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, But Not by Surface Pre-TCR Complexes, Are Able to Induce Maturation of an Early Thymic Lymphoma In Vitro1
Fox Chase Cancer Center, Immunobiology Working Group, Division of Basic Sciences, Philadelphia, PA 19111
Development of immature CD4-CD8-
(double-negative) thymocytes to the CD4+CD8+
(double-positive) stage is linked to productive rearrangement of the
TCRß locus by signals transduced through the pre-TCR. However, the
mechanism whereby pre-TCR signaling is initiated remains unclear, in
part due to the lack of an in vitro model system amenable to both
biochemical and genetic analysis. In this study, we establish the
thymic lymphoma Scid.adh as such a model system. Scid.adh responds to
Ab engagement of surface IL-2Ra (TAC):CD3
molecules (a signaling
chimera that mimics pre-TCR signaling in vivo) by undergoing changes in
gene expression observed following pre-TCR activation in normal
thymocytes. These changes include down-regulation of CD25,
recombinase-activating gene (RAG)-1, RAG-2, and pT
; and the
up-regulation of TCR germline transcripts. We term this complete set
of changes in gene expression, in vitro maturation. Interestingly,
Scid.adh undergoes only a subset of these changes in gene expression
following Ab engagement of the pre-TCR. Our findings make two important
points. First, because TAC:CD3 stimulation of Scid.adh induces
physiologically relevant changes in gene expression, Scid.adh is an
excellent cellular system for investigating the molecular requirements
for pre-TCR signaling. Second, Ab engagement of CD3 signaling
domains in isolation (TAC:CD3) promotes in vitro maturation of
Scid.adh, whereas engagement of CD3 molecules contained within the
complete pre-TCR fails to do so. Our current working hypothesis is that
CD3 fails to promote in vitro maturation when in the context of an
Ab-engaged pre-TCR because another pre-TCR subunit(s), possibly TCR
,
qualitatively alters the CD3 signal.
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