The development of colitogenic CD4(+) T cells is regulated by IL-7 in collaboration with NK cell function in a murine model of colitis.

We previously reported that IL-7(-/-)RAG(-/-) mice receiving naive T cells failed to induce colitis. Such abrogation of colitis may be associated with not only incomplete T cell maintenance due to the lack of IL-7, but also with the induction of colitogenic CD4(+) T cell apoptosis at an early stage of colitis development. Moreover, NK cells may be associated with the suppression of pathogenic T cells in vivo, and they may induce apoptosis of CD4(+) T cells.

Upregulated IL-7 receptor α expression on colitogenic memory CD4+ T cells may participate in the development and persistence of chronic colitis.

We have previously demonstrated that IL-7 is essential for the persistence of colitis as a survival factor of colitogenic IL-7Rα-expressing memory CD4(+) T cells. Because IL-7Rα is broadly expressed on various immune cells, it is possible that the persistence of colitogenic CD4(+) T cells is affected by other IL-7Rα-expressing non-T cells. To test this hypothesis, we conducted two adoptive transfer colitis experiments using IL-7Rα(-/-) CD4(+)CD25(-) donor cells and IL-7Rα(-/-) × RAG-2(-/-) recipient mice, respectively.

IL-2 is positively involved in the development of colitogenic CD4+ IL-7R alpha high memory T cells in chronic colitis.

IL-2 and IL-7 share a common gamma-chain receptor and are critical for T-cell homeostasis. We aimed to clarify the reciprocal roles of IL-2 and IL-7 in the development and persistence of chronic colitis. We performed a series of adoptive transfers of IL-2(-/-) CD4(+)CD45RB(high) T cells into RAG-2(-/-) mice and assessed the role of IL-2 in the induction of IL-7R alpha on colitogenic CD4(+) T cells and the development of chronic colitis.

Prevalence of metabolic syndrome is comparable between inflammatory bowel disease patients and the general population.

Background: Metabolic syndrome (MS) is associated with an increased risk of cardiovascular disease. However, its prevalence in inflammatory bowel disease (IBD) patients remains largely unknown. This study was planned to determine the prevalence of MS in Japanese IBD patients.

Long-lived colitogenic CD4+ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis.

To understand the perpetuation of inflammatory bowel disease (IBD), it is important to clarify whether the colitogenic CD4(+) T cells are self-limited effector or long-lived memory T cells. We here investigate the latency of colitogenic CD4(+) T cells in the remission stage of colitis under germfree (GF) conditions. We isolated splenic (SP) CD4(+) T cells from colitic CD4(+)CD45RB(high) T cell-injected SCID mice maintained under specific pathogen-free (SPF) conditions and transferred them into SPF or GF SCID mice.

IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4(+) memory T cells in chronic colitis.

We previously demonstrated that IL-7 is essential for the persistence of T-cell-mediated colitis, by showing that adoptive transfer of CD4(+)CD45RB(high) T cells into IL-7(-/-) x RAG-1(-/-) mice did not induce colitis; and that intestinal IL-7 is not essential for this colitis model, by showing that IL-7(-/-) x RAG-1(-/-) mice parabiosed with colitic CD4(+)CD45RB(high) T-cell-transferred RAG-1(-/-) mice developed colitis. Here, we investigated the role of IL-7 in the maintenance of colitogenic CD4(+) T cells by surgically separating these parabionts. Surprisingly, the separated IL-7(-/-) x RAG-1(-/-) mice were consistently diseased after separation, although no IL-7 mRNA was detected in the tissues of separated IL-7(-/-) x RAG-1(-/-) partners.

Homeostatic (IL-7) and effector (IL-17) cytokines as distinct but complementary target for an optimal therapeutic strategy in inflammatory bowel disease.

Purpose Of Review: This review focuses on CD4+ T cells involved in the mediation of inflammatory tissue damage in murine models of inflammatory bowel diseases (IBDs). In particular, we describe the distinct roles of the homeostatic cytokine IL-7, which is essential to the maintenance of colitogenic memory CD4+ cells, and the newly discovered effector cytokine IL-17. We also discuss the close correlation between colitogenic Th17-type CD4+ T cells and inducible CD4+CD25+Foxp3+ regulatory T cells.

RANK-RANKL signaling pathway is critically involved in the function of CD4+CD25+ regulatory T cells in chronic colitis.

It is now clear that functional CD4(+)CD25(+) regulatory T (T(R)) cells exist as part of the normal immune population and prevent the development of intestinal inflammation. We have recently shown that CD4(+)CD25(+) T(R) cells reside in the intestine and control intestinal homeostasis in humans and mice. In this study, we demonstrate that the TNF family molecule RANKL and its receptor RANK are critically involved in controlling the function of CD4(+)CD25(+) T(R) cells in the intestine.

Signaling pathway via TNF-alpha/NF-kappaB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis.

Treatment with anti-TNF-alpha MAb has been accepted as a successful maintenance therapy for patients with inflammatory bowel diseases (IBD). Moreover, it has been recently reported that blockade of TNF receptor (TNFR) 1 signaling in infiltrating hematopoietic cells may prevent the development of colitis-associated cancer (CAC). However, it remains unclear whether the TNF-alpha signaling in epithelial cells is involved in the development of CAC.

Persistent retention of colitogenic CD4+ memory T cells causes inflammatory bowel diseases to become intractable.

Despite the advent of an age when "malignant" leukemia is cured by bone marrow transplantation, "benign" inflammatory bowel diseases (IBDs) are still intractable lifelong diseases. Why is it that once an IBD develops it lasts a long time? We propose that, the same as in the response to vaccination, immune memory T cells that remember the disease are formed in IBDs and, perceiving them as "benign T-cell leukemia"-like lifelong pathology that hematogenously spreads throughout the body, we here propose that the bone marrow itself, which produces large amounts of the survival factor IL-7, is the reservoir for colitogenic CD4(+) memory T cells responsible for the intractability of IBDs.

FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4+ T cells in bone marrow.

2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720) suppresses T-cell egress from LN, thereby preventing pathogenic T cells from migrating toward disease sites. However, little is known about whether FTY720 could control the trafficking of T cells without the presence of lymphoid tissues. Here we demonstrate that FTY720 treatment suppresses the recirculation of CD4(+) T cells in splenectomized (SPX) lymphotoxin-alpha(-/-) (LT-alpha(-/-)) mice that lack LN and spleen, as shown by peripheral blood (PB) lymphopenia in FTY720-treated SPX LT-alpha(-/-) mice.

Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice.

Background: Although the clinical usefulness of leukocytapheresis for patients with inflammatory bowel disease (IBD) has been reported as a selective removal therapy targeting pathogenic immune cells in blood circulation, it remains unclear whether colitogenic CD4(+) T cells continuously recirculate in peripheral blood during the chronic phase of colitis.

Methods: To resolve this question we conducted a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of CD4(+)CD45RB(high) cells into SCID mice in combination with a parabiosis system.

Results: In colitic SCID recipients, first, almost all CD4(+) CD45RB(high) donor cells were converted to CD4(+)CD44(high)CD62L(-) IL-7Ralpha(high) effector-memory T (T(EM)) cells at 8 weeks after transfer and were distributed throughout the whole body, including colonic lamina propria, mesenteric lymph nodes, thoracic duct, peripheral blood, spleen, and bone marrow.

Negative feedback regulation of colitogenic CD4+ T cells by increased granulopoiesis.

Background: Chronic inflammatory diseases are characterized by massive infiltration of innate and acquired immune cells in inflammatory sites. However, it remains unclear how these cells cooperate in the development of disease. Although bone marrow (BM) is a primary site for hematopoiesis of immune cells except T cells, BM recruits memory T cells from the periphery.

Immunosenescent colitogenic CD4(+) T cells convert to regulatory cells and suppress colitis.

Inflammatory bowel diseases progress steadily by the expansion of colitogenic CD4(+) cells. However, it remains unknown whether colitogenic CD4(+) cells are long-living like memory cells or exhausted like effector cells. To assess the longevity of colitogenic lamina propria (LP) CD4(+) cells, we performed sequential transfers of LP CD4(+) cells from colitic CD4(+)CD45RB(high) cell-transferred SCID mice into new SCID mice.

Continuous generation of colitogenic CD4(+) T cells in persistent colitis.

Inflammatory bowel diseases take chronic courses due to the expansion of colitogenic CD4(+) cells. However, it is unclear whether the persistent disease is driven by continuous reactivation of colitogenic memory CD4(+) cells to generate effector CD4(+) cells or by continuous generation of effector CD4(+) cells from naïve cells. To clarify this issue, we performed a series of sequential adoptive transfers of Ly5.

MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4+ T cells in chronic colitis.

TLRs that mediate the recognition of pathogen-associated molecular patterns are widely expressed on/in cells of the innate immune system. However, recent findings demonstrate that certain TLRs are also expressed in conventional TCRalphabeta(+) T cells that are critically involved in the acquired immune system, suggesting that TLR ligands can directly modulate T cell function in addition to various innate immune cells. In this study, we report that in a murine model of chronic colitis induced in RAG-2(-/-) mice by adoptive transfer of CD4(+)CD45RB(high) T cells, both CD4(+)CD45RB(high) donor cells and the expanding colitogenic lamina propria CD4(+)CD44(high) memory cells expresses a wide variety of TLRs along with MyD88, a key adaptor molecule required for signal transduction through TLRs.

Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis.

We previously demonstrated that IL-7 is produced by intestinal goblet cells and is essential for the persistence of colitis. It is well known, however, that goblet cells are decreased or depleted in the chronically inflamed mucosa of animal colitis models or human inflammatory bowel diseases. Thus, in this study, we assess whether intestinal IL-7 is surely required for the persistence of colitis using a RAG-1/2-/- colitis model induced by the adoptive transfer of CD4+CD45RBhigh T cells in combination with parabiosis system.

Intestinal lamina propria retaining CD4+CD25+ regulatory T cells is a suppressive site of intestinal inflammation.

It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only does active suppression by regulatory T (T(REG)) cells play an important role in the normal intestinal homeostasis, but also that its dysregulation of immune response leads to the development of inflammatory bowel disease. In this study, we demonstrate that murine CD4(+)CD25(+) T cells residing in the intestinal lamina propria (LP) constitutively express CTLA-4, glucocorticoid-induced TNFR, and Foxp3 and suppress proliferation of responder CD4(+) T cells in vitro. Furthermore, cotransfer of intestinal LP CD4(+)CD25(+) T cells prevents the development of chronic colitis induced by adoptive transfer of CD4(+)CD45RB(high) T cells into SCID mice.

IL-7 Is essential for the development and the persistence of chronic colitis.

Although IL-7 has recently emerged as a key cytokine involved in controlling the homeostatic turnover and the survival of peripheral resting memory CD4(+) T cells, its potential to be sustained pathogenic CD4(+) T cells in chronic immune diseases, such as inflammatory bowel diseases, still remains unclear. In this study, we demonstrate that IL-7 is essential for the development and the persistence of chronic colitis induced by adoptive transfer of normal CD4(+)CD45RB(high) T cells or colitogenic lamina propria (LP) CD4(+) memory T cells into immunodeficient IL-7(+/+) x RAG-1(-/-) and IL-7(-/-) x RAG-1(-/-) mice. Although IL-7(+/+) x RAG-1(-/-) recipients transferred with CD4(+)CD45RB(high) splenocytes developed massive inflammation of the large intestinal mucosa concurrent with massive expansion of Th1 cells, IL-7(-/-) x RAG-1(-/-) recipients did not.

Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis.

Background & Aims: Although bone marrow (BM) is known as a primary lymphoid organ, it also is known to harbor memory T cells, suggesting that this compartment is a preferential site for migration and/or selective retention of memory T cells. We here report the existence and the potential ability to induce colitis of the colitogenic BM CD4+ memory T cells in murine colitis models.

Methods: We isolated BM CD4+ T cells obtained from colitic severe combined immunodeficient mice induced by the adoptive transfer of CD4+ CD45RB(high) T cells and colitic interleukin (IL)-10(-/-) mice that develop colitis spontaneously, and analyzed the surface phenotype, cytokine production, and potential activity to induce colitis.

Extracorporeal elimination of TNF-alpha-producing CD14(dull)CD16(+) monocytes in leukocytapheresis therapy for ulcerative colitis.

Background: In recent years leukocytapheresis using a leukocyte removal filter (known as lymphocytapheresis, LCAP) has been applied to the treatment of various autoimmune diseases including ulcerative colitis (UC). In the present study we aimed to clarify how LCAP therapy modifies inflammatory responses by modulating circulating TNF-alpha-producing monocytes.

Methods: Mononuclear cells were obtained from blood before and after the first treatment, and the expression profiles of various immune cells (naive versus.

Ameliorating effect of saporin-conjugated anti-CD11b monoclonal antibody in a murine T-cell-mediated chronic colitis.

Background: Crohn's disease (CD) is an inflammatory bowel disease that is associated with several changes in the immune system, including an increased number of infiltrating macrophages. These macrophages release a variety of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) which are critically involved in the onset and the development of CD. The present study was performed to explore the initial involvement of macrophages in the development of T-cell-mediated chronic colitis.

TH1/TH2-mediated colitis induced by adoptive transfer of CD4+CD45RBhigh T lymphocytes into nude mice.

Background: Transfer of CD4CD45RB T cells from normal donors to SCID/Rag-1, 2-deficient mice, which lack T and B cells, leads to the development of a TH1-mediated inflammatory bowel disease (IBD)-like syndrome characterized by extensive mononuclear cell infiltrates and epithelial cell hyperplasia. Because it is well known that B cells are also involved in a multitude of mechanistic pathways in human IBD, this study attempts to establish a new model of colitis in nude mice.

Methods: We transferred CD4CD45RB T cells into athymic nude mice, which lack thymus-dependent T cells but retain normal B cells, to establish and investigate a B cell-involving chronic colitis model.

Regulation of murine chronic colitis by CD4+CD25- programmed death-1+ T cells.

Naturally arising CD4(+)CD25(+) regulatory T (T(R)) cells are engaged in the maintenance of self tolerance and prevention of autoimmune diseases. However, accumulating evidence suggests that a fraction of peripheral CD4(+)CD25(-) T cells also possesses regulatory activity. Programmed death-1 (PD-1) is a new member of the CD28/CTLA-4 family, which has been implicated in the maintenance of peripheral self tolerance.

MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis.

Background: Gut commensal microbes affect the development and activation of the mucosal and systemic immune systems. However, the exact molecular mechanism of these microbes that is involved in the development of colitis remains unclear.

Methods: The present study was conducted to determine the distinct role of the innate immune system in the development of a dextran sulfate sodium (DSS) colitis model in MyD88(-/-) mice, because myeloid differentiation protein (MyD88) is a major adaptor molecule essential for signaling via Toll-like receptors (TLRs).