CD4+ T cells and Lactobacillus casei control relapsing colitis mediated by CD8+ T cells.

Evidence that CD4(+) regulatory T cells can control Ag-specific CD8(+) T cell-mediated colitis in immunocompetent mice is poorly documented. To examine the potential of CD4(+) T cells to control colitis, we used our model of CD8(+) T cell-mediated colitis induced by intracolonic sensitization followed by challenge with the hapten 2,4-dinitrobenzene sulfonic acid. The defect of CD4(+) T cells in MHC class II-deficient (Abeta(degrees/degrees)) mice allowed priming of 2,4-dinitrobenzene sulfonic acid-specific IFN-gamma-producing CD8 colitogenic effectors and development of colitis in the otherwise resistant C57BL/6 strain. Cotransfer experiments in RAG2(degrees/degrees) mice and ex vivo studies showed that CD4(+)CD25(+) T cells completely prevented CD8(+) T cell-mediated colitis and controlled CD8(+) T cell activation, respectively. In the susceptible BALB/c strain, Ab depletion revealed that lack of CD4(+) regulatory T cells resulted in 1) acute colitis elicited by a suboptimal dose of hapten challenge and 2) more severe relapsing episodes of colitis induced by effector/memory CD8(+) T cell-mediated colitis at an optimal dose of hapten challenge, even when CD4 depletion was performed just before the second challenge. Oral administration of the probiotic strain Lactobacillus casei DN-114 001 alleviated colitis and increased the suppressive function of Foxp3(+)CD4(+) regulatory T cells of colon lamina propria. These data demonstrate that CD4(+) regulatory T cells exert a protective effect on colitis by controlling colitogenic effector/memory CD8(+) T cells during the effector (symptomatic) phase of acute and relapsing colitis, respectively. Probiotics with natural adjuvant effects on mucosal regulatory T cells may represent a valuable approach to alleviate the colitogenic effect of Tc1-type CD8(+) effectors.

Therapy with anti-TNFα antibody enhances number and function of Foxp3(+) regulatory T cells in inflammatory bowel diseases.

BACKGROUND: Inflammatory bowel diseases (IBDs) are associated with up-regulation of TNFα, hyperactivation of proinflammatory effector T cells (Teffs) and inefficient control by regulatory CD4(+) CD25(+) Foxp3(+) T cells (Tregs). The aim of this prospective study was to investigate the short-term impact of treatment of IBD patients with anti-TNFα antibodies (infliximab or adalimumab) on the frequency, phenotype, and suppressive function of Tregs. METHODS: Active IBD patients including 16 with Crohn's disease and 9 with ulcerative colitis were treated with anti-TNFα mAb. PBMCs were harvested immediately before and 2 weeks after the first injection. The frequency and phenotype of circulating CD4(+) CD25(+) Foxp3(+) Tregs were analyzed by flow cytometry, and their suppressive function was assessed by the ability of purified CD4(+) CD25(+) CD127(-) Tregs to inhibit the proliferation of allogenic CD4(+) CD25(-) Teffs. RESULTS: CD4(+) CD25(+) Foxp3(+) Treg frequency was significantly lower in active IBD patients than in controls (2.8% ± 0.4% vs. 4.6% ± 0.6%, respectively; P = 0.01). On day 14 following the first anti-TNFα infusion, the frequency of circulating Tregs was significantly enhanced in IBD patients (4.0% ± 0.5% vs. 2.8% ± 0.4%, before treatment; P = 0.001), with a 2- to 3-fold increase in the intensity of Foxp3 expression. In addition, infliximab treatment enhanced the suppressive function of circulating Tregs, as shown by inhibition of Teff proliferation at a 1:8 Treg/Teff ratio (28% ± 5% vs. 66% ± 10%, after treatment; P = 0.04). CONCLUSIONS: These data demonstrate that anti-TNFα treatment of active IBD rapidly enhances the frequency of functional Foxp3(+) Tregs in blood and potentiates their suppressive function. This indicates that Treg potentiation may represent an unanticipated outcome of anti-TNFα biotherapy in IBD.

Blockade of LTB(4) /BLT(1) pathway improves CD8(+) T-cell-mediated colitis.

BACKGROUND: Leukotriene B4 (LTB(4) ) has chemotactic properties for activated T cells expressing the high-affinity receptor BLT(1) . This study investigated whether the LTB(4) antagonist (CP-105,693), selective for BLT(1) receptor, could protect mice from colitis mediated by specific cytotoxic CD8(+) T lymphocytes (CTL). METHODS: Virus-specific colitis was induced in C57Bl/6 mice transferred with lymphoid cells from P14 TcR Tg mice which are specific to class I GP33 peptide of LCMV. Mice were immunized with GP33-pulsed dendritic cells and colitis was elicited by intrarectal administration of the peptide. Colitis was evaluated by body weight loss and macroscopic and histological analysis of colon. In vivo priming of specific CD8(+) CTL was determined using interferon (IFN)-γ ELISPOT and in vivo CTL assays. In some experiments mice were treated with a selective LTB(4) receptor antagonist. RESULTS: Immunization with GP33-pulsed dendritic cells (DCs) induced priming of specific CD8(+) CTL, as shown by the presence of IFN-γ-producing CD8(+) T cells in colon draining lymph nodes and in vivo CTL assays. Intrarectal challenge with GP33 induced severe colitis and recruitment of granzyme B(+) P14 CD8(+) cells in colon. Treatment with the specific LTB(4) receptor antagonist before elicitation of colitis reduced the severity of colitis and decreased the frequency of specific effectors. CONCLUSIONS: Colitis can be induced by IFN-γ-producing cytotoxic CD8(+) CTL specific for viral antigen. Blockade of the LTB(4) /BLT(1) pathway by a selective BLT(1) receptor antagonist attenuates colitis by inhibiting CD8(+) effectors recruitment in colon. These data illustrate the therapeutic potential of LTB(4) receptor selective antagonists in protection from CD8(+) T-cell-mediated intestinal inflammation.