Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression (original) (raw)
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Thymic selection of the human T cell receptor V beta repertoire in SCID- hu mice
Journal of Experimental Medicine, 1992
Implantation of pieces of human fetal liver and thymus into SCID mice results in the development of a human thymus-like organ, in which sustained lymphopoiesis is reproducibly observed. In this model, T cell development can be experimentally manipulated. To study the influence of thymic selection on the development of the human T cell repertoire, the T cell receptor (TCR) Vfl gene repertoire of double-positive (CD4+CD8 +) and single-positive (CD4+CD8 -and CD4-CD8 +) T cells was analyzed in the SCID-hu thymus using a multiprobe ribonuclease protection assay. TCK diversity in double-positive SCID-hu thymocytes was found to be comparable with that present in the thymus of the fetal liver donor, did not change with time, and was independent of the origin of the thymus donor. Thymic selection in SCID-hu thymus induces changes in Vfl usage by the single-positive CD4 + or CD8 + T cells comparable with those previously reported for single-positive cells present in a normal human thymus. Finally, significant differences were observed in the Vfl usage by CD4 or CD8 single-positive T cells that matured from genetically identical stem cells in different thymic environments. Collectively, these data suggest: first, that the generation of TCK diversity at the double-positive stage is determined by the genotype of the stem cells; and second, that polymorphic determinants expressed by thymic epithelium measurably influence the Vfl repertoire of mature single-positive T cells.
Thymic Selection of the Human T Cell Receptor Vfl Repertoire in SC1D-hu Mice
Journal of Experimental Medicine
Implantation of pieces of human fetal liver and thymus into SCID mice results in the development of a human thymus-like organ, in which sustained lymphopoiesis is reproducibly observed. In this model, T cell development can be experimentally manipulated. To study the influence of thymic selection on the development of the human T cell repertoire, the T cell receptor (TCR) Vfl gene repertoire of double-positive (CD4+CD8 +) and single-positive (CD4+CD8 -and CD4-CD8 +) T cells was analyzed in the SCID-hu thymus using a multiprobe ribonuclease protection assay. TCK diversity in double-positive SCID-hu thymocytes was found to be comparable with that present in the thymus of the fetal liver donor, did not change with time, and was independent of the origin of the thymus donor. Thymic selection in SCID-hu thymus induces changes in Vfl usage by the single-positive CD4 + or CD8 + T cells comparable with those previously reported for single-positive cells present in a normal human thymus. Finally, significant differences were observed in the Vfl usage by CD4 or CD8 single-positive T cells that matured from genetically identical stem cells in different thymic environments. Collectively, these data suggest: first, that the generation of TCK diversity at the double-positive stage is determined by the genotype of the stem cells; and second, that polymorphic determinants expressed by thymic epithelium measurably influence the Vfl repertoire of mature single-positive T cells.
2010
The differentiation of intestinal intraepithelial lymphocytes (IEL) remains controversial, which may be due in part to the phenotypic complexity of these T cells. We have investigated here the development of IEL in mice on the recombination activating gene (RAG)-2 Ϫ / Ϫ background which express a T cell antigen receptor (TCR) transgene specific for an H-Y peptide presented by D b (H-Y/D b ϫ RAG-2 Ϫ mice). In contrast to the thymus, the small intestine in female H-Y/D b ϫ RAG-2 Ϫ mice is severely deficient in the number of IEL; TCR transgene ϩ CD8 ␣␣ and CD8 ␣ are virtually absent. This is similar to the number and phenotype of IEL in transgenic mice that do not express the D b class I molecule, and which therefore fail positive selection. Paradoxically, in male mice, the small intestine contains large numbers of TCR ϩ IEL that express high levels of CD8 ␣␣ homodimers. The IEL isolated from male mice are functional, as they respond upon TCR cross-linking, although they are not autoreactive to stimulator cells from male mice. We hypothesize that the H-Y/D b TCR fails to undergo selection in IEL of female mice due to the reduced avidity of the TCR for major histocompatibility complex peptide in conjunction with the CD8 ␣␣ homodimers expressed by many cells in this lineage. By contrast, this reduced TCR/CD8 ␣␣ avidity may permit positive rather than negative selection of this TCR in male mice. Therefore, the data presented provide conclusive evidence that a TCR which is positively selected in the thymus will not necessarily be selected in IEL, and furthermore, that the expression of a distinct CD8 isoform by IEL may be a critical determinant of the differential pattern of selection of these T cells.
Pnas, 1987
Considerable evidence now exists to support the notion that the 50-kDa sheep erythrocyte-binding protein, T1l, represents an essential cell surface component of a human T-cell lineage activation pathway. Furthermore, it is known that the human T3-Ti T-cell antigen/major histocompatibility complex receptor complex is capable of regulating cell growth mediated by the Til structure. Here we show that, within the T3' thymocyte compartment, T3-Ti crosslinking rapidly inhibits Til-initiated interleukin 2 (IL-2) gene transcription and translation. This inhibition is restricted to the IL-2 gene (IL2) as transcription of both the IL-2-receptor gene (JL2R) and the Ti fl-chain gene (TCRB) are not affected (human gene designations are in parentheses). Perhaps more importantly, T3-Timediated IL-2 inhibition of this type is not operational in peripheral T lymphocytes. The results imply that the majority of T3V thymocytes are functionally distinct from peripheral T lymphocytes despite their T3' phenotype and must possess a unique endogenous regulatory component for suppressing IL-2 gene activity. Moreover, since IL-2 is likely rate-limiting for growth within the thymus, the findings provide one plausible mechanism for thymic selection-namely, T3-Ti crosslinking of thymocytes upon interaction with self-major histocompatibility complex inhibits clonal expansion of high-affinity autoreactive cells.
Alteration of T-cell Receptor Repertoires During Thymic T-cell Development
Scandinavian Journal of Immunology, 2006
The majority of thymocytes die in the thymus, whereas small populations of T cells that are able to specifically recognize an antigen are considered to survive. Although the thymic selection is thought to have a profound effect on T-cell receptor (TCR) repertoire, little is known how TCR repertoire is formed during the thymocyte developmental process. We examined TCRa-and b-chain variable regions (TCRAV and TCRBV) repertoire in thymic T-cell subpopulations from mice bearing different major histocompatibility (MHC) haplotypes. In Balb/c mice, but not C57BL/6, remarkable alterations of the TCR repertoire were observed in mature T-cell subpopulations as previously reported. In contrast, there were no significant differences of TCRBV repertoire between DN3 (CD25 + CD44 ) ) and DN4 (CD25 ) CD44 ) ), and between DN4 and DP. These results suggest that (1) TCR repertoire of mature T cells was formed mainly under the influence of endogenous superantigens, while MHC haplotypes played the least role; (2) the 'b-selection' process during immature stages had little impact on TCRBV repertoire formation; and (3) TCR repertoire in immature T-cell subpopulations was extremely similar between different strains of mice. We thus consider that pre-selection TCR repertoire in immature T cells could be determined by some genetic factors conserved among different strains.
European Journal of Immunology, 1994
We have characterized a prominent (15-20 % ) thymocyte population expressing CD4 at a high and CD8 at a low level (CD4+81°) in mice transgenic for a T cell receptor (TCR) restricted by major histocompatibility complex (MHC) class I molecules. The results demonstrate that the CD4+S1" population is an intermediate stage between immature CD4+8+ and end-stage CD4+8-thymocytes and that the survival of these cells crucially depends on the successful interaction of the transgenicTCR with self MHC class I molecules. In addition we demonstrate that the avidity of the interaction betweenTCR and self MHC class I molecules determines whether CD4+8I0 thymocytes are found in significant numbers in this transgenic model. Our findings support a selective and multi-step model of T cell differentiation in the thymus.
Proceedings of the National Academy of Sciences, 1986
Considerable evidence now exists to support the notion that the 50-kDa sheep erythrocyte-binding protein, T1l, represents an essential cell surface component of a human T-cell lineage activation pathway. Furthermore, it is known that the human T3-Ti T-cell antigen/major histocompatibility complex receptor complex is capable of regulating cell growth mediated by the Til structure. Here we show that, within the T3' thymocyte compartment, T3-Ti crosslinking rapidly inhibits Til-initiated interleukin 2 (IL-2) gene transcription and translation. This inhibition is restricted to the IL-2 gene (IL2) as transcription of both the IL-2-receptor gene (JL2R) and the Ti fl-chain gene (TCRB) are not affected (human gene designations are in parentheses). Perhaps more importantly, T3-Timediated IL-2 inhibition of this type is not operational in peripheral T lymphocytes. The results imply that the majority of T3V thymocytes are functionally distinct from peripheral T lymphocytes despite their T3' phenotype and must possess a unique endogenous regulatory component for suppressing IL-2 gene activity. Moreover, since IL-2 is likely rate-limiting for growth within the thymus, the findings provide one plausible mechanism for thymic selection-namely, T3-Ti crosslinking of thymocytes upon interaction with self-major histocompatibility complex inhibits clonal expansion of high-affinity autoreactive cells.
Failure of HY-Specific Thymocytes to Escape Negative Selection by Receptor Editing
Immunity, 2002
been investigated in detail only in B cell development University of Cologne (for review see Radic and Zouali, 1996; Nemazee, 2000). Weyertal 121 Newly arising B cells were shown to be insensitive to D-50931 Cologne induction of apoptosis by BCR crosslinking; instead, Germany increased RAG gene expression was observed (Mel-2 INSERM Unit 429 amed et al., 1998). Only at the following developmental Hô pital Necker Enfants Malades stage BCR engagement resulted in deletion (Melamed 149 Rue de Sè vres et al., 1998). Direct evidence for editing of the BCR came 75015 Paris from mouse strains expressing a transgenic BCR from France VJ joints introduced into the Ig locus. Such VJ 3 Institute of Medical Microbiology, Immunology joints were shown to be genomically replaced by secand Hygiene ondary rearrangements in cases when an autoreactive Technical University of Munich BCR was encoded (Pelanda et al., 1997). In T cells, the Trogerstr. 4b TCR␣ locus is especially suited for secondary re-81675 Munich arrangements due to its high number of V (104) (Glusman Germany et al., 2001) and J (61) (Koop et al., 1994) gene segments and the lack of D elements. Recombination of the TCR␣ loci takes place predominantly at the CD4 ϩ CD8 ϩ (double Summary positive; DP) stage and results in the deletion of the intervening TCR␦ locus. Receptor change by thymo-Editing of autoreactive antigen receptors by secondcytes was first observed in the thymoma cell line M14T ary V(D)J recombination efficiently rescues B lympho-(Marolleau et al., 1988), which continuously rearranges cyte precursors from apoptosis induced by negative its TCR␣ chain. Also, the V␣J␣ joints found on excision selection, but its role has not been rigorously assessed circles in thymocytes could be the products of secondin T cell development. We therefore generated a transary recombination events (Okasaki and Sakano, 1988). genic mouse model in which self-reactive thymocytes One study showed that 3Ј V␣ elements recombine prefcould edit their TCR by secondary recombination at erentially with 5Ј J␣ elements and 5Ј V␣ elements mainly the TCR␣ locus. For this purpose, the V␣J␣ exon of a join 3Ј J␣ elements (Roth et al., 1991), possibly a result male-specific TCR was inserted into the TCR␣ locus of nested rearrangements. However, these data were followed by Cre-loxP-mediated deletion of the TCR␦ questioned in another recent study (Davodeau et al., locus. In this model, only few thymocytes escaped 2001). Nevertheless, there is agreement that the initial negative selection by change of specificity, probably recombination is targeted to the most 5Ј J␣ elements through recombination before encounter of autoantiby the strong germline transcript initiating at the T early gen. In the absence of the restricting MHC element, ␣ (TEA) element (Thompson et al., 1990; Villey et al., however, developing thymocytes replaced the in-1996). Another characteristic of the TCR␣ locus is its serted TCR␣ exon efficiently. lack of allelic exclusion (for review see von Boehmer, 1990; Malissen et al., 1992), in contrast to the immuno
Journal of Experimental Medicine, 1984
Athymic H-2b nude mice received grafts from C57BL/6 (Sendai virus and H-Y antigen cytotoxic T lymphocyte [CTL] responder type), bm1 (H-2Kb mutant, Sendai CTL nonresponder type), or bm12 (H-21-A mutant, H-Y CTL nonresponder type) neonates. In observations of the CTL response to H-Y, both recipients and thymus donors were female. All types of thymus engraftment resulted in mature H-2b splenic T lymphocyte surface phenotype in nude hosts. T cell immunocompetence (as measured by major histocompatibility complex [MHC] CTL responses to allogeneic cells) was restored, and induced nonresponsiveness to the MHC determinants of the engrafted thymus in the nude host. The CTL reaction to Sendai virus in both responder type C57BL/6 and nonresponder type bm1 neonatal thymuses allowed maturation of Sendai-specific, H-2Kb-restricted CTL. For the CTL reaction to H-Y, only responder type C57BL/6 thymuses restored the CTL response, whereas this was not achieved with thymuses from nonresponder type bm12...