IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4(+) memory T cells in chronic colitis.
We previously demonstrated that IL-7 is essential for the persistence of T-cell-mediated colitis, by showing that adoptive transfer of CD4(+)CD45RB(high) T cells into IL-7(-/-) x RAG-1(-/-) mice did not induce colitis; and that intestinal IL-7 is not essential for this colitis model, by showing that IL-7(-/-) x RAG-1(-/-) mice parabiosed with colitic CD4(+)CD45RB(high) T-cell-transferred RAG-1(-/-) mice developed colitis. Here, we investigated the role of IL-7 in the maintenance of colitogenic CD4(+) T cells by surgically separating these parabionts. Surprisingly, the separated IL-7(-/-) x RAG-1(-/-) mice were consistently diseased after separation, although no IL-7 mRNA was detected in the tissues of separated IL-7(-/-) x RAG-1(-/-) partners. CD4(+) T cells isolated from the separated RAG-1(-/-) or IL-7(-/-) x RAG-1(-/-) mice were then transferred into new RAG-1(-/-) or IL-7(-/-) x RAG-1(-/-) mice. Regardless of the source of donor cells, RAG-1(-/-) recipients developed colitis, whereas IL-7(-/-) x RAG-1(-/-) recipients did not. Collectively, these results demonstrate that IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4(+) T cells rather than the maintenance of those cells in established colitic mice. They also provide a basis for the timing of IL-7/IL-7R blockade for the treatment of inflammatory bowel diseases.
Tomita
Takayuki
T
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Kanai
Takanori
T
Totsuka
Teruji
T
Nemoto
Yasuhiro
Y
Okamoto
Ryuichi
R
Tsuchiya
Kiichiro
K
Sakamoto
Naoya
N
Ohteki
Toshiaki
T
Hibi
Toshifumi
T
Watanabe
Mamoru
M
D019264:Adoptive Transfer; D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002452:Cell Count; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics; D015851:Interleukin-7 / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D008231:Lymphopenia / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology; D010227:Parabiosis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D019409:Interleukin-15; D015851:Interleukin-7; C499308:Rag2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein; D007371:Interferon-gamma