Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn disease
Timothy S. Olson, … , Fabio Cominelli, Klaus Ley
Timothy S. Olson, … , Fabio Cominelli, Klaus Ley
Published August 1, 2004
Citation Information: J Clin Invest. 2004;114(3):389-398. https://doi.org/10.1172/JCI20855.
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Article Autoimmunity

Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn disease

Abstract

SAMP1/YitFc mice develop discontinuous, transmural inflammatory lesions in the terminal ileum, similar to what is found in human Crohn disease. Compared with the mesenteric lymph nodes (MLNs) of AKR control mice, SAMP1/YitFc MLNs contain a 4.3-fold expansion in total B cell number and a 2.5-fold increased percentage of CD4+ T cells expressing the αEβ7 integrin. Although αEβ7+CD4+ T cells possess a regulatory phenotype (CD25+, L-selectinlo, and CD45RBlo), express IL-10, and suppress effector T cell proliferation in vitro, they cannot prevent ileitis development in SCID mice adoptively transferred with effector CD4+ T cells, although the CD4+CD25+ subset, which overlaps with the αEβ7+CD4+ subset, prevents colitis. The αEβ7+CD4+ T cells express high levels of ICOS, a costimulatory molecule that augments B cell function, suggesting their involvement in the increase in B cells, IgA+ cells, and soluble IgA found within the MLNs and ileum of SAMP1/YitFc mice. MLN B cell numbers correlate with ileitis severity in SAMP1/YitFc mice, and cotransfer of SAMP1/YitFc MLN B cells along with CD4+ T cells increases ileitis severity in SCID mice compared with transfer of CD4+ T cells alone. SAMP1/YitFc B cells prevent αEβ7+CD4+ T cells from suppressing effector T cell proliferation. We conclude that SAMP1/YitFc MLN B cells contribute to the development of SAMP1/YitFc ileitis.

Authors

Timothy S. Olson, Giorgos Bamias, Makoto Naganuma, Jesús Rivera-Nieves, Tracy L. Burcin, William Ross, Margaret A. Morris, Theresa T. Pizarro, Peter B. Ernst, Fabio Cominelli, Klaus Ley

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SAMP1/YitFc Treg populations block colitis, but not ileitis, in the CD4+...
SAMP1/YitFc Treg populations block colitis, but not ileitis, in the CD4+ T cell adoptive transfer model. (A) Comparison of adoptively transferred ileitis severity (6 weeks after transfer, mean ± SEM) in SCID recipients (n = 4 in each group) induced by 5 × 105 SAMP1/YitFc total MLN CD4+ T cells, αE–CD4+ T cells, αE+CD4+ T cells, or combination treatment using αE+CD4+ T cells injected 3 weeks (3wk) before, at the same time as, or 3 weeks after αE–CD4+ T cells. (B) In a separate cohort of SCID mice, severity of ileitis induced by 5 × 105 SAMP1/YitFc CD4+ T cells (n = 4) was not decreased by coinjection of 5 × 105 AKR MLN CD4+ T cells (n = 5). Total inflammatory scores represent the sum of three individual histological indices, including active inflammation, chronic inflammation, and villus architectural distortion. (C) In a third cohort, adoptively transferred ileitis and colitis severities were compared among SCID mice 6 weeks after mice received 5 × 105 SAMP1/YitFc MLN unfractionated CD4+, CD45RBhiCD4+, CD45RBloCD4+, CD25–CD4+, or CD25+CD4+ T cells. Because villus distortion is not measured in colitis, the sum of active and chronic inflammatory scores was used for this comparison. Data are expressed as mean ± SEM. *Significantly decreased (P < 0.05) compared with ileitis severity in mice receiving αEβ7–CD4+ cells. #Significantly increased compared with colitis severity in mice receiving unfractionated CD4+ T cells.