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

Abstract

Id-specific B cells recognize conformational determinants on complete Ig-moleculesImmunoglobulin V-regions are extremely diversified due to V(D)J recombination and somatic hypermutation [1]. Thus, immunoglobulin V-regions probably represent the largest collection of diverse antigenic determinants on self molecules within the body. B cell recognition of such Id determinants depend on association of L-and H-chain V-regions, which enormously increases the number of serological Id determinants expressed on Ig molecules in the body [2]. It has been argued that the immune system cannot be tolerant to all these conformational Id determinants, otherwise, dangerous holes in the B-cell repertoire for external antigens, such as viruses, would be generated. The lack of B-cell tolerance to V-region antigenic determinants is supported by the observation that immunization with monoclonal Ig readily generates anti-Id antibodies in an individual [3], which is the basis for Jerne's Network theory [4]. Id-specific T cells recognize V-region sequence determinants displayed on MHC moleculesSo what about T cell recognition of Id? In the 1980s it became clear that immunoglobulins are processed and presented by antigen-presenting cells (APC) and that V-region-derived Id-peptides are displayed on MHC class II molecules to Id-specific CD4 + T cells [5][6][7][8]. It was further demonstrated that B cells continuously processed their own BCR and constitutively presented Id-peptides on their MHC class II molecules [9][10][11] [12]. Thus, B cells express two types of Id: (1) conformational Id determinants expressed on intact BCR, serologically detected by anti-Id antibodies and (2) short Id-peptides that are presented on MHC class II molecules to Id-specific T cells [9]. Id-peptide ⁄ MHC II presentation to CD4 + T cells represented at that time a novel type of interaction between T and B cells in the absence of external antigen, and it was suggested that such Id-driven T-B collaboration could play a role in immune regulation, autoimmunity and memory [13]. Later, similar ideas were expressed by others [14,15]. Id-specific T cells in immune regulation and diseaseThis hypothesis has gained support from experiments where Id-driven T-B collaboration was made chronic by use of 'paired' Ig and TCR-transgenic mice as sources of Id + B cells and CD4 + T cells respectively. Perpetual Id-driven T-B collaboration was shown to result in 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.

Upfront immunization with autologous recombinant idiotype Fab fragment without prior cytoreduction in indolent B-cell lymphoma

“…[33][34][35][36] In these models, idiotype-specific T cells recognize preferentially unique epitopes from complementarity-determining region or generated through somatic hypermutation, whereas the natural T-cell receptor repertoire is considered tolerant toward germline-encoded immunoglobulin sequences. 37 We have recently demonstrated that T regulatory cells (Tregs) appear to play an important role in the suppression of effector T cells with specificity for framework region epitopes. 38 In accordance with these animals studies, the Poisson regression analyses of the ELISpot results in our consecutive trials, 10 and our in vitro experiments with idiotype-transfected surrogate target cells 19 suggest that vaccination-induced T-cell activity is directed predominantly against individual rather than shared idiotype peptides.…”

Comparative analysis of predicted HLA binding of immunoglobulin idiotype sequences indicates T cell–mediated immunosurveillance in follicular lymphoma

“…10,11 The available in silico tools permit only limited analyses for human MHC class II. Therefore, our study had to focus on HLA class I.…”

“…8,9 These findings are in accordance with animal studies demonstrating T-cell tolerance for germlineencoded immunoglobulin sequences but responsiveness to novel idiotopes arising from junctional diversity or somatic mutations. 10 Because mouse models have also shown T cell-mediated immunosurveillance against hypervariable idiotypic peptides, 11 we sought to obtain evidence that spontaneous idiotype-directed T-cell immunity is operational in nonimmunized lymphoma patients and impairs expansion of malignant B-cell clones that express an idiotype with high immunogenicity. To test this hypothesis, we performed a "reverse immunology" bioinformatics study in 39 FL patients.…”

Antibody humanization by structure-based computational protein design

“…23 Antibody humanization pursues the complementary goals of increasing acceptability to the immune system while maintaining stability, specificity, and affinity. In general, humanization relies on the fact that the human immune system is relatively tolerant of human antibodies, 24 and that antibodies of any given isotype have similar modular structure and sequence-structure-function relationships. For example, standard grafting-based humanization techniques leverage antibody structural modularity to incorporate key functional parts of the exogenous antibody on a human antibody framework, with the aim of maximizing the human portion of the antibody while maintaining antigen binding.…”