Profoundly Expanded T-cell Clones in the Inflamed and Uninflamed Intestine of Patients With Crohn's Disease.
OBJECTIVE
T cells are key players in the chronic intestinal inflammation that characterises Crohn's disease. Here we aim to map the intestinal T-cell receptor [TCR] repertoire in patients with Crohn's disease, using next-generation sequencing technology to examine the clonality of the T-cell compartment in relation to mucosal inflammation and response to therapy.


METHODS
Biopsies were taken from endoscopically inflamed and uninflamed ileum and colon of 19 patients with Crohn's disease. From this cohort, additional biopsies were taken after 8 weeks of remission induction therapy from eight responders and eight non-responders. Control biopsies from 11 patients without inflammatory bowel disease [IBD] were included. The TCRβ repertoire was analysed by next-generation sequencing of biopsy RNA.


RESULTS
Both in Crohn's disease patients and in non-IBD controls, a broad intestinal T-cell repertoire was found, with a considerable part consisting of expanded clones. Clones in Crohn's disease were more expanded [p = 0.008], with the largest clones representing up to as much as 58% of the total repertoire. There was a substantial overlap of the repertoire between inflamed and uninflamed tissue and between ileum and colon. Following therapy, responders showed larger changes in the T-cell repertoire than non-responders, although a considerable part of the repertoire remained unchanged in both groups.


CONCLUSIONS
The intestinal T-cell repertoire distribution in Crohn's disease is different from that in the normal gut, containing profoundly expanded T-cell clones that take up a large part of the repertoire. The T-cell repertoire is fairly stable regardless of endoscopic mucosal inflammation or response to therapy.
Amsterdam Rheumatology and immunology Center, Academic Medical Center, Amsterdam, The Netherlands.|Laboratory for Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
M E
ME
Doorenspleet
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
L
L
Westera
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
C P
CP
Peters
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
T B M
TBM
Hakvoort
Amsterdam Rheumatology and immunology Center, Academic Medical Center, Amsterdam, The Netherlands.|Laboratory for Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
R E
RE
Esveldt
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
E
E
Vogels
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherland.
A H C
AHC
van Kampen
Laboratory for Genome Analysis, Academic Medical Center, Amsterdam, The Netherlands.
F
F
Baas
Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands.
C
C
Buskens
Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands.
W A
WA
Bemelman
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
G
G
D'Haens
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
C Y
CY
Ponsioen
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
A A
AA
Te Velde
Amsterdam Rheumatology and immunology Center, Academic Medical Center, Amsterdam, The Netherlands.
N
N
de Vries
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.|Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
G R
GR
van den Brink
D000068879:Adalimumab / Q000627:therapeutic use; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001706:Biopsy; D019819:Budesonide / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D002999:Clone Cells / Q000187:drug effects; D003106:Colon / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D005260:Female; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D006801:Humans; D007082:Ileum / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D000069285:Infliximab / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D011948:Receptors, Antigen, T-Cell; D019819:Budesonide; D002097:C-Reactive Protein; D000069285:Infliximab; D000068879:Adalimumab
Crohn’s disease; TCR; next-generation sequencing