Long-Lived Colitogenic CD4+ Memory T Cells Residing Outside the Intestine Participate in the Perpetuation of Chronic Colitis

• Published in: The Journal of immunology (1950) 2009-10, Vol.183 (8), p.5059-5068
• Main Authors: Nemoto, Yasuhiro, Kanai, Takanori, Kameyama, Kaori, Shinohara, Tamako, Sakamoto, Naoya, Totsuka, Teruji, Okamoto, Ryuichi, Tsuchiya, Kiichiro, Nakamura, Tetsuya, Sudo, Tetsuo, Matsumoto, Satoshi, Watanabe, Mamoru
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antibodies - pharmacology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Germ-Free Life - immunology; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - metabolism; Interleukin-7 - immunology; Interleukin-7 - metabolism; Intestines - immunology; Intestines - metabolism; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; Receptors, Interleukin-7 - antagonists & inhibitors; Receptors, Interleukin-7 - immunology; Receptors, Interleukin-7 - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0803684

To understand the perpetuation of inflammatory bowel disease (IBD), it is important to clarify whether the colitogenic CD4(+) T cells are self-limited effector or long-lived memory T cells. We here investigate the latency of colitogenic CD4(+) T cells in the remission stage of colitis under germfree (GF) conditions. We isolated splenic (SP) CD4(+) T cells from colitic CD4(+)CD45RB(high) T cell-injected SCID mice maintained under specific pathogen-free (SPF) conditions and transferred them into SPF or GF SCID mice. Donor colitic SP CD4(+) T cells have a characteristic CD44(high)CD62L(-)IL-7Ralpha(high) effector-memory T-type phenotype. Six weeks after transfer of cells to GF SCID mice, one group of mice was continued in GF conditions (GF-->GF), and the other was transferred into SPF conditions (GF-->SPF). GF-->SPF but not GF-->GF SCID mice developed colitis with elevated production of Th1 and Th17 cytokines at 4 wk after transfer. Surprisingly, a large number of CD4(+) effector-memory T cells and a small but substantial number of central-memory T cells remained resident in SP and bone marrow, but not in lamina propria, of the GF-->GF SCID recipients. Consistent with this, GF-->SPF but not GF-->GF SCID mice rapidly developed colitis. Taken together, these findings suggest that long-lived colitogenic memory CD4(+) cells can be established even in the presence of commensal Ags, reside outside the intestine in the absence of commensal bacteria, and participate in the perpetuation of colitis. Thus, blocking a stimulus of colitogenic memory CD4(+) cells such as IL-7 may have therapeutic benefit for treatment of inflammatory bowel disease.