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CD4⁺ T Cells and Lactobacillus casei Control Relapsing Colitis Mediated by CD8⁺ T Cells¹

Feriel Hacini-Rachinel,^2* Stephane Nancey,^2* Gilles Boschetti,^* Fatima Sardi,^* Remi Doucet-Ladevèze,^* Pierre-Yves Durand,^* Bernard Flourié, and Dominique Kaiserlian^3*

^*INSERM, Unité 851, Institut Fédératif de Recherche-128, Lyon, France; Université de Lyon, Lyon, France; and Hospices Civils de Lyon, Service de Gastroentérologie, Centre Hospitalier Lyon Sud, Lyon, France

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 (Aβ°^/°) mice allowed priming of 2,4-dinitrobenzene sulfonic acid-specific IFN--producing CD8 colitogenic effectors and development of colitis in the otherwise resistant C57BL/6 strain. Cotransfer experiments in RAG2°^/° 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by an institutional grant from INSERM and from grants from Danone Research Center (Palaiseau, France) and the Association François Aupetit. F.H.-R. is the recipient of a Convention Industrielle de Formation par la Recherche thesis grant from Danone.

² F.H.R. and S.N. are equal contributors.

³ Address correspondence and reprint requests to Dr. Dominique Kaiserlian, INSERM Unité 851, Institut Fédératif de Recherche-128 Bioscience Lyon Gerland, 21, Avenue Tony Garnier, 69365 Lyon CX 07, France. E-mail address: dominique.kaiserlian{at}inserm.fr

⁴ Abbreviations used in this paper: IBD, inflammatory bowel disease; nTreg, natural regulatory T cell; DTH, delayed-type hypersensitivity; DNBS, 2,4-dinitrobenzene sulfonic acid; MLN, mesenteric lymph node; SFC, spot-forming cell; LP, lamina propria; Treg, regulatory T cell; Tconv, conventional T cell.