Review: To What Extent are T Cells Tolerant to Immunoglobulin Variable Regions?

Abstract During the last 25 years it has become increasingly clear that short peptides derived from Ig V‐regions are displayed on MHC class II molecules. Recognition of such idiotypic(Id)‐peptide/MHC class II complexes by Id‐specific CD4 + T cells plays a role in (1) Id‐driven T‐B collaboration, (2) immunosurveillance of B cell cancers and (3) Id‐vaccination. A crucial question is then: to what extent are T cells tolerized to Ig V‐region sequences? Or rephrased: how large is the T‐cell repertoire for Ig V‐region sequences presented by MHC class II molecules? We argue that T cells are to a large extent tolerant to germline‐encoded V‐region sequences but that there is a T‐cell repertoire for rare Id‐sequences that arise as a consequence of somatic hyper mutation or N‐region diversity. Moreover, when otherwise rare Id‐sequences increase in concentration, T‐cell tolerance is induced ( Fig. 1). For these reasons, T cells that recognize rare Id‐peptides, arising as a consequence of somatic genetic events unique to each B cell, may play a special importance in Id‐driven T–B collaboration, immunosurveillance of B‐cell malignancies, and Id‐vaccination. 1 Ig V‐region Id‐peptides and T‐cell tolerance. Germline‐encoded Id‐peptides are expressed by relatively many B cells and Ig molecules in the body and are therefore considered “frequent”. Experimental evidence reviewed in the text suggests that T cells are tolerant such frequent Id‐peptides. By contrast, V‐region Id‐peptides that express either somatic mutations or N‐region diversity are restricted to only few B cells and Ig molecules and are therefore considered ‘rare’. T cells apparently are not tolerant and can respond to such rare Id‐peptides. Note that an otherwise rare Id‐peptide may upon clonal expansion, like e.g. in multiple myeloma, become frequent and induce T‐cell tolerance.