CD8+CD122+ Regulatory T Cells (Tregs) and CD4+ Tregs Cooperatively Prevent and Cure CD4+ Cell-Induced Colitis (original) (raw)
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Abbreviations used in this paper: APC, antigen-presenting cell; CFSE, 5(6)-carboxyfluorescein diacetate N-succinimidyl ester; dnTRII, dominant negative transforming growth factor  receptor II; FITC, fluorescein isothiocyanate; IEL, intraepithelial lymphocyte; IFN, interferon; IL, interleukin; LAP, latency-associated peptide; LPL, lamina propria lymphocyte; MHC, major histocompatibility complex; PE, phycoerythrin; TGF, transforming growth factor.
F1000 - Post-publication peer review of the biomedical literature, 2005
Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic selftolerance. Neutralization of circulating IL-2 by anti-IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabetes and produces a wide spectrum of T cell-mediated autoimmune diseases, including gastritis, thyroiditis, sialadenitis, and notably, severe neuropathy. Such treatment selectively reduces the number of Foxp3-expressing CD25 ϩ CD4 ϩ T cells, but not CD25 Ϫ CD4 ϩ T cells, in the thymus and periphery of normal and thymectomized mice. IL-2 neutralization inhibits physiological proliferation of peripheral CD25 ϩ CD4 ϩ T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia-induced homeostatic expansion in a T cell-deficient environment. In normal naive mice, CD25 low CD4 ϩ nonregulatory T cells actively transcribe the IL-2 gene and secrete IL-2 protein in the physiological state. IL-2 is thus indispensable for the peripheral maintenance of natural CD25 ϩ CD4 ϩ regulatory T cells (T reg cells). The principal physiological source of IL-2 for the maintenance of T reg cells appears to be other T cells, especially CD25 low CD4 ϩ activated T cells, which include self-reactive T cells. Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease.
European Journal of Immunology, 2001
IL-12 promotes Th1 cell differentiation and cell-mediated immunity. In the present study, the potential role of IL-12 was analyzed in an experimental colitis model in scid mice reconstituted with syngeneic CD45RB high CD4 + T cells. Real-time reverse transcription-PCR studies demonstrated that IL-12 p40 mRNA in inflamed colon is induced shortly after T cell transfer and maintained at a stable level after week 4, at the time when wasting disease starts. Administration of anti-IL-12 on days 0, 14, and 28 (early treatment) or on days 28, 42, and 56 (delayed treatment) after T cell transfer, effectively prevented or, respectively cured wasting disease and colitis in scid recipients. Anti-IL-12 treatment abrogated mucosal inflammation with significantly diminished leukocyte infiltration (CD4 cells, macrophages) and CD54 expression, and down-regulated proinflammatory cytokines IFN-+ and IL-2. Of note, although splenic CD4 + T cells are unable to induce disease as a result of the presence of regulatory CD45RB low cells, splenic CD4 + T cells, preactivated by IL-12 and anti-CD3 in vitro, were highly pathogenic in inducing severe mucosal inflammation, suggesting that IL-12 and anti-CD3 abrogated regulatory T cell function. These findings indicate that IL-12 is important for the induction of experimental colitis through effects on proinflammatory cytokine production and on regulatory T cell function.
Immunology, 2004
Regulatory T (Treg) cells, derived from co-cultures of unfractionated CD4 + T cells and immature dendritic cells (DC), suppress enteroantigen-induced proliferation of CD4 + CD25 ) T cells. The DC-induced Treg cells are a mixture of CD25 + (10-20%) and CD25 ) (80-90%) T cells. However, all the suppressor activity in vitro and in vivo resides in the CD25 + T-cell subset. The CD25 + DC-induced Treg cells can inhibit enteroantigen-induced proliferation in vitro through a transwell membrane, and their function does not appear to depend on previous activation. DC-induced CD25 + Treg cells display a naı¨ve phenotype, expressing high levels of CD45RB and L-selectin (CD62L). In addition, the DC-induced Treg cells mediate a stronger suppressive activity than prototype CD25 + regulatory T cells. The DC-induced Treg cells, and hereof purified CD25 + and CD25 ) T-cell fractions, were co-injected into severe combined immunodeficiency (SCID) mice with colitis-inducing CD4 + CD25 ) T cells. Both unfractionated CD4 + and purified CD25 + Treg cells fully protected the recipients against the development of colitis. In contrast, co-transfer of fractionated CD25 ) T cells offered no protection against disease development. Enterobacterial antigen-exposed CD4 + T cells of the protected mice secreted higher levels of interleukin-10 and lower levels of interferon-c than the unprotected mice. The present data demonstrate DC-induced CD4 + CD25 + Treg cells, which phenotypically and functionally differ from the generally accepted prototype of CD25 + Treg cells. These data may initiate new procedures for the expansion of Treg cells for clinical use.
T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice
1996
Mice rendered deficient in the production of interleukin 10 (IL-10 -/-) develop a chronic inflammatory bowel disease (IBD) that predominates in the colon and shares histopathological features with human IBD. Our aim was to identify which cell type(s) can mediate colitis in IL-10 -/-mice. We detected an influx ofimmunoglobulin-positive cells into the colon and the presence of colon-reactive antibodies in the serum of IL-10 -/-mice. To assess a pathogenic role for B cells, we generated a B cell-deficient (B -/-) strain oflL-10 -/-mice. B-/-IL-10 -/-mice acquired a severe colitis analogous to that oflL-10 -/-mice, implying that B cells were not the primary mediator of IBD in this model. A series of cell transfer experiments was performed to assess a pathogenic role for T cells. When IL-10 -/-T cell-enriched lamina propria lymphocytes (LPL) or intraepithelial lymphocytes (IEL) were transferred into immunodeficient recombinase-activating gene (RAG)-2 -/-recipients, a mild to severe colitis developed, depending on the cell number transferred. Lymphocytes recovered from the colon of transplanted R.AG-2 -/mice with colitis were predominantly otI~TCR+CD4 +, including a large proportion of CD4 § + cells. These cells were also CD45RB -/l~ and CD44 +, indicative of an activated/memory population. Individual populations of CD4+CD80~ -, CD4+CD8oe + and CD4-CD8ot + T cells were then isolated from the lamina propria compartment of IL-10 -/mice and transferred into RAG-2 -/-recipients. Only IL-10 -/-CD4-expressing LPL, including both the CD4+CD8ot -and CD4+CD8r + populations, induced colitis in recipient mice. Interferon-',/, but little to no IL-4, was produced by CD4+CD8o~ -and CD4+CD8ot § LPL recovered from the inflamed colons of RAG-2 -/-recipients implicating a T helper cell 1 (TH1)-mediated response. We thus conclude that colitis in IL-10 -/-mice is predominantly mediated by THl-type cll3TCtk + T cells expressing CD4 alone, or in combination with the CD8ct molecule.