T-cell Receptor Sequencing Reveals the Clonal Diversity and Overlap of Colonic Effector and FOXP3+ T Cells in Ulcerative Colitis

Lord, James D.; Chen, Janice; Thirlby, Richard C.; Sherwood, Anna; Carlson, Christopher S.

doi:10.1097/mib.0000000000000242

Cited by 27 publications

(24 citation statements)

References 29 publications

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“…Lord et al. have also deep‐sequenced Helios − and Helios + Treg, along with effector CD4 + T cells, from inflamed versus non‐inflamed colon of patients with ulcerative colitis . Little overlap (5–10%) of Helios − and Helios + Treg sequences was observed and even less overlap between either Treg subpopulation and effector CD4 + Foxp3 − cells regardless of location which is in agreement with our study.…”

Section: Discussionsupporting

confidence: 92%

Helios⁺ and Helios⁻ Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires

et al. 2019

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The transcription factor Helios is expressed in a large subset of Foxp3+ Tregs. We previously proposed that Helios is a marker of thymic derived Treg (tTreg), while Helios− Treg were induced from Foxp3− T conventional (Tconv) cells in the periphery (pTreg). To compare the two Treg subpopulations, we generated Helios‐GFP reporter mice and crossed them to Foxp3‐RFP reporter mice. The Helios+ Treg population expressed a more activated phenotype, had a slightly higher suppressive capacity in vitro and expressed a more highly demethylated TSDR but were equivalent in their ability to suppress inflammatory bowel disease in vivo. However, Helios+ Treg more effectively inhibited the proliferation of activated, autoreactive splenocytes from scurfy mice. When Helios+ and Helios− Treg were transferred to lymphoreplete mice, both populations maintained comparable Foxp3 expression, but Foxp3 expression was less stable in Helios− Treg when transferred to lymphopenic mice. Gene expression profiling demonstrated a large number of differentially expressed genes and showed that Helios− Treg expressed certain genes normally expressed in CD4+Foxp3− T cells. TCR repertoire analysis indicated very little overlap between Helios+ and Helios− Treg. Thus, Helios+ and Helios− Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires.

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Section: Discussionsupporting

confidence: 92%

Helios⁺ and Helios⁻ Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires

et al. 2019

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“…In addition, unique Treg clones were identified in the CNS in each independent experimental infection, suggesting that variable(s) other than infection shape the repertoire of Tregs in the CNS. Our results are in agreement with several studies that also did not detect overlap in TCR sequences between regulatory and effector CD4 + T cell populations in diverse settings of tissue inflammation (46)(47)(48)(49).…”

Section: Discussionsupporting

confidence: 93%

CD11c-Expressing Cells Affect Regulatory T Cell Behavior in the Meninges during Central Nervous System Infection

OʼBrien

Overall

Konradt

et al. 2017

The Journal of Immunology

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Treg cells play an important role in the CNS during multiple infections as well as autoimmune inflammation, but the behavior of this cell type in the CNS has not been explored. In mice, infection with Toxoplasma gondii leads to a Th1-polarized parasite-specific effector T cell response in the brain. Similarly, the Treg cells in the CNS during T. gondii infection are Th1-polarized, exemplified by T-bet, CXCR3, and IFN-γ expression. Unlike effector CD4+ T cells, an MHC Class II tetramer reagent specific for T. gondii did not recognize Treg cells isolated from the CNS. Likewise, TCR sequencing revealed minimal overlap in TCR sequence between effector and regulatory T cells in the CNS. Whereas effector T cells are found in the brain parenchyma where parasites are present, Treg cells were restricted to the meninges and perivascular spaces. The use of intravital imaging revealed that activated CD4+ T cells within the meninges were highly migratory, while Treg cells moved more slowly and were found in close association with CD11c+ cells. To test whether the behavior of Tregs in the meninges is influenced by interactions with CD11c+ cells, mice were treated with anti-LFA-1 antibodies to reduce the number of CD11c+ cells in this space. The anti-LFA-1 treatment led to fewer contacts between Tregs and the remaining CD11c+ cells and increased the speed of Treg cell migration. These data suggest that Treg cells are anatomically restricted within the CNS and the interaction with CD11c+ populations regulates their local behavior during T. gondii infection.

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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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T-cell Receptor Sequencing Reveals the Clonal Diversity and Overlap of Colonic Effector and FOXP3+ T Cells in Ulcerative Colitis

Cited by 27 publications

References 29 publications

Helios⁺ and Helios⁻ Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires

Helios⁺ and Helios⁻ Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires

CD11c-Expressing Cells Affect Regulatory T Cell Behavior in the Meninges during Central Nervous System Infection

Altered T cell receptor beta repertoire patterns in pediatric ulcerative colitis

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