Immunosenescent colitogenic CD4+ T cells convert to regulatory cells and suppress colitis

Inflammatory bowel diseases progress steadily by the expansion of colitogenic CD4⁺ cells. However, it remains unknown whether colitogenic CD4⁺ cells are long-living like memory cells or exhausted like effector cells. To assess the longevity of colitogenic lamina propria (LP) CD4⁺ cells, we performed sequential transfers of LP CD4⁺ cells from colitic CD4⁺CD45RB^high cell-transferred SCID mice into new SCID mice. Although SCID mice transferred with colitic LP CD4⁺ cells stably developed colitis until at least the sixth transfer, the interval to the development of colitis gradually lengthened as the number of transfers increased. The incidence of colitis gradually decreased after the seventh transfer. Furthermore, non-colitic LP CD4⁺ cells from mice transferred over seven times expressed significantly higher levels of PD-1 and produced significantly lower amounts of IFN-γ, TNF-α, and IL-17 than colitic LP CD4⁺ cells recovered after the first transfer. Most notably, we found that re-transfer of non-colitic LP CD4⁺ cells recovered after multiple transfers prevented the development of colitis in SCID mice co-transferred with CD4⁺CD45RB^high cells. Thus, colitogenic LP CD4⁺ cells may be exhausted over time, become non-functional, convert to regulatory cells, and finally suppress colitis in the process of immunosenescence.