T-LYMPHOCYTE DEVELOPMENT IN P56(LCK) DEFICIENT MICE - ALLELIC EXCLUSION OF THE TCR-BETA LOCUS IS INCOMPLETE BUT THYMOCYTE DEVELOPMENT IS NOT RESTORED BY TCR-BETA OR TCR-ALPHA-BETA TRANSGENES

The protein tyrosine kinase, p56(lck), is involved in signal transduct ion in mature T cells and in the molecular events controlling early th ymocyte differentiation. Thymuses of mice deficient for p56(lck) expre ssion (p56(lck-/-)) consist of immature CD4(-)CD8(-) double-negative ( DN) and CD4(+)CD8(+) double-positive (DP) thymocytes and are severely reduced in total cell number. In this report we have studied DN thymoc ytes from p56(lck-/-) mice and found an increase in the proportion of the CD44(-)CD25(+) subset, suggesting that transit through this stage, which is known to require T cell receptor (TcR) beta expression, may be delayed in the absence of p56(lck) expression. In addition, the exp ression of a transgenic TcR beta chain or TcR alpha beta pair did not restore thymic development in p56(lck-/-) mice. However, in contrast t o mice expressing a dominant negative isoform of p56(lck) in which DP thymocytes do not develop, DP thymocytes still develop in nontransgeni c and TcR transgenic p56(lck-/-) mice. These results demonstrate that expansion of the DP subset is impaired in p56(lck-/-) mice. In contras t, allelic exclusion is not severely compromised. Although there was a n increase in the number of peripheral T cells expressing more than on e V beta chain in TcR transgenic p56(lck-/-) mice, we found that inhib ition of endogenous TcR beta gene rearrangement was almost complete in thymocytes of V beta transgenic p56(lck-/-) mice and we could not det ect any peripheral T cells that expressed more than one V beta chain i n non-transgenic p56(lck-/-) mice.