activation and propagation of the lines and clones derived from them. The direct implications of these findings relate to interpretations of Ir gene phenomena. A greater role must be reserved in such discussion for the concept that within the T cell repertoire are potential clones whose expression depends on forces connected to the selecting agent, the antigen. Ir gene regulation cannot be considered simply a direct consequence of the presence or absence of available determinants on the antigen, or owing to T cell repertoire gaps in the haplotype. For example, the failure to respond to non-T11 determinants after L2 immunization is neither a presentational nor a repertoire deficiency problem. Rather, crucial regulatory influences occurring during selection must be considered, which can determine a hierarchy of responsiveness. Whether the results reflect an intrinsic difference in the efficiency of presentation of T11 vs. non-T11 determinants by the antigen-presenting cells given L2 or HEL and/or whether other regulatory cells such as amplifier/suppressor T cells are involved in the selection of the developing clones awaits further study.

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