Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway.
OBJECTIVE
CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) have been shown to cause T-cell tolerance in tumor-bearing mice; however, little is known about the role of MDSCs in chronic inflammation. Here, for the first time, we have identified and analyzed their role in inflammatory bowel disease (IBD).


METHODS
Repetitive adoptive transfer of clone 4/T-cell receptor (CL4-TCR) transgenic CD8(+) T cells into VILLIN-hemagglutinin (HA) transgenic mice was performed on days 1, 12, and 27. Recipient mice were analyzed for immunopathology, HA-specific CD8(+) T-cell responses, and CD11b(+)Gr-1(+) MDSCs (frequency, phenotype, expression analysis, and in vitro as well as in vivo function). In addition, peripheral blood from patients with active Crohn's disease and ulcerative colitis was examined for the presence and function of human MDSCs denoted as CD14(+)HLA-DR(-/low) cells.


RESULTS
Repetitive transfer of HA-specific CD8(+) T cells prevented VILLIN-HA recipient mice from development of severe enterocolitis, which is seen after a single transfer of T cells. Repeated transfer of antigen-specific T cells led to an increase in the frequency of nitric oxide synthase 2 and arginase-expressing CD11b(+)Gr-1(+) MDSCs in spleen and intestine of VILLIN-HA mice with immunosuppressive function. Cotransfer of MDSCs with HA-specific CD8(+) T cells into naive VILLIN-HA mice ameliorated enterocolitis, indicating a direct immune regulatory effect of MDSCs on induction of IBD by antigen-specific T cells. Finally, an increase in the frequency of human MDSCs with suppressor function was observed in peripheral blood from patients with IBD.


CONCLUSIONS
These results identify MDSCs as a new immune regulatory pathway in IBD.
Haile
Lydia A
LA
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany.
von Wasielewski
Reinhard
R
Gamrekelashvili
Jaba
J
Krüger
Christine
C
Bachmann
Oliver
O
Westendorf
Astrid M
AM
Buer
Jan
J
Liblau
Roland
R
Manns
Michael P
MP
Korangy
Firouzeh
F
Greten
Tim F
TF
D019264:Adoptive Transfer; D000328:Adult; D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004760:Enterocolitis / Q000276:immunology*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013154:Spleen / Q000276:immunology
D039481:CD11b Antigen; D011948:Receptors, Antigen, T-Cell