Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis.
OBJECTIVE
Although bone marrow (BM) is known as a primary lymphoid organ, it also is known to harbor memory T cells, suggesting that this compartment is a preferential site for migration and/or selective retention of memory T cells. We here report the existence and the potential ability to induce colitis of the colitogenic BM CD4+ memory T cells in murine colitis models.


METHODS
We isolated BM CD4+ T cells obtained from colitic severe combined immunodeficient mice induced by the adoptive transfer of CD4+ CD45RB(high) T cells and colitic interleukin (IL)-10(-/-) mice that develop colitis spontaneously, and analyzed the surface phenotype, cytokine production, and potential activity to induce colitis. Furthermore, we assessed the role of IL-7 to maintain the colitogenic BM CD4+ T cells.


RESULTS
A high number of CD4+ T cells reside in the BM of colitic severe combined immunodeficient mice and diseased IL-10(-/-) mice, and they retain significant potential to induce type-1 T helper-mediated colitis in an IL-7-dependent manner. These resident BM CD4+ T cells have an effector memory (T(EM); CD44(high)CD62L(-)IL-7R(high)) phenotype and preferentially are attached to IL-7-producing BM cells. Furthermore, the accumulation of BM CD4+ T(EM) cells was decreased significantly in IL-7-deficient recipients reconstituted with the colitogenic lamina propria CD4+ T(EM) cells.


CONCLUSIONS
Collectively, these findings suggest that BM-retaining colitogenic CD4+ memory T cells in colitic mice play a critical role as a reservoir for persisting lifelong colitis.
Nemoto
Yasuhiro
Y
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Kanai
Takanori
T
Makita
Shin
S
Okamoto
Ryuichi
R
Totsuka
Teruji
T
Takeda
Kiyoshi
K
Watanabe
Mamoru
M
D019264:Adoptive Transfer; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002908:Chronic Disease; D003092:Colitis / Q000188:drug therapy / Q000276:immunology*; D003106:Colon / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006706:Homeostasis / Q000276:immunology; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics; D007376:Interleukin-2 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D015851:Interleukin-7; C499308:Rag2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1