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Max-Planck-Institut für Immunbiologie, Freiburg, Germany
Maturation to the CD4+8+ double-positive
(DP) stage of thymocyte development is restricted to cells that have
passed TCRß selection, an important checkpoint at which immature
CD4-8- double-negative (DN) cells that
express TCRß polypeptide chains are selected for further maturation.
The generation of DP thymocytes following TCRß selection is dependent
on cellular survival, differentiation, and proliferation, and the
entire process appears to be mediated by the pre-TCR/CD3 complex. In
this study, we investigate the signaling requirements for TCRß
selection using mice single deficient and double deficient for
CD3
/
and/or p56lck. While the
numbers of DP cells are strongly reduced in the single-deficient mice,
a further drastic reduction in the generation of DP thymocytes is seen
in the double-deficient mice. The poor generation of DP cells in the
mutant mice is primarily due to an impaired ability of
CD25+ DN thymocytes to proliferate following expression of
a TCRß-chain. Nevertheless, the residual DP cells in all mutant mice
are strictly selected for expression of TCRß polypeptide chains. DN
thymocytes of mutant mice expressed TCRß and CD3
at the cell
surface and contained mRNA for pre-T
, but not for clonotypic
TCR-chains, together suggesting that TCRß selection is mediated by
pre-TCR signaling in all cases. The data suggest differential
requirements of pre-TCR signaling for cell survival on the one hand,
and for the proliferative burst associated with TCRß selection on the
other.
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