Cytotoxic T Cell Reponses Against Immunoglobulin in Malignant and Normal B Cells: Implications for Tumor Immunity and Autoimmunity

Clair   S.   Gricks; John   G.   Gribben

Abstract

There is compelling evidence in murine model systems and from human clinical trials that immunotherapy approaches can induce immune responses against tumors. The idiotypic determinants (Id) of the rearranged immunoglobulin proteins of malignant B cells were the first tumor-specific antigens to be recognized and provide a target of an immune mediated response against malignant B cells. Id was thought of as not only tumor-specific but also patient-specific since every patients malignant B cell clone expresses a unique sequence that is determined by the third complementary determinant regions (CDRIII) of the Id. Although CD4+ T cell responses against Id have been demonstrated, the role of CD8+ T lymphocytes in induction of responses against Id has remained elusive. The requirements for peptides to bind to HLA molecules and elicit T cell responses have been studied extensively and are best characterized for HLA class I molecules that elicit CD8+ cytotoxic T lymphocyte (CTL) responses. We applied a bioinformatics approach to the immunoglobulin sequences of malignant and normal B cells. We identified and characterized epitopes recognized by CTLs within these sequences and could generate CTL responses against Id determinants of both normal B cells and malignant B cell. Class I binding immunoglobulin derived sequences had weak binding affinity but were capable in some cases of inducing CTL mediated immune response. More surprisingly, these sequences were not derived from unique sequences within the CDRIII region but were more often from framework region sequences that were often shared among patients and were also found in the immunoglobulin sequences of normal B cells. It was possible to increase binding affinity by single amino acid substitutions at the residues responsible for binding to HLA class I molecules. These “heteroclitic” peptides resulted in generation of T cells with increased ability to kill targets expressing not only the altered peptides, but also the native sequences from which these peptides had been derived. These findings have implications not only for tumor immunity, but also for regulation of B cell dependent autoimmune responses.

Keywords: cytotoxic t cell reponses, tumor immunity, autoimmunity, immunoglobulin proteins, malignant b cells, tumor-specific antigens, complementary determinant regions, heteroclitic peptides