Positive Selection Is Not Required for Thymic Maturation ofTransgenic ~8 T Cells

Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0420, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 06/1996; 183(5):2033-41. DOI: 10.1084/jem.183.5.2033
Source: PubMed


Previously published reports describing thymic differentiation in two TCR gamma delta transgenic mouse models have suggested that gamma delta T cells require MHC-mediated positive selection to reach full maturity. Recent studies indicate that recognition of antigen by mature gamma delta T cells is not MHC restricted, raising the issue of why developing gamma delta T cells would even require MHC-driven positive selection. Therefore, we have reinvestigated the requirements for development and selection in G8 gamma delta T cell receptor (TCR) transgenic mice. Analyses of absolute cell numbers, phenotypic subsets, and functional competence of thymic and peripheral G8 gamma delta T cells indicate that these cells can fully mature in class I MHC-deficient mice. Moreover, mixed bone marrow chimeras demonstrate that gamma delta T cells of mutant B2-microglobulin (beta 2m zero) origin are partially deleted in the presence of H-2d-bearing thymocytes (previously believed to be the haplotype mediating positive selection). We conclude that there is no requirement for class I-like molecules for the maturation/development of these transgenic gamma delta T cells and that the differences in thymocyte phenotype and number observed are, instead, attributable to effects of clonal deletion.

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    • "Presumably, most of the strongly autoreactive clones are already silenced in the thymus. When Ags or their homologues are already present in the thymus (IPP, T10/T22), γδ T cells with intermediate affinities for " Ag plus context " might also be positively selected in a manner not unlike that for αβ T cells, although this does not seem to be required for γδ T-cell thymic maturation (Schweighoffer and Fowlkes 1996). "
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    ABSTRACT: After more than two decades of investigation, the biological role of the gammadelta T-cell receptors (TCRs) remains elusive. In fact, a theory of ligand recognition is still lacking that accounts for their adaptable structure, their peripheral selection, and the observed responses of gammadelta T cells, which do not require immunization but only include cells sharing germline-encoded components of the TCR. Assuming that all gammadelta T cells recognize ligands by a common mechanism, we now propose that germline-encoded components of the gammadelta TCRs provide for the specific recognition of a select set of antigenic determinants (Ags) which appear on the cell surface in various molecular associations. Furthermore, we hypothesize that the adaptivity of the gammadelta TCRs serves to increase affinity for the molecules with which these Ags associate rather than for the Ags themselves. Here we outline this hypothetical mechanism and discuss its possible implications for thymic selection and potential for complementing known innate and adaptive mechanisms of immune defense.
    Archivum Immunologiae et Therapiae Experimentalis 04/2009; 57(2):129-35. DOI:10.1007/s00005-009-0017-x · 3.18 Impact Factor
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    • "In the data presented here we show that a population of antigen specific γδ T cells is neither positively nor negatively selected in the thymus. This is in contrast to some (but not all (Schweighoffer and Fowlkes, 1996)) of the previous findings using mice expressing transgenic TCRs with the same specificity. These differences may also be due to the tendency of endogenous pre-rearranged TCR genes to skew T lymphocyte development (Serwold et al., 2007). "
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    ABSTRACT: gammadelta T cells uniquely contribute to host immune defense, but how this is accomplished remains unclear. Here, we analyzed the nonclassical major histocompatibility complex class I T10 and T22-specific gammadelta T cells in mice and found that encountering antigen in the thymus was neither required nor inhibitory for their development. But when triggered through the T cell receptor, ligand-naive lymphoid-gammadelta T cells produced IL-17, whereas ligand-experienced cells made IFN-gamma. Immediately after immunization, a large fraction of IL-17(+) gammadelta T cells were found in the draining lymph nodes days before the appearance of antigen-specific IL-17(+) *beta T cells. Thus, thymic selection determines the effector fate of gammadelta T cells rather than constrains their antigen specificities. The swift IL-17 response mounted by antigen-naive gammadelta T cells suggests a critical role for these cells at the onset of an acute inflammatory response to novel antigens.
    Immunity 08/2008; 29(1):90-100. DOI:10.1016/j.immuni.2008.04.022 · 21.56 Impact Factor
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    • "Notably, all TCRγδ+ cells assumed this phenotype in wells coated with TCRγδ antibodies, not only those converted away from the αβ lineage, indicating that this phenotype results from strong TCR signaling in all γδ thymocytes. In fact, previous data had shown that numbers of mature CD24lo γδ lineage cells were increased among TCRγδ transgenic cells when a cognate ligand was expressed in the thymus or on the stroma cells in fetal thymic organ culture (10), even though this was not observed with another transgenic TCRγδ (20). Thus, γδ lineage cells generated in the co-culture system share phenotypic properties with a subpopulation of γδ thymocytes and resemble NKT cells in some aspects of their surface phenotype. "
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    ABSTRACT: alphabeta and gammadelta T cell lineages develop in the thymus from a common precursor. It is unclear at which stage of development commitment to these lineages takes place and in which way T cell receptor signaling contributes to the process. Recently, it was demonstrated that strong TCR signals favor gammadelta lineage development, whereas weaker TCR signals promote alphabeta lineage fate. Two models have been proposed to explain these results. The first model suggests that commitment occurs after TCR expression and TCR signaling directly instructs lymphocytes to adopt one or the other lineage fate. The second model suggests that commitment occurs before TCR expression and that TCR signaling merely confirms the lineage choice. By tracing the fate of single T cell precursors, this study shows that there is no commitment to either the alphabeta or gammadelta lineage before TCR expression and that modulation of TCR signaling in progeny of a single TCR-expressing cell changes lineage commitment.
    Journal of Experimental Medicine 06/2008; 205(5):1173-86. DOI:10.1084/jem.20072425 · 12.52 Impact Factor
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