Negative feedback regulation of colitogenic CD4+ T cells by increased granulopoiesis

Chronic inflammatory diseases are characterized by massive infiltration of innate and acquired immune cells in inflammatory sites. However, it remains unclear how these cells cooperate in the development of disease. Although bone marrow (BM) is a primary site for hematopoiesis of immune cells except T cells, BM recruits memory T cells from the periphery. We have recently demonstrated that colitogenic CD4(+) memory T cells reside in BM of colitic CD4(+)CD45RB(high) T-cell-transferred SCID mice. Based on this background we here investigate whether granulocytes promote or suppress the expansion of colitogenic CD4(+) T cells.

First, we show that Gr-1(high)CD11b(+) granulocytes were significantly increased in colitic BM along with a significant increase of peripheral granulocytes. Consistently, the colony-forming unit (CFU) assay revealed that granulocyte colony formation was dominantly induced by supernatants from anti-CD3-stimulated colitic BM CD4(+) T cells.

Administration of granulocyte-depleting anti-Gr-1 mAb to colitic mice did not ameliorate the colitis, but exacerbated the wasting disease with an increased expansion of systemic, but not lamina propria, CD4(+) T cells with activated phenotype.

These results suggest that the increased granulopoiesis by colitogenic BM CD4(+) T cells represent a negative feedback mechanism to control systemic inflammation.