IL-7 Is Essential for the Development and the Persistence of Chronic Colitis

Abstract

Although IL-7 has recently emerged as a key cytokine involved in controlling the homeostatic turnover and the survival of peripheral resting memory CD4+ T cells, its potential to be sustained pathogenic CD4+ T cells in chronic immune diseases, such as inflammatory bowel diseases, still remains unclear. In this study, we demonstrate that IL-7 is essential for the development and the persistence of chronic colitis induced by adoptive transfer of normal CD4+CD45RBhigh T cells or colitogenic lamina propria (LP) CD4+ memory T cells into immunodeficient IL-7+/+ × RAG-1−/− and IL-7−/− × RAG-1−/− mice. Although IL-7+/+ × RAG-1−/− recipients transferred with CD4+CD45RBhigh splenocytes developed massive inflammation of the large intestinal mucosa concurrent with massive expansion of Th1 cells, IL-7−/− × RAG-1−/− recipients did not. Furthermore, IL-7−/− × RAG-1−/−, but not IL-7+/+ × RAG-1−/−, mice transferred with LP CD4+CD44highCD62L−IL-7Rαhigh effector-memory T cells (TEM) isolated from colitic CD4+CD45RBhigh-transferred mice did not develop colitis. Although rapid proliferation of transferred colitogenic LP CD4+ TEM cells was observed in the in IL-7−/− × RAG-1−/− mice to a similar extent of those in IL-7+/+ × RAG-1−/− mice, Bcl-2 expression was significantly down-modulated in the transferred CD4+ T cells in IL-7−/− × RAG-1−/− mice compared with those in IL-7+/+ × RAG-1−/− mice. Taken together, IL-7 is essential for the development and the persistence of chronic colitis as a critical survival factor for colitogenic CD4+ TEM cells, suggesting that therapeutic approaches targeting IL-7/IL-7R signaling pathway may be feasible in the treatment of inflammatory bowel diseases.

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

“…Furthermore, accumulating evidence suggests that IL-7 dependency is a reliable assumption for CD4 + memory T cells in vivo [31]. Consistently, we previously demonstrated that colitic LP CD4 + T cells from colitic CD4 + CD45RB high T cell-transferred RAG-2 -/-mice express representative cell surface markers of memory T cells such as IL-7Ra and CD44 at a high level, and that the IL-7 -/-Â RAG-1 -/-recipient mice transferred with CD4 + CD45RB high T cells or colitic LP CD4 + T cells never develop colitis [17].…”

“…SCID mice transferred with such colitic LP CD4 + T cells (the second transfer) develop colitis similar to the original CD4 + CD45RB high T cell-transferred colitis in an IL-7-dependent manner [17]. This adoptive transfer model is also characterized by the rapid proliferation of donor CD4 + T cells by lymphopeniadriven proliferation [9,17], which provides an advantageous tool to assess the longevity and change in characteristics of these colitic LP CD4 + T cells during repetitive transfer into SCID mice (Fig. 1A).…”

“…Furthermore, colitogenic CD4 + T cells in this colitis model proliferate and expand in response to foreign antigens more rapidly in immunodeficient SCID mice than do slow-dividing antigen-specific 'true' memory T cells [17]. We thus hypothesized that the colitogenic LP CD4 + T cells gradually convert after multiple transfers to cytokine-non-producing CD4 + Treg cells that have not only lost the ability to induce colitis but, conversely, gained the ability to suppress colitis.…”

“…They were observed for clinical signs of illness [40]: hunched over appearance, piloerection of the coat, diarrhea, and blood in the stool. When mice were killed at a predetermined time point, their clinical score was assessed as the sum (0-8 points) of four parameters: hunching and wasting, 0 or 1; colon thickening, 0-3 (0, no colon thickening; 1, mild thickening; 2, moderate thickening; 3, extensive thickening); stool consistency, 0-3 (0, normal beaded stool; 1, soft stool; 2, diarrhea); and gross blood, 0 or 1 [17]. For the sequential adoptive transfers, we monitored the clinical signs during the observation period, and the ongoing clinical score was defined as the sum (0-5 points) of the above-parameters other than colon thickening [40].…”

Continuous generation of colitogenic CD4+ T cells in persistent colitis

“…To clarify this issue, splenic Ly5.1 + and Ly5.2 + CD4 + T cells from three groups were analyzed for their TCR Vb repertoire by three-color flow cytometry. It is reasonable to use SP CD4 + T cells in place of LP CD4 + T cells for this assay, since we previously demonstrated that colitic SP CD4 + T cells had similar characteristics in that they were CD4 + CD44 high CD62L -IL-7Ra high T EM -like cells [14], and were also colitogenic cells by which colitis can be transferred to new recipient mice [15]. As shown in Fig.…”