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Effect of intestinal microbiota on the induction of regulatory CD25+ CD4+ T cells

When oral tolerance was induced in either specific pathogen‐free (SPF) or germ‐free (GF) mice, ovalbumin (OVA) feeding before immunization induced oral tolerance successfully in SPF mice. On the other hand, OVA‐specific immunoglobulin G1 (IgG1) and IgE titres in OVA‐fed GF mice were comparable to those in phosphate‐buffered saline‐fed GF mice, thus demonstrating that oral tolerance could not be induced in GF mice. The frequencies of CD25+ CD4+/CD4+ cells in the mesenteric lymph node (MLN) and the absolute number of CD25+ CD4+ cells in the Peyer's patches and MLN of naive GF mice were significantly lower than those in naive SPF mice. In an in vitro assay, the CD25+ CD4+ cells from the naive SPF mice suppressed more effectively the proliferation of responder cells in a dose‐dependent manner than those from the GF mice. In addition, the CD25+ CD4+ regulatory T (Treg) cells from the naive SPF mice produced higher amounts of interleukin (IL)‐10 and transforming growth factor (TGF)‐β than those from the GF mice. When anti‐TGF‐β neutralizing antibody, but not anti‐IL‐10 neutralizing antibody, was added to the in vitro proliferation assay, the suppressive effect of the CD25+ CD4+ Treg cells from the SPF mice was attenuated to the same level as that of the CD25+ CD4+ cells from the GF mice. In conclusion, the TGF‐β‐producing CD25+ CD4+ Treg cells from the MLN of SPF mice played a major role in oral tolerance induction. In addition, as the regulatory function of the CD25+ CD4+ cells from the naive GF mice was much lower than that of the CD25+ CD4+ Treg cells from the SPF mice, indigenous microbiota are thus considered to contribute to the induction and maintenance of CD25+ CD4+ Treg cells.