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

Abstract

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-γ-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.