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.
