FTY720 suppresses CD4(+)CD44(high)CD62L(-) effector memory T cell-mediated colitis

Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.74). 09/2006; 291(2):G267-74. DOI: 10.1152/ajpgi.00496.2005
Source: PubMed

ABSTRACT FTY720, a sphingosine-derived immunomodulator, causes immunosuppression via enhancement of lymphocyte sequestration into secondary lymphoid organs, thereby preventing their antigen-activated T cell egress to sites of inflammation. FTY720 is highly effective in inhibiting autoimmunity in various animal models. However, there is little known about how FTY720 controls the migration property of memory T cells. Here, we demonstrated that FTY720 prevents the development of colitis induced by the adoptive transfer of lamina propria (LP) colitogenic effector memory CD4+ T cells (TEM cells; CD45RB(low)CD44(high)CD62L-) into severe combined immunodeficiency (SCID) mice and suppresses interferon-gamma, interleukin-2, and tumor necrosis factor-alpha production by LP CD4+ T cells. The numbers of spleen, peripheral blood, mesenteric lymph node, and LP CD4+ T cells in FTY720-treated mice were significantly reduced compared with those in control mice. Notably, LP CD4+ TEM cells as well as splenic CD4+CD45RBhigh T cells expressed several spingosine-1-phosphate receptors that are targets for FTY720. Furthermore, FTY720 also prevented the development of colitis induced by the adoptive transfer of splenic CD4+CD45RBhigh T cells into SCID mice. Collectively, the present data indicate that FTY720 treatment may offer the potential not only to prevent the onset of disease but also to treat memory T cell-mediated autoimmune diseases including inflammatory bowel diseases.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Necrotizing enterocolitis (NEC) is an inflammatory disease with evidence of increased production of proinflammatory cytokines in the intestinal mucosa. Lactobacillus reuteri DSM17938 (LR17938) has been shown to have anti-inflammatory activities in an experimental model of NEC. Activated effector lymphocyte recruitment to sites of inflammation requires the sequential engagement of adhesion molecules such as CD44. The phenotype of CD44(+)CD45RB(lo) separates T effector/memory (Tem) cells from naïve cells (CD44(-)CD45RB(hi)). It is unknown whether these Tem cells participate in the inflammation associated with NEC and can be altered by LR17938. NEC was induced in 8-10-day old C57BL/6J mice by gavage feeding with formula and exposure to hypoxia and cold stress for 4 days. Survival curves and histological scores were analyzed. Lymphocytes isolated from mesenteric lymph nodes (MLNs) and ileum were labeled for CD4, CD44, CD45RB, intracellular Foxp3, and Helios and were subsequently analyzed by flow cytometry. LR17938 decreased the mortality, and incidence and severity of NEC. The percentage of Tem cells in the ileum and MLNs was increased in NEC but was decreased by LR17938. Conversely, the CD4(+)Foxp3(+) regulatory T cells (Tregs) in the intestine decreased during NEC and were restored to normal by LR17938. The majority of the Tregs preserved by LR17938 were Helios(+) subsets, possibly of thymic origin. In conclusion, LR17938 may represent a useful treatment to prevent NEC. The mechanism of protection by LR17938 involves modulation of the balance between Tem and Treg cells. These T cell subsets might be potential biomarkers and therapeutic targets during intestinal inflammation.
    AJP Gastrointestinal and Liver Physiology 05/2014; 307(2). DOI:10.1152/ajpgi.00038.2014 · 3.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The gut is equipped with a unique immune system for maintaining immunological homeostasis, and its functional immune disruption can result in the development of immune diseases such as food allergy and intestinal inflammation. Accumulating evidence has demonstrated that nutritional components play an important role in the regulation of gut immune responses and also in the development of intestinal immune diseases. In this review, we focus on the immunological functions of lipids, vitamins, and nucleotides in the regulation of the intestinal immune system and as potential targets for the control of intestinal immune diseases.
    Journal of Gastroenterology and Hepatology 12/2013; 28(S4). DOI:10.1111/jgh.12259 · 3.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The UBASH3/STS/TULA family consists of two members sharing substantial homology and a similar multi-domain architecture, which includes a C-terminal histidine phosphatase domain capable of dephosphorylating phosphotyrosine-containing substrates. TULA-family proteins act as downregulators of receptor-induced activation in several cell types, including T cells and platelets. Deletion of both family members in mice has been shown to result in hyperresponsiveness of T cells to T-cell receptor (TCR)/CD3 complex engagement, but little is known about the biological consequences of double knockout (dKO) and especially of either single KO (sKO). We elucidated the biological consequences of the lack of TULA-family proteins in dKO and TULA and TULA-2 sKO animals. In order to do so, we examined immune responses in Trinitrobenzene sulfonic acid (TNBS)-induced colitis, a mouse model of human inflammatory bowel disease, which is characterized by the involvement of multiple cell types, of which T cells have a crucial role, in the development of a pathological inflammatory condition. Our data indicate that TNBS treatment upregulates T-cell responses in all KO mice studied to a significantly higher degree than in wild-type mice. Although the lack of either TULA-family member exacerbates inflammation and T-cell responses in a specific fashion, the lack of both TULA and TULA-2 in dKO exerts a higher effect than the lack of a single family member in TULA and TULA-2 sKO. Analysis of T-cell responses and TCR-mediated signaling argues that the proteins investigated affect T-cell signaling by regulating phosphorylation of Zap-70, a key protein tyrosine kinase.Immunology and Cell Biology advance online publication, 22 July 2014; doi:10.1038/icb.2014.60.
    Immunology and Cell Biology 07/2014; DOI:10.1038/icb.2014.60 · 4.21 Impact Factor