Senescent B lymphopoiesis is balanced in suppressive homeostasis: decrease in interleukin-7 and transforming growth factor-beta levels in stromal cells of senescence-accelerated mice.

The suppression of the B cell population during senescence has been considered to be due to the suppression of interleukin-7 (IL-7) production and responsiveness to IL-7; however, the upregulation of transforming growth factor-beta (TGF-beta) was found to contribute to B cell suppression. To investigate the mechanism of this suppression based on the interrelationship between IL-7 and TGF-beta during senescence, senescence-accelerated mice (SAMs), the mouse model of aging, were used in this study to elucidate the mechanisms of B lymphopoietic suppression during aging. Similar to regular senescent mice, SAMs showed a decrease in the number of IL-7-responding B cell progenitors (i.e., colony-forming unit pre-B [CFU-pre-B] cells in the femoral bone marrow [BM]). A co-culture system of B lymphocytes and stromal cells that the authors established showed a significantly lower number of CFU-pre-B cells harvested when BM cells were co-cultured with senescent stromal cells than when they were co-cultured with young stromal cells. Interestingly, cells harvested from a senescent stroma and those from the control culture without stromal cells were higher in number than those harvested from a young stroma, thereby implying that an altered senescent stromal cell is unable to maintain self-renewal of the stem cell compartment. Because TGF-beta is supposed to suppress the proliferative capacity of pro-B/pre-B cells, we added a neutralizing anti-TGF-beta antibody to the co-culture system with a pro-B/pre-B cell-rich population to determine whether such suppression may be rescued. However, unexpectedly, any rescue was not observed and the number of CFU-pre-B cells remained unchanged when BM cells were co-cultured with senescent stromal cells compared with the co-culture with young stromal cells, which essentially showed an increase in the number of CFU-pre-B cells (P < 0.001 in 5 microg/ml). Furthermore, TGF-beta protein level in the supernatant of cultured senescent stroma cells was evaluated by enzyme-linked immunoabsorbent assay, but surprisingly, it was found that TGF-beta concentration was significantly lower than that of cultured young stromal cells. Thus, TGF-beta activity was assumed to decline particularly in a senescent stroma, which means a distinct difference between the senescent suppression of B lymphopoiesis and secondary B lymphocytopenia. Concerning proliferative signaling, on the other hand, the level of IL-7 gene expression in cells from freshly isolated BM decreased significantly with age. Therefore, the acceleration of proliferative signaling and the deceleration of suppressive signaling may both be altered and weakened in a senescent stroma (i.e., homeosuppression).

Selective accumulation of type 1 effector cells expressing P-selectin ligand and/or alpha(4)beta(7)-integrin at the lesions of autoimmune gastritis.

T(h)1 cells but not T(h)2 cells accumulate at the inflamed gastric mucosa (GM), while both subsets co-exist in the regional lymph node (RLN) in a murine experimental model for autoimmune gastritis (AIG). To understand the relationship between the immuno-microenvironment and effector localization in GM versus RLN of AIG-bearing mice, cells or tissue sections were stained with several mAb against adhesion molecules. The expression of RNA of various cytokines at these contrasting sites was also assessed. IFN-gamma-producing memory CD4(+) (T(h)1) and CD8(+) T cells as well as IL-12-producing mature macrophages which express P-selectin ligand and/or alpha(4)beta(7)-integrin selectively accumulated in the inflamed GM. Vessel endothelium at the site of infiltration expressed those counter-receptors, P-selectin and mucosal adressin cell adhesion molecule-1. Therefore, the tissue destruction of target tissue in autoimmune diseases might be promoted by a vicious circle between the selective accumulation of type 1 effectors mediated by multiple adhesion molecules and following an unusual type 1-biased microenvironment away from the type 2 response.