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PubMed2005

A controlled study of colonic immune activity and beta7+ blood T lymphocytes in patients with irritable bowel syndrome.

BACKGROUND & AIMS: The mechanisms behind irritable bowel syndrome (IBS) are incompletely understood. Recently several studies have suggested a low-grade colonic inflammation as initiator of the gut dysfunctions recorded in this patient group. The aim of this study was to characterize the phenotype and homing properties of colonic and peripheral blood lymphocytes in patients with IBS. METHODS: Patients with IBS (n=33), defined by the Rome II criteria, were compared with UC patients (n=23) and control subjects (n=15) without gastrointestinal symptoms. Colonic and peripheral blood lymphocytes were analyzed by flow cytometry. Secretion of IFN-gamma from intestinal biopsies was determined by enzyme-linked immunosorbent assay, and immunohistochemical staining of colonic biopsies was performed. RESULTS: IBS patients displayed an increased frequency of peripheral blood CD4+ and CD8+ T cells expressing the gut homing integrin beta7. Accordingly, IBS and UC patients had an augmented frequency of lamina propria CD8+ T cells in the ascending colon as compared with control subjects. The frequency of intestinal T cells expressing integrin beta7+ was unaltered in IBS and UC patients, although the expression of mucosal addressin cell adhesion molecule-1+ endothelium, the ligand for integrin beta7, was increased in the ascending colon of IBS and UC patients as compared with control subjects. CONCLUSIONS: Patients with IBS exhibit an enhanced immune activity in the gut and an increased frequency of integrin beta7+ T lymphocytes in the peripheral blood. Our data further support the hypothesis of IBS being at least partially an inflammatory disorder.

Adult↗

PubMed2000

Heritable susceptibility for colitis in mice induced by IL-10 deficiency.

Severity of inflammatory bowel disease in IL-10 gene-targeted mice is in part determined by genetic background. In the current study, a targeted IL-10 gene was transferred into the C3H/HeJBir substrain, known to exhibit high T-cell and B-cell responses to enteric flora, and to be highly sensitive to colitigenic stress. IL-10-deficient C3H/HeJBir mice developed early onset colitis in contrast to IL-10-deficient C57BL/6J congenic mice. Histopathologic analysis of disease in C3H/HeJBir.Il10-/- and C57BL/6J.Il10-/- mice showed significant differences at all ages studied. Hybrids of these congenic strains (F1.Il10-/-) were produced to study the mode of inheritance as well as subphenotypes that correlated with histopathology. Lesions in F1 mice were intermediate between parental strains. C3H-contributed subphenotypes that correlated best with histopathology were peripheral blood granulocyte percentage, serum amyloid A concentration, spleen weight/body weight ratio, and mesenteric lymph node weight/ body weight ratio. Neither enhanced humoral immunity (secretory IgA, anti-Escherichia coli cellular membrane Ig) characteristic of C3H/HeJBir, nor T-cell percentages in peripheral blood correlated as well. This study represents a necessary step in elucidating murine genetic modifiers controlling colitis sensitivity.

Animals↗

PubMed2000

Analysis of cytokine production in the colon of nude mice with experimental colitis induced by adoptive transfer of immunocompetent cells from mice infected with a murine retrovirus.

LP-BM5 murine leukemia virus (MuLV) is known to induce murine AIDS (MAIDS). We have shown that Sjögren's syndrome (SjS)-like exocrinopathy can be induced in mice with MAIDS and that adoptive transfer of spleen cells from MAIDS mice can induce inflammatory bowel disease-like colitis as well as SjS-like exocrinopathy in nude mice. To assess the role of interferon (IFN)-gamma and interleukin (IL)-10 in the pathogenesis of our experimental model, we tried to identify the cells producing these cytokines and their localization in the colitis lesions in situ. Expression of mRNA for IFN-gamma and IL-10 was assessed by RT-PCR, and protein expression of these cytokines was also analyzed in frozen sections of colon by double-color-staining immunofluorescence (IF). An increase of IFN-gamma and IL-10 mRNA was detected in the colon of mice with colitis, but not in that of control mice. Double-color IF showed that Mac-1(+) cells were positive for IFN-gamma or IL-10 and that most CD4(+) T cells were positive for IL-10, although the population of IFN-gamma-positive CD4(+) T cells was low. In our experimental colitis model, Mac-1(+) macrophages that produce both IFN-gamma and IL-10 might play a crucial role in the pathogenesis of colitis in combination with CD4(+) T cells.

Adoptive Transfer↗

PubMed2001

Antibody response to dietary and autoantigens in G alpha i2-deficient mice.

BACKGROUND: Mice with a targeted mutation in the G protein subunit G alpha i2 gene develop a colonic mucosal inflammation, with a highly activated B-cell response. We wanted to investigate whether this increased B-cell activity was directed against dietary antigens and/or various self tissues. METHODS: The level of antibodies specific for dietary (gliadin, soya and fish meal) antigens was measured by ELISA. Reactivity against self antigens was measured by immunohistochemistry on cryo-sectioned mouse and rat tissue. Sera and intestinal lavages were analysed from G alpha i2-/- mice before and after development of colitis and in age-matched wild type litter mates. RESULTS: Titres of antibodies against dietary antigens were significantly enhanced both in serum and in large intestinal lavages from G alpha i2-/- mice with ongoing colitis but not prior to disease, as compared to wild type mice. The autoreactivity to self tissues was significantly increased in G alpha i2-/- mice both before and after development of colitis as compared to litter mate control animals. Self tissue reactivity was directed not only against epithelial cells of the colon, small intestine and gastric glands, but also against smooth muscle cells, hepatocytes, bile duct cells, renal tubule and collecting tubule cells of the kidney. In analogy to human ulcerative colitis, autoantibodies against epithelial cells, bile duct epithelium and neutrophil granulocytes were found. CONCLUSIONS: Earlier increase in levels of autoantibodies (before onset of colitis) than of food antibodies (after onset of colitis) suggests the latter response to be a secondary phenomenon to e.g. a destroyed barrier function.

Animals↗

PubMed2003

CD8 alpha beta T cells are not essential to the pathogenesis of arthritis or colitis in HLA-B27 transgenic rats.

The class I MHC allele HLA-B27 is highly associated with the human spondyloarthropathies, but the basis for this association remains poorly understood. Transgenic rats with high expression of HLA-B27 develop a multisystem inflammatory disease that includes arthritis and colitis. To investigate whether CD8alphabeta T cells are needed in this disease, we depleted these cells in B27 transgenic rats before the onset of disease by adult thymectomy plus short-term anti-CD8alpha mAb treatment. This treatment induced profound, sustained depletion of CD8alphabeta T cells, but failed to suppress either colitis or arthritis. To address the role of CD8alpha(+)beta(-) cells, we studied four additional groups of B27 transgenic rats treated with: 1) continuous anti-CD8alpha mAb, 2) continuous isotype-matched control mAb, 3) the thymectomy/pulse anti-CD8alpha regimen, or 4) no treatment. Arthritis occurred in approximately 40% of each group, but was most significantly reduced in severity in the anti-CD8alpha-treated group. In addition to CD8alphabeta T cells, two sizeable CD8alpha(+)beta(-) non-T cell populations were also reduced by the anti-CD8alpha treatment: 1) NK cells, and 2) a CD4(+)CD8(+)CD11b/c(+)CD161a(+)CD172a(+) monocyte population that became expanded in diseased B27 transgenic rats. These data indicate that HLA-B27-retricted CD8(+) T cells are unlikely to serve as effector cells in the transgenic rat model of HLA-B27-associated disease, in opposition to a commonly invoked hypothesis concerning the role of B27 in the spondyloarthropathies. The data also suggest that one or more populations of CD8alpha(+)beta(-) non-T cells may play a role in the arthritis that occurs in these rats.

Animals↗

PubMed2006

Colitogenic and non-colitogenic commensal bacteria differentially trigger DC maturation and Th cell polarization: an important role for IL-6.

We investigated whether commensal bacteria modulate activation and maturation of bone marrow-derived DC and their ability to prime CD4(+) T cells. We used Escherichia coli mpk, which induces colitis in gnotobiotic IL-2-deficient (IL-2(-/-)) mice, and Bacteroides vulgatus mpk, which prevents E. coli-induced colitis. Stimulation of DC with E. coli induced TNF-alpha, IL-12 and IL-6 secretion and expression of activation markers. Moreover, stimulation of DC with E. coli increased T cell activation and led to Th1 polarization. Stimulation with B. vulgatus led only to secretion of IL-6, and DC were driven into a semi-mature state with low expression of activation markers and did not promote Th1 responses. B. vulgatus-induced semi-mature DC were non-responsive to stimulation by E. coli in terms of maturation, T cell priming and TNF-alpha but not IL-6 production. The non-responsiveness of B. vulgatus-stimulated DC was abrogated by addition of anti-IL-6 mAb or mimicked with rIL-6. These data suggest that B. vulgatus-induced IL-6 drives DC into a semi-mature state in which they are non-responsive to proinflammatory activation by E. coli. This in vitro mechanism might contribute to the prevention of E. coli-triggered colitis development by B. vulgatus in vivo; high IL-6 mRNA expression was consistently found in B. vulgatus-colonized or B. vulgatus/E. coli co-colonized IL-2(-/-) mice and was associated with absence of colitis.

Animals↗

PubMed2003

Galectin-1 suppresses experimental colitis in mice.

BACKGROUND & AIMS: Uncontrolled T-cell activation plays a critical role in the pathogenesis of inflammatory bowel diseases. Therefore, pharmacologic strategies directed to restore the normal responsiveness of the immune system by deleting inappropriately activated T cells could be efficacious in the treatment of these pathologic conditions. Galectin-1 is an endogenous lectin expressed in lymphoid organs that plays a role in the maintenance of central and peripheral tolerance. The aim of the present study was to evaluate the therapeutic effects of galectin-1 on T-helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. METHODS: Cells and tissues from mice with TNBS colitis receiving treatment with several doses of human recombinant galectin-1 (hrGAL-1) were analyzed for morphology, cytokine production, and apoptosis. RESULTS: Prophylactic and therapeutic administration of rhGAL-1 resulted in a striking improvement in the clinical and histopathologic aspects of the disease. hrGAL-1 reduced the number of hapten-activated spleen T cells, decreased inflammatory cytokine production, and profoundly reduced the ability of lamina propria T cells to produce IFN gamma in vitro. Moreover, hrGAL-1 led to the appearance of apoptotic mononuclear cells in colon tissue when administered in vivo and induced selective apoptosis of TNBS-activated lamina propria T cells in vitro. CONCLUSION: Collectively, these data show that hrGAL-1 exerts protective and immunomodulatory activity in TNBS-induced colitis and it might be effective in the treatment of inflammatory bowel diseases.

Animals↗

PubMed2002

The interrelated roles of TGF-beta and IL-10 in the regulation of experimental colitis.

In the present study, we define the relation between TGF-beta and IL-10 in the regulation of the Th1-mediated inflammation occurring in trinitrobenzene sulfonic acid (TNBS)-colitis. In initial studies, we showed that the feeding of trinitrophenol-haptenated colonic protein to SJL/J mice induces CD4(+) regulatory T cells that transfer protection from induction of TNBS-colitis, and that such protection correlates with cells producing TGF-beta, not IL-10. Further studies in which SJL/J mice were fed haptenated colonic protein, and then administered either anti-TGF-beta or anti-IL-10 at the time of subsequent TNBS administration per rectum, showed that while both Abs abolished protection, anti-TGF-beta administration prevented TGF-beta secretion, but left IL-10 secretion intact; whereas anti-IL-10 administration prevented both TGF-beta secretion and IL-10 secretion. Thus, it appeared that the protective effect of IL-10 was an indirect consequence of its effect on TGF-beta secretion. To establish this point further, we conducted adoptive transfer studies and showed that anti-IL-10 administration had no effect on induction of TGF-beta producing T cells in donor mice. However, it did inhibit their subsequent expansion in recipient mice, probably by regulating the magnitude of the Th1 T cell response which would otherwise inhibit the TGF-beta response. Therefore, these studies suggest that TGF-beta production is a primary mechanism of counter-regulation of Th1 T cell-mediated mucosal inflammation, and that IL-10 is necessary as a secondary factor that facilitates TGF-beta production.

Adjuvants, Immunologic↗

PubMed1996

Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance.

In previous studies we showed that a chronic colitis associated with a Th1 T cell response can be induced by the rectal administration of the haptenizing reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). We report here that oral administration of haptenized colonic proteins (HCP) before rectal administration of TNBS effectively suppresses the ability of the latter to induce colitis. This suppression (oral tolerance) appears to be due to the generation of mucosal T cells producing TGF-beta and Th2-type cytokines after oral HCP administration. Peyer's patch and lamina propria CD4+ T cells from HCP-fed animals stimulated with anti-CD3/anti-CD28 had a 5-10-fold increase in their production of TGF-beta and secreted increased amounts of IL-4 and IL-10 but lower levels of IFN-gamma in comparison to T cells from ovalbumin-fed control animals. In addition, the colons of HCP-fed mice showed strikingly increased TGF-beta but decreased IL-12 expression by immunohistochemical studies and isolated mononuclear cells from HCP-fed animals secreted less IL-12 heterodimer. Finally, and most importantly, the suppressive effect of orally administered HCP was abrogated by the concomitant systemic administration of anti-TGF-beta or rIL-12 suggesting a reciprocal relationship between IL-12 and TGF-beta on tolerance induction in TNBS-induced colitis. In parallel studies we demonstrated that TNBS-induced colitis can be transferred to naive recipient animals with purified CD4+ T cells from the colon of TNBS-treated animals and that such animals develop lethal pancolitis when exposed to very low doses of TNBS. Feeding of HCP suppressed this sensitivity to TNBS, indicating that oral feeding can suppress the response of pre-committed T cells in vivo. These studies suggest for the first time that TGF-beta production can abrogate experimental granulomatous colitis even after such colitis is established, and thus, that regulation of TGF-beta levels may have relevance to the treatment of human inflammatory bowel disease.

Animals↗

PubMed2004

Bacterial colonization and the development of intestinal defences.

In humans, intestinal defences develop during gestation and, at full term, have the capacity to respond in an appropriate manner to infectious agents and foreign antigens. Before an active protective response can occur, however, the gut must first be exposed to colonizing bacteria. Colonization with diverse intestinal microbes is necessary for the development of important gut defenses such as the synthesis and secretion of polymeric immunoglobulin A and the generation of a balanced T helper (Th) cell response. Insights into normal immune physiological development of the gut have been made by studying the germ-free animal and intestinal defenses. These studies have provided insights into the physiology of immune responses. Two important immunological functions are the secretion of polymeric immunoglobulin A to protect the intestinal surface against harmful stimuli and inhibition of the systemic response to commensal bacteria and food proteins (eg, oral tolerance) to prevent chronic inflammation. Neither function exists in the germ-free state, but rapidly develops after conventionalization (colonization) of the germ-free animal. In the present review, the importance of bacterial colonization on the appearance of normal mucosal immune function and to the clinical consequences of inadequate colonization to the development of disease will be discussed. For example, excessive Th2 activity can lead to atopy, whereas Th1 predominance is found in conditions such as Helicobacter pylori gastritis and Crohn's disease. With the eradication of infectious diseases in developed countries in the past three decades, the incidence of atopic and autoimmune diseases has increased. This epidemiological observation has been explained by the 'hygiene hypothesis', which suggests that a reduction in microbial burden by public health measures has contributed to an immunological imbalance in the intestine. A family of pattern recognition receptors (Toll-like receptors) on gut lymphoid and epithelial cells mediates innate immune responses to bacterial molecular patterns and, thereby, orchestrates acquired immunity. As the role of bacterial communication within the gut (bacterial-epithelial cross-talk) is clarified, physicians should be able to modulate gut immune responses, for example, by the use of probiotics.

Antigens, Bacterial↗

PubMed2006

Protective effect of geranylgeranylacetone on trinitrobenzene sulfonic acid-induced colitis in mice.

Geranylgeranylacetone (GGA) has recently been reported to have a protective effect against ischemic, injurious and apoptotic stress in several tissues. The aim of this study was to determine the effect of GGA on colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. Colitis was induced by intrarectal instillation of TNBS in 50% ethanol in BALB/c mice. Survival, change in body weight and change in wet colon weight were assessed. Histological score in the colon was evaluated 5 days after TNBS treatment. The level of myeloperoxidase (MPO) activity in the colon was also determined. Immunohistochemistry for CD4 in the colon was performed. In addition, the level of heat shock protein (HSP) 70 in the colon was determined by Western blot analysis. Mice were orally treated with GGA (300 mg/kg) 2 h before and every other day after starting TNBS administration. Treatment with GGA markedly improved the survival rate, and reduced the loss of body weight and loss of wet colon weight in mice with TNBS-induced colitis. GGA also suppressed the increase in MPO activity and the number of CD4-positive cells infiltrating the colons of mice with TNBS-induced colitis. Furthermore, treatment with GGA remarkably up-regulated the expression of HSP70 in the colons of mice with TNBS-induced colitis. Our results provide further evidence that GGA has therapeutic potential for intestinal inflammation.

Animals↗

PubMed1976

Anergy to dinitrochlorobenzene and depression of T-lymphocytes in Crohn's disease and ulcerative colitis.

Skin reactivity to dinitrochlorobenzene (DNCB) and levels of circulating T-lymphocytes were measured in 15 patients with ulcerative colitis, 15 patients with Crohn's disease, and 12 normal control subjects. Diminished reactivity to DNCB was demonstrated in 87% of patients with Crohn's disease (P less than 0-001) and in 53% with ulcerative colitis (P less than 0-02), as compared with only 8-5% of controls; anergy was more frequent in Crohn's disease than in ulcerative colitis (P less than 0-05). Levels of circulating T-lymphoctes were also depressed in both Crohn's disease and ulcerative colitis (P less than 0-001) as compared with controls, with the values lower in Crohn's disease than in ulcerative colitis (P less than 0-02). There were no correlations of DNCB response with extent, duration, or severity of disease nor with T-cell levels within any patient group. These data provide further support for the concept that there is impairment of cell-mediated immunity among many patients with chronic inflammatory bowel disease, including both Crohn's disease and ulcerative colitis.

Colitis, Ulcerative↗

PubMed2002

Differential localization of colitogenic Th1 and Th2 cells monospecific to a microflora-associated antigen in mice.

BACKGROUND & AIMS: Clonal expansion of T cells is associated with inflammatory bowel diseases, which indicates antigenic activation of the T cells. We investigated whether the introduction of CD4 T cells specific to a microflora would initiate colitis and assessed the cytokine requirements for colitogenic CD4 T cells. METHODS: Severe combined immunodeficiency disease (SCID) mice were reconstituted with CD4 T cells, which were either deficient in interleukin (IL)-4/interferon (IFN)-gamma production or differentiated in vitro to T-helper (Th) 1/Th 2 and bearing a transgenic T-cell receptor (TCR) specific to ovalbumin (OVA), and then inoculated with an Escherichia coli-producing OVA (ECOVA). Clinical and histologic manifestations of colitis were assessed. RESULTS: Mice with ECOVA colonization and OVA-specific CD4 T cells developed colitis with histologic features of focal infiltration by mononuclear cells, destruction of crypts, and loss of goblet cells. Further, infiltration was initiated in pre-existing lymph follicles. Th1- and IL-4 deficient T cells were diffusely localized in the lamina propria and submucosa, whereas Th2- and IFN-gamma-deficient T cells were localized preferentially in lymph follicles. CONCLUSIONS: A microbe-associated antigen, non-cross-reactive to colonic tissue, can drive antigen-specific CD4 T cells to cause colitis in SCID mice. Although the presence of IFN-gamma and IL-4 in the effector CD4 T cells was not an absolute requirement for the development of colitis, they seemed to regulate it in part by modulating migration of the effector T cells.

Animals↗

PubMed2006

The T cell response to persistent herpes virus infections in common variable immunodeficiency.

We show that at least half of patients with common variable immunodeficiency (CVID) have circulating CD8(+) T cells specific for epitopes derived from cytomegalovirus (CMV) and/or the Epstein-Barr virus (EBV). Compared to healthy age-matched subjects, more CD8(+) T cells in CVID patients were committed to CMV. Despite previous reports of defects in antigen presentation and cellular immunity in CVID, specific CD4(+) and CD8(+) T cells produced interferon (IFN)-gamma after stimulation with CMV peptides, and peripheral blood mononuclear cells secreted perforin in response to these antigens. In CVID patients we found an association between a high percentage of circulating CD8(+) CD57(+) T cells containing perforin, CMV infection and a low CD4/CD8 ratio, suggesting that CMV may have a major role in the T cell abnormalities described previously in this disease. We also show preliminary evidence that CMV contributes to the previously unexplained severe enteropathy that occurs in about 5% of patients.

CD8-Positive T-Lymphocytes↗

PubMed2005

Regulatory T cells in experimental colitis.

Induction and maintenance of peripheral tolerance are important mechanisms to maintain the balance of the immune system. Growing evidence indicates that dysregulation of mucosal T cell responses may lead to loss of tolerance to commensal flora and to the development of inflammatory bowel diseases (IBD). Many studies suggest that active suppression of enteroantigen reactive cells mediated by regulatory T cells contributes to the maintenance of natural intestinal immune homeostasis. The use of the multiple animal models has not only improved our understanding of IBD, but also contributed to new suggestions of treatment strategies involving the use of regulatory T cells. The present review summarizes our current knowledge of regulatory T cells and their involvement in experimental IBD. The well-characterized SCID T cell transfer model and the naturally occurring regulatory CD4+CD25+ T cells are highlighted.

Animals↗

PubMed2002

Immunoregulation in the gut: success and failures in human disease.

In normal conditions, human gut mucosa is infiltrated with a large number of mononuclear cells. This is a reflection of the fact that human intestine is continuously subjected to a massive stimulation by luminal antigens. This state of "physiological" inflammation is a tightly controlled phenomenon, as several mucosal cells interact to generate and maintain an appropriate local immune response. Changes in cell type number and/or function, including the release of soluble mediators, have been associated with the development of chronic inflammatory diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease. Evidence also indicates that the type of inflammatory response occurring in the intestine of patients with CD differs from that in UC, and this probably reflects distinct pathways of immune activation. In CD mucosa, a Th1 response with high IL-12 and IFNgamma production prevails, while in UC a humoral immunity appears to be predominant. Despite this, CD and UC share downstream inflammatory events, characterised by high levels of inflammatory cytokines, free radicals, matrix-degrading enzymes and growth factors.

CD4-Positive T-Lymphocytes↗

PubMed2001

The majority of lamina propria CD4(+) T-cells from scid mice with colitis undergo Fas-mediated apoptosis in vivo.

We have previously shown that adoptively transferred CD4(+) T-cells mediate an chronic colitis in severe combined immune deficient (scid) mice. Colitis is accompanied by activation and apoptosis of Fas ligand and TNF-alpha expressing CD4(+) T-cells in the diseased colonic lamina propria (Eur. J. Immunol. 28:3655 (1998)). Here we investigate the apoptosis-inducing mechanism in these lamina propria infiltrating CD4(+) T-cells. We observe that freshly isolated lamina propria CD4(+) T-cells can kill Fas transfected P815 mastocytoma cells in a TCR/CD3 redirected chromium-release assay, but do not express TNF-alpha mediated cytotoxicity. Pre-incubation of the isolated lamina propria CD4(+) T-cells with an anti-FasL antiserum partially blocked killing of the Fas transfected target cells, indicating a role for the Fas-FasL system in the killing process. Treatment of scid mice with colitis with anti-FasL antiserum for 12 h blocked the apoptotic process in lamina propria CD4(+) T-cells by more than 65% compared to mice treated with control antiserum. Together, these results point towards the Fas-FasL and not the TNF-alpha-TNF-alpha receptor system as the primary apoptosis-inducing mechanism of lamina propria CD4(+) T-cells in this model of murine chronic colitis, and suggest an important role for the Fas-FasL system in the maintenance of homeostasis of locally proliferating T-cells.

Adoptive Transfer↗

PubMed2002

Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora.

We showed previously that cecal bacterial Ag (CBA)-specific CD4(+) T cells induce colitis when transferred into SCID mice. The purpose of this study was to generate and characterize CBA-specific regulatory T cells in C3H/HeJBir (Bir) mice. CD4(+) T cells were stimulated with CBA-pulsed APC in the presence of IL-10 every 10-14 days. After four or more cycles, these T cells produced high levels of IL-10, low levels of IL-4 and IFN-gamma, and no IL-2, consistent with the phenotype of T regulatory-1 (Tr1) cells. Bir Tr1 cells proliferated poorly, but their proliferation was dependent on CD28-B7 interactions and was MHC class II-restricted. Transfer of Bir Tr1 cells into SCID mice did not result in colitis, and cotransfer of Bir Tr1 T cells with pathogenic Bir CD4(+) Th1 cells prevented colitis. Bir Tr1 cells inhibited proliferation and IFN-gamma production of a CBA-specific Th1 cell line in vitro. Such inhibition was partly due to IL-10 and TGFbeta1, but cognate interactions with either APCs or Th1 cells were also involved. Normal intestinal lamina propria CD4(+) T cells had Tr1-like activity when stimulated with CBA-pulsed APCs. We conclude that CD4(+) T cells with the properties of Tr1 cells are present in the intestinal lamina propria and hypothesize that these cells maintain intestinal immune homeostasis to the enteric flora.

Adoptive Transfer↗