| Budget Amount *help |
¥11,400,000 (Direct Cost: ¥11,400,000)
Fiscal Year 2006: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2005: ¥5,900,000 (Direct Cost: ¥5,900,000)
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| Research Abstract |
The aim of this study is to assess the role of intestinal bacteria in the development and the persistence of colitogenic CD4^+ memory T cells in chronic colitic mice. To do it, we used a chronic colitis model induced by adoptive transfer of CD4^+CD45RB^<high> T cells into immunodeficient Rag-2^<-/-> mice. Lamina propria CD4^+ T cells obtained from colitic CD4^+CD45RB^<high> T cell-transferred mice have a characteristic of CD44^<high>CD62L^-CD69^+IL-7Ra^<high> effector T or effector-memory (T_<EM>) phenotype. SPF, but not germ free (GF), Rag-2^<-/-> mice re-transferred with these colitic LP CD4^+ T cells developed colitis showing higher histological scores and elevated production of Th1 cytokines 10 wk after retransfer. Surprisingly, however, albeit less compared with SPF Rag-2^<-/-> mice, significant number of CD4^+ TEM cells remained to reside in various sites, such as spleen, mesenteric lymph nodes, and bone marrow in GF Rag-2^<-/-> mice. Furthermore, GF→SPF, but not GF→GF, SCID mice rapidly developed colitis 2 wk after transferring to SPF condition. In another experiment, we further evaluated the role of toll-like receptor (TLR) signaling in donor CD4^+ T cells using MyD88^<-/-> mice. Interestingly, we found that the severity of colitis in MyD88^<-/-> CD4^+CD45RB^<high> T cell-transferred Rag-^<2-/-> mice was significantly decreased as compared with that in wild-type CD4^+CD45RB^<high> T cell-transferred Rag-2^<-/-> mice, indicating that donor CD4^+ T cells expressed some TLRs, and their TLR signaling tunes the maintenance of colitogenic CD4^+ memory T cells.
Collectively, We found that intestinal bacteria are critical important for the persistence of colitogenic CD4^+ memory T cells in chronic colitic mice, but not essential for the survival of these cells.
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