CD45 can act as a negative regulator for the transition from early to lateCD4(+)CD8(+) thymocytes

The differentiation process from CD4(-)CD8(-) double-negative (DN) thymocyt es to CD4(+)CD8(+) double-positive (DP) stage is accompanied by vigorous pr oliferation. The resulting DP cells contain a sizable proportion of large c ycling cells, but most DP cells are small resting cells. To explore the mol ecular mechanisms which regulate cell proliferation of DP thymocytes prior to further development, we used TCR-transgenic (Tg) mice with non-selecting MHC (Tg-Neut), which contain almost exclusively DP thymocytes that are not subject to either positive or negative selection. In Tg-Neut, the thymus c ontained DP cells of relatively large size, which showed higher extracellul ar signal-regulated kinase activity and enhanced responsiveness to mitogen compared to small DP cells. This indicates that all the large DP cells in t he thymus are not positively selected and that they possess proliferative p otential. When Tg-Neut mice were backcrossed with CD45 knockout mice (CD45( -/-) Tg-Neut), the thymus showed an increase of large DP cells and cycling cells, but a decrease of apoptotic cells, Furthermore, Bcl-2 expression and Jun N-terminal kinase activity, which are associated with resistance to ap optosis, were enhanced. These observations suggest that thymocyte prolifera tion in the DP stage is suppressed by st CD45-related process with regulati on of mitogen-activated protein kinase and Bcl-2 unless DP cells receive TC R-mediated signals.