Long-lived colitogenic CD4+ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis.
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.
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Yasuhiro
Y
Nemoto
Takanori
T
Kanai
Kaori
K
Kameyama
Tamako
T
Shinohara
Naoya
N
Sakamoto
Teruji
T
Totsuka
Ryuichi
R
Okamoto
Kiichiro
K
Tsuchiya
Tetsuya
T
Nakamura
Tetsuo
T
Sudo
Satoshi
S
Matsumoto
Mamoru
M
Watanabe
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005856:Germ-Free Life / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; D004268:DNA-Binding Proteins; D015851:Interleukin-7; C499308:Rag2 protein, mouse; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain