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T cell precursors arising from hematopoietic stem cells colonize the thymus during ontogeny, where they undergo a complex maturational process involving genotypic and phenotypic changes in the expression of distinct surface molecules. Later, they migrate to the periphery as immunocompetent T cells expressing clonally distributed TCR structures (1-4). Four different TCR genes (a, a, y, and S) have thus far been identified and shown to be specifically rearranged and expressed throughout intrathymic T cell development (5-13) . They code for two distinct types of heterodimericTCR:
the common MHC-restricted a/(3 heterodimer expressed on most functional
T lymphocytes (14-16), and the recently described y/8 TCRcomplex, expressed
on a minor T cell subset (17-19). Both structures are expressed in association with
the monomorphic CD3 (T3) complex, but they seem to be acquired independently by distinct intrathymic subpopulations (20, 21) .
Developmental studies in mice support that the TCRy/S appears first in ontogeny
on early double-negative (CD4- CD8- ) thymocytes. Further maturation leads to a
gradual decrease of y/8-bearing cells . In contrast, TCRa/Q expression increases
throughout T cell ontogeny concomitantly with the acquisition ofCD4 and/or CD8
molecules by mature T cells, expression of TCRy/S being restricted to a small population of CD4" CD8- adult thymocytes and peripheral T cells (3, 4) . These findings suggest that y/8-bearing CD4- CD8- cells may define a separate T cell lineage
whose intrathymic development precedes that of classical a/a mature T cells (21,
22). Nonetheless, the presence of y gene rearrangements in mature a/0-bearing T
cells (23), as well as the finding of partial a gene rearrangements in TCRy/S+ cells (22), indicate that both T cell lineages may derive from a common precursor (24).
At present, however, the regulatory mechanisms underlying these developmental
processes remain poorly understood, and precursor-product relationships involving
the various intrathymic subpopulations continue to be disputed, making it difficult
to establish direct correlations between the described patterns of TCR gene expression and a functional pathway of T cell development.
Here, in vitro differentiation approaches were used to analyze the precursor potential
and the putative progeny of a minor population of adult human thymocytes that
lack conventional T cell markers (CD2-1-3-4-8- ; i.e., Tll - 6-3- 4- 8-) but express
CD45 (i.e., T200) and CD7 molecules, suggesting that they are the most immature
intrathymic progenitors (25) . Moreover, only y chain functional RNA messages are
expressed in this subset, whereas a and Q chain TCR genes remain in germline
configuration . Interestingly enough, in vitro culture of this subpopulation in the
presence of IL-2 led to an extensive cellular proliferation and the concomitant differentiation into both TCR-y/S` and TCR-a/(3 + thymic subsets . These data support the involvement of the IL-2 pathway in the intrathymic maturation of early T cell
precursors. Furthermore, they provide a useful in vitro system to induce expression
of TCR-a/(3 as well asTCRy/S structures in developing thymocytes, making it feasible
to investigate the cellular and molecular basis for T cell repertoire selection and development operating in T cell differentiation . |
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