Involvement of P38 Mitogen-Activated Protein Kinase in Different Stages of Thymocyte Development

Abstract

Positive selection of thymocytes during T-cell development is mediated by T-cell receptor (TCR)-activated signals. For different mitogen-activated protein kinases (MAPKs) activated by TCR complex, a selective involvement of extracellular signal-regulated kinase, but not p38 MAPK, in positive selection has been suggested. Using transgenic mice with dominant-negative mutation of both MAP kinase kinase 3 (MMK3) and MKK6, we obtained mice with different extents of inhibition of p38 MAPK activation. Partial inhibition of p 38 MAPK impaired CD4(-)CD8(-) thymocyte development and T- cell proliferation, but not positive selection. Interference with thymocyte positive selection was observed in mice with effective suppression of p38 MAPK. Our results suggest that , in addition to early thymocyte development, p38 is involved in positive selection.