Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1356-1361
Thymocyte development past the CD4+CD8+
stage requires an active p38 mitogen-activated protein kinase
Edgar Fernández
From the Structural Biology Section, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Rockville, MD.
Activation of the p38 mitogen-activated protein kinase (MAPK)
pathway is important for some T-cell functions, but its role in
intrathymic development is unclear. To investigate the function of p38
MAPK during the late stages of thymocyte differentiation, pharmacologic
and genetic manipulations were used to inhibit p38 MAPK activity in
developing thymocytes. Ligation of the T-cell antigen receptor (TCR) on
either thymocytes or a thymocyte cell line resulted in p38 MAPK
activation. Selective pharmacologic inhibition of p38 MAPK activity
with the pyridinyl imidazole drug SB203580 severely impaired the
development of mature CD4+ and CD8+ single
positive (SP) thymocytes from their
CD4+CD8+ double positive (DP) precursors in
fetal thymic organ culture (FTOC). Further, pharmacologic or genetic
suppression of p38 MAPK activity, the latter achieved by overexpressing
a catalytically inactive p38 MAPK, resulted in a blockade of the
DP-to-SP transition of a thymocyte cell line in a novel in vitro
differentiation assay. Taken together, these data constitute the first
demonstration that p38 MAPK plays a critical role in the DP-to-SP
differentiation of thymocytes during late intrathymic development.
