Mouse Lysozyme-M Knockout Mice Reveal How the Self-Determinant Hierarchy Shapes the T Cell Repertoire against This Circulating Self Antigen in Wild-Type Mice

Abstract

We have studied T cell tolerance to defined determinants within ML-M using wild-type (WT; ML-M+/+) and LysMcre (ML-M−/−) C3H (H-2k) mice to determine the relative contribution of ML-M-derived epitopes vs those from other self Ags in selection of the ML-M-specific T cell repertoire. ML-M was totally nonimmunogenic in WT mice, but was rendered immunogenic in LysMcre mice. Most of the response to ML-M in LysMcre mice was directed to the immunodominant determinant region 105–119. This determinant is spontaneously displayed (without adding exogenous ML-M) by macrophages of WT, but not LysMcre, mice and is stimulatory for peptide 105–119 (p105–119)-primed T cells. Moreover, neonatal tolerization of LysMcre mice with p105–119 or ML-M abrogated the T cell response to subsequent challenge with ML-M or p105–119. Furthermore, p95–109 and p110–125 of ML-M were immunogenic in LysMcre mice, but not in WT mice, thereby representing subdominant, tolerance-inducing epitopes of ML-M. As expected, the T cell repertoire to cryptic ML determinants in WT mice was also intact in LysMcre mice. Furthermore, the pattern of response to the related homologue of ML-M, hen eggwhite lysozyme, was similar in these two groups of mice. Thus, several codominant T cell determinants within ML-M contribute significantly to tolerance induction, and the anti-cryptic T cell repertoire to ML-M was positively selected on non-ML-M self ligands. These results reveal that the induction of self tolerance to a multideterminant protein follows the quantitative hierarchy of self-determinant expression and are of relevance in understanding the pathogenesis of autoimmunity.

A murine model for catheter-associated candiduria

“…At the time of our study, the LysM 2/2 mice were not entirely back-crossed to the C57BL/6 mice, which limited our ability to draw definitive conclusions on the importance of lysozyme as an effector molecule. Other LysM 2/2 mice have also been cloned (Sinha et al, 2004) and could potentially be used in future experiments.…”

Autoimmune Diseases: The Role of Environment and Gene Interactions

“…This means that certain 'dominant self' epitopes are well processed and presented, whereas others, the (cryptic or recessive self) (Sercarz et al, 1993) ones are poorly or never processed and presented. Thus this type of staging of determinants (dominance/crypticity) in turn plays a critical role in thymus gradation of the T cell repertoire: the T cells specific for dominant self epitopes are tolerized with ease while those purportly aimed at cryptic self epitopes evade tolerance induction and become part of the mature T cell repertoire (Gammon and Sercarz, 1989;Cibotti et al, 1992;Sinha et al, 2004). T cells that evade tolerance induction are capable of being activated in the periphery under certain stressful inflammatory circumstances such as occur during infection; this has the consequence of enhanced processing and presentation of once latent (cryptic) determinants (Lehmann et al, 1992;Lanzavecchia, 1995).…”

Insertion of the Dibasic Motif in the Flanking Region of a Cryptic Self-Determinant Leads to Activation of the Epitope-Specific T Cells

“…B oth self and foreign Ags possess T cell determinants that are either well processed and presented (dominant determinants) or poorly processed (cryptic determinants) from whole (native) protein (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). The dominant epitopes of a foreign Ag are immunogenic, whereas those of a self Ag are generally tolerogenic (4,5,(11)(12)(13)(14)(15).…”

“…The dominant epitopes of a foreign Ag are immunogenic, whereas those of a self Ag are generally tolerogenic (4,5,(11)(12)(13)(14)(15). However, cryptic epitopes of both self and foreign Ags are potentially immunogenic in the preprocessed (peptide) form (2,3).…”

“…Although this association has been documented in different experimental models of autoimmunity (9,16,20,21), there is meager experimental evidence showing that deliberate unmasking of a specific preselected cryptic epitope within a native self Ag can induce epitope-specific immune response and overcome self tolerance in vivo. In addition, crypticity of antigenic determinants has been attributed to multiple factors (2,4,6,19,(22)(23)(24)(25)(26)(27)(28), but sufficient experimental evidence has been gathered to date only for a limited number of these proposed mechanisms. Further defining the mechanisms underlying the crypticity of T cell epitopes is critical for better understanding of the role of cryptic self-determinants in the induction of autoimmunity (2,4,9,11,16,19,20), graft rejection (29), and antitumor immunity (30 -32).…”