Profoundly Expanded T-cell Clones in the Inflamed and Uninflamed Intestine of Patients With Crohn’s Disease

Doorenspleet, Marieke E.; Westera, Liset; Peters, Charlotte P.; Hakvoort, T. B. M.; Esveldt, Rebecca E. E.; Vogels, Esther; Kampen, Antoine H. C. van; Baas, Frank; Buskens, C J; Bemelman, Willem A.; D’Haens, Geert R.; Ponsioen, Cyriel Y.; Velde, Anje A. te; Vries, Niek de; Brink, Gijs R. van den

doi:10.1093/ecco-jcc/jjx012

Cited by 31 publications

(36 citation statements)

References 26 publications

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“…29 Similarly another report of TCR repertoire in the inflamed gut of Crohn's patients found clonal expansion of single clones at up to 58% (no analysis of sharing among the 19 patients studied), though this could reflect the low numbers of clonotypes examined (5000 per sample) and use of 454 sequencing technology. 32 Moreover, in several reports, the predicted amino acid sequence of the largest clones' CDR3 regions from specific individuals could also be found in our dataset such as SARGDSNQPQH seen in one and ASSSGTSGYNEQF seen in three of our active CD patients (these reports do not show sharing of these regions among their small numbers of patients, but they were seen in 5−15% of our active Crohn's patient CDR3 sequence dataset). 33 Our focus on CD4 CDR3 clones characterized by high copy number was intended to identify T cells that were likely to be enriched for disease-relevant antigen-reactive clonotypes.…”

Section: Discussionsupporting

confidence: 58%

“…Clonotypes are also widely shared between inflamed and non-inflamed areas of the gut within the same subject. 32 When we looked at sequences expanded in the lamina propria, in most of the patients these clonotypes were not expanded as often in the peripheral blood, but there were 25-43% of sequences similarly expanded in both compartments and 4.9−7.0% with expansion restricted to the gut tissue alone.…”

Section: Discussionmentioning

confidence: 96%

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Expanded TCRβ CDR3 clonotypes distinguish Crohn's disease and ulcerative colitis patients

Pendegraft

Byrne‐Steele

et al. 2018

Mucosal Immunology

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We aimed to determine whether the TCR repertoires of Crohn's disease (CD) patients contain highly prevalent disease-specific T-cell clonotypes reflective of the characteristic and highly shared aberrant serum antibody reactivity to gut commensal flagellin antigens. The CD4 TCRβ CDR3 sequence repertoires from active CD (n = 20) and ulcerative colitis (UC) (n = 10) patients were significantly more diverse, and individual sequences over-represented, compared to healthy controls (HC) (n = 97). While a very small number of expanded public CDR3 sequences are highly shared between active CD and UC, the majority of significantly expanded TCRβ CDR3 clonotypes are private to CD and UC patients with equivalent prevalence among IBD patients. Further defining TCR clonotypes by Vβ-CDR3 linkage showed significant differences in the TCR repertoires between UC and CD. Flagellin antigen exposure induced expansion of several TCRβ CDR3 sequences in CD4 cells from a flagellin-seropositive subject including sequences highly shared by or relatively private to CD (and UC) patients. These data suggest that flagellin-reactivity contributes to the expansion of a small number of CD4 clonotypes but does not support flagellin antigens as predominantly driving CD4 cell proliferation in CD. Disease-specific expanded TCRβ CDR3 clonotypes characterize CD and UC and the shared exposure to the gamut of gut microbial antigens.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 96%

Expanded TCRβ CDR3 clonotypes distinguish Crohn's disease and ulcerative colitis patients

Pendegraft

Byrne‐Steele

et al. 2018

Mucosal Immunology

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“…Indeed, a break in tolerance to commensal antigens is thought to induce chronic intestinal inflammation in humans 65 . Increased expansion and skewing of T cells has been reported in patients with IBD 39,66 and in the CD4 + CD45RB hi adoptive transfer mouse model 67 . The clonal expansion that we observed here in adoptive transferred Rag -/mice fed with diet 2019 suggest that these expanded clones are pathogenic, but further studies are required to test this hypothesis.…”

Section: Discussionmentioning

confidence: 98%

“…In the homeostatic stage, the intestinal mucosal T cell repertoire is shaped by environmental antigens. Under chronic intestinal inflammation, the TCR repertoire is thought to be more profoundly shaped by immune response against lumen antigens 39 . We hypothesized that IL-23 expression resulted in generation of CD4 + T cells present in mLN and colon that could rapidly respond to microbiome changes induced by the diet.…”

Section: Dietsmentioning

confidence: 99%

Diet Modifies Colonic Microbiota and CD4⁺ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Chen

Iuga

Filho

et al. 2018

Preprint

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A wealth of experimental data points to immunological and environmental factors in the pathogenesis of inflammatory bowel disease (IBD). Here we study the role of IL-23, the microbiome, and the diet in the development of colitis. To promote IL-23 expression in vivo,we generated a mouse model in which IL-23 was conditionally expressed by CX 3 CR1 + myeloid cells, upon cyclic administration of tamoxifen in a specific diet (diet 2019). IL-23 expression induced an intestinal inflammatory disease that resembled ulcerative colitis in humans with cycles of acute disease and remission. The relapses were caused by the diet switch from the conventional diet used in our facility (diet 5053) to the diet 2019, and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota, but did not alter the levels of IL-23. Colitis induction depended on the microbiota and required CD4 T lymphocytes. Colitis-inducing CD4 + T cells were found in the mesenteric lymph node and large intestine during remission and were able to trigger disease when transferred to lymphopenic mice, but only upon diet modification. The CD4 TCR repertoire in the diseased recipient Rag -/-mice had reduced diversity associated with the expansion of dominant T cell clones. These findings reveal a critical role for IL-23 in generation of a CD4 + T cell population in mice that is sensitive to a modification of intestinal bacterial flora subsequent to a dietary manipulation. Dietary changes occurring in the context of altered IL-23 expression may contribute to the onset and progression of IBD.

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“…Earlier studies have documented increased clonality of lamina propriaresiding T cells [13] and differential TCR-β chain usage between IBD subjects and non-IBD controls [13][14][15][16][17]. In recent years, only few studies using HTS of the TCR repertoire were performed in IBD patients, showing restricted TCR repertoires in CD and UC patients, although these analyses focused on the clones present in lamina propria [18][19][20][21]. We hypothesized that pediatric patients with UC possess unique T cell clones, and their expansion may correlate with degree of intestinal inflammation.…”

Section: Clinical and Experimental Immunologymentioning

confidence: 99%

Altered T cell receptor beta repertoire patterns in pediatric ulcerative colitis

Werner

Nunberg

Rechavi

et al. 2019

Clinical &Amp; Experimental Immunology

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The antigenic specificity of T cells occurs via generation and rearrangement of different gene segments producing a functional T cell receptor (TCR). High-throughput sequencing (HTS) allows in-depth assessment of TCR repertoire patterns. There are limited data concerning whether TCR repertoires are altered in inflammatory bowel disease. We hypothesized that pediatric ulcerative colitis (UC) patients possess unique TCR repertoires, resulting from clonotypical expansions in the gut. Paired blood and rectal samples were collected from nine newly diagnosed treatmentnaive pediatric UC patients and four healthy controls. DNA was isolated to determine the TCR-β repertoire by HTS. Significant clonal expansion was demonstrated in UC patients, with inverse correlation between clinical disease severity and repertoire diversity in the gut. Using different repertoire variables in rectal biopsies, a clear segregation was observed between patients with severe UC, those with mild-moderate disease and healthy controls. Moreover, the overlap between autologous blood-rectal samples in UC patients was significantly higher compared with overlap among controls. Finally, we identified several clonotypes that were shared in either all or the majority of UC patients in the colon. Clonal expansion of TCRβ-expressing T cells among UC patients correlates with disease severity and highlights their involvement in mediating intestinal inflammation.

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Profoundly Expanded T-cell Clones in the Inflamed and Uninflamed Intestine of Patients With Crohn’s Disease

Cited by 31 publications

References 26 publications

Expanded TCRβ CDR3 clonotypes distinguish Crohn's disease and ulcerative colitis patients

Expanded TCRβ CDR3 clonotypes distinguish Crohn's disease and ulcerative colitis patients

Diet Modifies Colonic Microbiota and CD4⁺ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Altered T cell receptor beta repertoire patterns in pediatric ulcerative colitis

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Profoundly Expanded T-cell Clones in the Inflamed and Uninflamed Intestine of Patients With Crohn’s Disease

Cited by 31 publications

References 26 publications

Expanded TCRβ CDR3 clonotypes distinguish Crohn's disease and ulcerative colitis patients

Expanded TCRβ CDR3 clonotypes distinguish Crohn's disease and ulcerative colitis patients

Diet Modifies Colonic Microbiota and CD4+ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Altered T cell receptor beta repertoire patterns in pediatric ulcerative colitis

Contact Info

Product

Resources

About

Diet Modifies Colonic Microbiota and CD4⁺ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23