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Involvement of the interleukin 2 pathway in the rearrangement and expression of both [alfa/beta] and [gamma/delta] T cell receptor genes in human T cell precursors

AuthorsToribio, María Luisa CSIC ORCID; Hera, Antonio de la ; Borst, Jannie; Borst, Jannie; Marcos, Miguel A. R.; Márquez, Carlos; Alonso, José M. CSIC; Bárcena, Alicia; Martínez-Alonso, Carlos
Issue DateDec-1988
PublisherRockefeller University Press
CitationThe Journal of Experimental Medicine, Volume 168, December 1988, pp. 2231-2249
AbstractT 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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