Th1/Th17-Mediated Interstitial Pneumonia in Chronic Colitis Mice Independent of Intestinal Microbiota

Although intestinal microbiota are essential for the development of T cell-mediated colitis, it remains undetermined whether they enhance or suppress the chronic extraintestinal inflammation that often complicates inflammatory bowel diseases. In this study, we investigate the role of intestinal microbiota in the development of colitis and extraintestinal manifestations in a mouse model in which colitis was induced in SCID mice by adoptive transfer of CD4(+)CD45RB(high) T cells. Under specific pathogen-free conditions, these mice developed both colitis and extraintestinal interstitial pneumonia, whereas mice given a mixture of antibiotics did not develop colitis, but, surprisingly, developed Th1/Th17-mediated IP. Irrespective of antibiotic treatment, cotransfer of CD4(+)CD25(+) regulatory T cells suppressed the development of pneumonitis and colitis, with all local CD4(+)CD45RB(high) T cell-derived cells converted to CD44(high)CD62L(-)IL-7Rα(high) effector-memory T cells. Retransfer of CD4(+) effector-memory T cells from the lungs of antibiotic-treated mice with IP not only induced IP in both antibiotic-treated and -untreated recipients but also induced colitis in the untreated recipients. In summary, we have established a unique model of Th1/Th17-mediated IP in microbiota-free and antibiotic-treated mice. This model may be valuable in investigating the immunological mechanisms underlying extraintestinal disorders in patients with inflammatory bowel disease.