Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC

Maverakis, Emanual; Beech, Jonathan T; Stevens, David B.; Ametani, Akio; Brossay, Laurent; Elzen, Peter van den; Mendoza, Richard; Thai, Quoc; Macías, Luis Hernando Moreno; Ethell, Douglas W.; Campagnoni, Celia W.; Campagnoni, Anthony T.; Sette, Alessandro; Sercarz, Eli E.

doi:10.1073/pnas.0936151100

Cited by 26 publications

(20 citation statements)

References 20 publications

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“…However, previously nonimmunogenic self epitopes could also be revealed to the immune system in an immunogenic form involving post-translational modification of self epitopes (62). Moreover, other mechanisms besides crypticity have also been invoked in permitting potentially autoreactive T cells to escape thymic negative selection (63)(64)(65)(66).…”

Section: Discussionmentioning

confidence: 99%

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

Sinha

Howard

Kim

et al. 2004

The Journal of Immunology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Sinha

Howard

Kim

et al. 2004

The Journal of Immunology

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“…Our data concerning the adoptive transfer of T cells from tg mice expressing the 1934.4 and 172.10 TCRs that have different affinities for Ag (32) are in accord with the concept that above a certain avidity threshold, cells of both high and low avidity can be involved in disease progression. However, this does not exclude a role for high-avidity "driver" clones such as T cells bearing the 172.10 TCR (with CDR3␤ "DAGGGY" motif) in the development of EAE (72)(73)(74).…”

Section: Discussionmentioning

confidence: 99%

Feedback Regulation of Murine Autoimmunity via Dominant Anti-Inflammatory Effects of Interferon γ

Minguela

Pastor

et al. 2007

The Journal of Immunology

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There is a paucity of knowledge concerning the immunologic sequelae that culminate in overt autoimmunity. In the present study, we have analyzed the factors that lead to disease in the model of autoimmunity, murine experimental autoimmune encephalomyelitis (EAE). EAE in H-2u mice involves autoreactive CD4+ T cells that are induced by immunization with the immunodominant N-terminal epitope of myelin basic protein. The affinity of this epitope for I-Au can be increased by substituting lysine at position 4 with tyrosine, and this can be used to increase the effective Ag dose. Paradoxically, high doses of Ag are poorly encephalitogenic. We have used quantitative analyses to study autoreactive CD4+ T cell responses following immunization of mice with Ag doses that are at the extremes of encephalitogenicity. A dose of autoantigen that is poorly encephalitogenic results in T cell hyperresponsiveness, triggering an anti-inflammatory feedback loop in which IFN-γ plays a pivotal role. Our studies define a regulatory mechanism that serves to limit overly robust T cell responses. This feedback regulation has broad relevance to understanding the factors that determine T cell responsiveness.

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“…Because the Vβ8.2Jβ2.7 response to Ac1-9 arises after priming with Ac1-9, Ac1-20, MBP, or whole spinal cord homogenate, where the amino terminus is relatively available, we synthesized LDVM1-9 (Y4), which includes the adjacent 5′ Golli (genes of the oligodendrocyte lineage) residues, LDVM. In this peptide, the 4K-to-4Y substitution is required for induction of 1-9 reactivity because it allows the peptide to bind in the appropriate register to the MHC class II I-A u molecule (19). Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In fact, several autoreactive clones induce disease only when transferred in high numbers. It is likely that among the diverse sets of T cells potentially expandable to a selfantigen, only a small proportion are able to induce and drive states of autoimmunity, a group we have called driver clones (7,8,19). Thus, even if a mimic can activate self-directed T cells, it may not stimulate the pathogenic subset; individual T cells may respond to unique sets of molecular mimics.…”

Section: Discussionmentioning

confidence: 99%

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Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity

Maverakis

Menezes

Ametani

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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To determine the role that competition plays in a molecular mimic's capacity to induce autoimmunity, we studied the ability of naïve encephalitogenic T cells to expand in response to agonist altered peptide ligands (APLs), some capable of stimulating both self-directed and exclusively APL-specific T cells. Our results show that although the APLs capable of stimulating exclusively APLspecific T cells are able to expand encephalitogenic T cells in vitro, the encephalitogenic repertoire is effectively outcompeted in vivo when the APL is used as the priming immunogen. Competition as a mechanism was supported by: (i) the demonstration of a population of exclusively APL-specific T cells, (ii) an experiment in which an encephalitogenic T cell population was successfully outcompeted by adoptively transferred naïve T cells, and (iii) demonstrating that the elimination of competing T cells bestowed an APL with the ability to expand naïve encephalitogenic T cells in vivo. In total, these experiments support the existence of a reasonably broad T cell repertoire responsive to a molecular mimic (e.g., a microbial agent), of which the exclusively mimic-specific component tends to focus the immune response on the invading pathogen, whereas the rare cross-reactive, potentially autoreactive T cells are often preempted from becoming involved.experimental autoimmune encephalomyelitis | molecular mimicry | multiple sclerosis | driver clones | autoimmune T cell recognition is degenerate; a single T cell can react to a heterogeneous assortment of ligands (1-5). The use of synthetic combinatorial peptide libraries has revealed two key features of this degeneracy: (i) There are a vast number of agonistic ligands for a single clone (possibly >10 6 ) each falling along a spectrum of stimulatory potencies and (ii) the native self determinant is often "suboptimal" when compared with many of the synthetic mimic peptides (4). The concept of molecular mimicry describes a situation in which a foreign microbe can initiate an immune response in which a T or B cell component cross-recognizes self. The amino acid sequence in the mimic determinant and the native self-determinant can be very different and in some instances, apparently chemically unrelated. Although several groups have demonstrated degenerate recognition by autoreactive T cells (1, 6, 7), molecular mimicry as a direct cause of autoimmunity has only rarely been shown (6).We have used the term "driver" to refer to individual selfdirected T cell clones that are required to propagate an autoimmune response. In this paper we ask whether APL-specific, nonself-directed T cells can outcompete naïve driver pathogenic clones for activation. The APLs used in our study can be considered analogous to microbial molecular mimics. The ability of these APLs to induce non-self-directed exclusively APL-specific clones was studied in the myelin basic protein (MBP):Ac1-9-induced B10.PL (H-2 u ) model of experimental autoimmune encephalomyelitis (EAE). EAE is an autoimmune demyelinating disease of the cent...

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Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC

Cited by 26 publications

References 20 publications

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

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

Feedback Regulation of Murine Autoimmunity via Dominant Anti-Inflammatory Effects of Interferon γ

Molecular mimics can induce a nonautoaggressive repertoire that preempts induction of autoimmunity

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