Preferential Use of Public TCR during Autoimmune Encephalomyelitis

Zhao, Yunqian; Nguyen, Phuong; Ma, Jing; Wu, Tianhua; Jones, Lindsay L.; Pei, Deqing; Cheng, Cheng; Geiger, Terrence L.

doi:10.4049/jimmunol.1501029

Cited by 36 publications

(45 citation statements)

References 42 publications

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“…TRBV13-2 is the dominant TCRβ in MOG-specific T cells22. Our results indicated the presence of a diverse, public TCR repertoire within the autoimmune response, and that T cells bearing public TCR were preferentially deployed relative to private TCR from the pre-immune repertoire17. This suggested a role for public sequences in predisposing the repertoire toward autoreactivity.…”

Section: Resultsmentioning

confidence: 65%

“…To understand the composition and dynamics of autoimmune effector and regulatory repertoires, we previously performed saturation sequencing of splenic and CNS T cells from 12 mice with MOG 35-55 -induced EAE and 5 healthy controls, analyzing >18 × 10 6 CD4 + Foxp3 – (Tconv) and Foxp3 + (Treg) TRBV13-2 + TCRβ61718192021. TRBV13-2 is the dominant TCRβ in MOG-specific T cells22.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous results using high-throughput sequencing of the TCRβ repertoire during myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) indicated that a diverse public TCRβ repertoire is preferentially deployed relative to the non-shared, or private, pre-immune repertoire17. Here we assess the contribution of individual public and private TCRβ sequences to the autoimmune response during MOG 35-55 -induced EAE.…”

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confidence: 93%

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Autoimmune susceptibility imposed by public TCRβ chains

Zhao

Nguyen

Vogel

et al. 2016

Sci Rep

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Although the TCR repertoire is highly diverse, a small fraction of TCR chains, referred to as public, preferentially form and are shared by most individuals. Prior studies indicated that public TCRβ may be preferentially deployed in autoimmunity. We hypothesized that if these TCRβ modulate the likelihood of a TCRαβ heterodimer productively engaging autoantigen, because they are widely present in the population and often high frequency within individual repertoires, they could also broadly influence repertoire responsiveness to specific autoantigens. We assess this here using a series of public and private TCRβ derived from autoimmune encephalomyelitis-associated TCR. Transgenic expression of public, but not private, disease-associated TCRβ paired with endogenously rearranged TCRα endowed unprimed T cells with autoantigen reactivity. Further, two of six public, but none of five private TCRβ provoked spontaneous early-onset autoimmunity in mice. Our findings indicate that single TCRβ are sufficient to confer on TCRαβ chains reactivity toward disease-associated autoantigens in the context of diverse TCRα. They further suggest that public TCR can skew autoimmune susceptibility, and that subsets of public TCR sequences may serve as disease- specific biomarkers or therapeutic targets.

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Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 93%

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Autoimmune susceptibility imposed by public TCRβ chains

Zhao

Nguyen

Vogel

et al. 2016

Sci Rep

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“…Such sharing of specific TCRs is expected from the relatively low diversity of antigen‐specific sequences revealed by in vitro multimer‐staining experiments 11, 12. A very similar idea has been exploited by several groups to identify TCRs specific to the Cytomegalovirus,30 Type‐1 diabetes,48, 49 arthritis50 and other immune diseases 51. In these studies, there is no theoretical expectation from the recombination model.…”

Section: Public Specific Responsementioning

confidence: 97%

Predicting the spectrum of TCR repertoire sharing with a data‐driven model of recombination

Elhanati

Sethna

Callan

et al. 2018

Immunological Reviews

126

159

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SummaryDespite the extreme diversity of T‐cell repertoires, many identical T‐cell receptor (TCR) sequences are found in a large number of individual mice and humans. These widely shared sequences, often referred to as “public,” have been suggested to be over‐represented due to their potential immune functionality or their ease of generation by V(D)J recombination. Here, we show that even for large cohorts, the observed degree of sharing of TCR sequences between individuals is well predicted by a model accounting for the known quantitative statistical biases in the generation process, together with a simple model of thymic selection. Whether a sequence is shared by many individuals is predicted to depend on the number of queried individuals and the sampling depth, as well as on the sequence itself, in agreement with the data. We introduce the degree of publicness conditional on the queried cohort size and the size of the sampled repertoires. Based on these observations, we propose a public/private sequence classifier, “PUBLIC” (Public Universal Binary Likelihood Inference Classifier), based on the generation probability, which performs very well even for small cohort sizes.

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“…4). Culturing NFM primed splenocytes with NFM was a means to enhance T cell recognition and activation on NFM to enhance expansion encephalitogenic NFM or MOG specific T cell clones (14, 64, 65). As previously reported, NFM expanded T cells were able to passively transfer EAE, but we found this was associated with transfer of cross-reactive MOG 38-49 tetramer positive T cells capable of enrichment in the CNS (Fig.…”

Section: Discussionmentioning

confidence: 99%

NFM Cross-Reactivity to MOG Does Not Expand a Critical Threshold Level of High-Affinity T Cells Necessary for Onset of Demyelinating Disease

Blanchfield

Sabatino

Lawrence

et al. 2017

The Journal of Immunology

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Of interest to the etiology of demyelinating autoimmune disease is the potential to aberrantly activate CD4+ T cells due to cross-recognition of multiple self-epitopes such as has been suggested for MOG35-55 and NFM15-35. NFM15-35 is immunogenic in C57BL/6 mice but fails to induce demyelinating disease by polyclonal T cells despite having the same TCR contact residues as MOG35-55, a known encephalitogenic antigen. Despite reported cross-reactivity with MOG specific T cells, the polyclonal response to NFM15-35 did not expand threshold numbers of MOG38-49 tetramer positive T cells. Furthermore, NFM lacked functional synergy with MOG to promote EAE because NFM-/- mice developed an identical disease course to wild type mice after challenge with MOG35-55. Single cells analysis of encephalitogenic T cells using the pMHC monomer based 2D micropipette adhesion frequency assay confirmed that NFM was not a critical antigen driving demyelinating disease because NFM18-30 specific T cells in the CNS were predominantly reactive to MOG38-49. The absence of NFM contribution to disease allowed mapping of the amino acids required for encephalitogenicity and expansion of high affinity, MOG specific T cells that defined the polyclonal response. Alterations of N-terminal residues outside of the NFM15-35 core nonamer promoted expansion of high affinity, MOG38-49 tetramer positive T cells and promoted consistent EAE induction, unlike mice challenged with NFM15-35. While NFM15-35 is immunogenic and cross-reactive with MOG at the polyclonal level, it fails to expand a threshold level of encephalitogenic, high affinity MOG specific T cells.

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Preferential Use of Public TCR during Autoimmune Encephalomyelitis

Cited by 36 publications

References 42 publications

Autoimmune susceptibility imposed by public TCRβ chains

Autoimmune susceptibility imposed by public TCRβ chains

Predicting the spectrum of TCR repertoire sharing with a data‐driven model of recombination

NFM Cross-Reactivity to MOG Does Not Expand a Critical Threshold Level of High-Affinity T Cells Necessary for Onset of Demyelinating Disease

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