Self-reactive T cells and Degeneracy of T Cell Recognition: Evolving Concepts—from Sequence Homology to Shape Mimicry and TCR Flexibility

Maverakis, Emanual; Elzen, Peter van den; Sercarz, Eli E.

doi:10.1006/jaut.2000.0493

Cited by 52 publications

(30 citation statements)

References 97 publications

(102 reference statements)

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“…24,25 Indeed, promiscuity of peptide binding to HLA molecules and T cell receptor degeneracy are well known mechanisms that allow the immune system to mature by developing a wide T cell repertoire that can recognize a huge array of antigen specificities. [32][33][34] Therefore, our results indicate that the epitopes that are present in the GX301 peptides may be commonly expressed in the thymus where they select both CD4C and CD8C specific T cell clones. Accordingly, 100% of the subjects in our study showed an immune response to at least one peptide, regardless of the expression of the HLA-A2 molecule.…”

Section: Discussionmentioning

confidence: 65%

Immunogenicity of GX301 cancer vaccine: Four (telomerase peptides) are better than one

Fenoglio

Parodi

Lavieri³

et al. 2015

Human Vaccines & Immunotherapeutics

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Peptide 540-548 , peptide [611][612][613][614][615][616][617][618][619][620][621][622][623][624][625][626] , peptide [672][673][674][675][676][677][678][679][680][681][682][683][684][685][686] and peptide [766][767][768][769][770][771][772][773][774][775][776][777][778][779][780] , which are derived from human telomerase, constitute the immunogenic component of the GX301 cancer vaccine. The relative immunogenicity of these peptides is unknown, thus it is unsure whether their combined use offers real advantages over single peptide stimulation. Hence, this study compared the number of specific immune responses and responders to each peptide, as well as to their mixture (meaning the co-presence of the 4 peptides in the same culture well), achieved after ex vivo stimulation of PBMC from 21, HLA-A2C (n.11) or HLA-A2-(n.10), healthy donors. The study was performed on freshly collected PBMC (T0) and on PBMC stimulated for 10 d with single peptides or their mixture (T1). Peptide-specific immune responses were analyzed by Elispot and cytokine intracellular staining by flow cytometry. The results showed that each peptide induced specific immune responses in some subjects, with different panels of responders among the peptides. Moreover, the numbers of responses and responders to the single peptides or their mixture were comparable. Importantly, the overall number of responders to the 4 peptides was higher than to each single peptide, or to their mixture, both at T0 and T1. These data demonstrate the immunogenicity of each of the 4 GX301 telomerase peptides. Moreover, they show the advantage of multi-peptide over single peptide stimulation, providing a clear support to their combined administration in vaccination protocols. However, the data pose a warning against peptide administration as a mixture due to possible interference phenomena during antigen presentation processes.

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Section: Discussionmentioning

confidence: 65%

Immunogenicity of GX301 cancer vaccine: Four (telomerase peptides) are better than one

Fenoglio

Parodi

Lavieri³

et al. 2015

Human Vaccines & Immunotherapeutics

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“…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%

“…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).…”

mentioning

confidence: 99%

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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“…Cross-reactivity is necessary for T-cell development and is critical given the fixed size of the T-cell repertoire relative to the vast universe of potential antigens (Bhardwaj et al, 1993;Evavold et al, 1995;Mason, 1998;Maverakis et al, 2001;Wilson et al, 2004;Wucherpfennig and Strominger, 1995). Mason et al estimated that each T-cell is capable of reacting with ~10 6 different MHC-associated peptide epitopes (Mason, 1998), and Hiemstra et al further confirmed the estimation through deduction of effective concentrations of agonist ligands in a peptide-"gemisch" (Hiemstra et al, 1998).…”

Section: Does Mog-specific T-cell Cross-react With Alternative Self-amentioning

confidence: 99%

T-cell Receptor CDR3 Sequence but Not Recognition Characteristics Distinguish Autoreactive Effector and Foxp3+ Regulatory T-cells

Liu¹

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Self-reactive T cells and Degeneracy of T Cell Recognition: Evolving Concepts—from Sequence Homology to Shape Mimicry and TCR Flexibility

Cited by 52 publications

References 97 publications

Immunogenicity of GX301 cancer vaccine: Four (telomerase peptides) are better than one

Immunogenicity of GX301 cancer vaccine: Four (telomerase peptides) are better than one

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

T-cell Receptor CDR3 Sequence but Not Recognition Characteristics Distinguish Autoreactive Effector and Foxp3+ Regulatory T-cells

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