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The introduction of a soluble TCR (sTCR) recognizing class I major histocompatibility complex (MHC) in the fetal thymic microenvironment in vitro produces the selection of thymocytes with enhanced avidity for self class I MHC (8). The sTCR was supposed to impose enhanced avidity for self MHC at an early degenerate phase of TCR-driven selection. This could determine increased reactivity to self at later stages of differentiation when specificity of TCR-ligand interaction augments and the effect of sTCR vanishes. This hypothesis was based on the observed deletion of CD4+8+ thymocytes upon upregulation of TCR and the increase in cell size of some CD8+ cells which are expanded in long-term fetal thymus organ cultures (FTOC) as well as in the periphery of adoptively transferred nude mice. Here we show that the developing alphabeta thymocyte which does not express CD8 at the cell surface has a selective advantage in FTOC with sTCR, thus suggesting that participation of CD8 in self peptide/MHC recognition confers specificity to T-cell selection and results in excessive signaling in thymocytes in spite of the presence of sTCR.
Cell Mol Biol (Noisy-le-grand) 2001 Feb
PMID:A role for CD8 in limiting degeneracy of thymocyte selection. 1129 47

During thymic development, immature thymocytes are selected through the interaction with self peptides loaded on self MHC molecules. Although there is a great deal of debates on how specifically thymocytes recognize self peptides during thymic selection, recent data suggest an important role of peptide diversity in selecting an adequate T-cell repertoire in the thymus. The findings that human T-cells, unlike mouse T-cells, express MHC class II molecules on their surfaces and can play as antigen presenting cells suggesting possible peripheral T-T interaction network has not been intensively studied so far. However, the facts that human thymocytes have surface expression of MHC class II molecules and thymocytes can be selected by thymocytes in in vitro re-aggregation culture system led us to propose a novel hypothesis - "T-T interaction during thymic selection". Our proposition is that peripheral T-T interaction through TCR-derived peptides might reflect the selection process in the thymus and that T-T interaction also plays an important role in thymic selection. This review deals with our thymic T-T interaction hypothesis and its implications on human T-cell development.
Cell Mol Biol (Noisy-le-grand) 2001 Feb
PMID:T-T interaction during thymic selection. 1129 48

Remarkably normal cellular immune function, along with specific T-cell tolerance to highly disparate xenogeneic donors, can be achieved by grafting fetal pig thymus (FP THY) tissue to T and NK cell-depleted, thymectomized (ATX) mice. Porcine MHC can mediate positive selection of mouse CD4+ T-cells with a mouse MHC-restricted TCR in FP THY-grafted, T- and NK cell-depleted, ATX TCR-transgenic "AND" mice. However, functional studies were not performed on transgenic mouse T-cells selected in a FP THY graft. We have now performed further studies to confirm the ability of porcine MHC to mediate the positive selection of mouse T-cells with a mouse MHC-restricted TCR, and to exclude the possibility that the maturation of mouse T-cells with a mouse MHC-restricted TCR in FP THY grafts in ATX "AND" mice is a special case. For this purpose, TCR-transgenic mice with an unrelated transgenic TCR ["3A9", specific for hen egg lysozyme (HEL) peptide 46-61 presented by I-Ak] were employed. Similar to FP THY-grafted ATX "AND" mice, large numbers of mouse CD4 single positive thymocytes expressing the transgenic TCR (Vbeta8.2) and expressing a mature phenotype (Qa-2high and heat stable antigen, HSAlow) were detected in FP THY grafts. Porcine thymus grafting led to a high level of peripheral repopulation with mouse naive-type (CD44low CD45RBhigh CD62Lhigh) CD4+ cells expressing the transgenic TCR in T and NK cell-depleted ATX "3A9" mice, regardless of whether the recipients had a positive selecting or a non-selecting, class II deficient MHC background. The mouse CD4+ T-cells expressing the "3A9" TCR showed efficient primary proliferative responses to the protein antigen (HEL) when it was presented by mouse class II+ antigen presenting cells (APC) in vitro. These results, collectively, support the general conclusion that discordant xenogeneic porcine MHC can mediate positive selection of mouse T-cells with mouse MHC-restricted TCR. This study has implications for the potential clinical use of xenogeneic thymus transplantation to reconstitute cellular immunity in the setting of thymic insufficiency or thymectomy, and hence for its applicability to the induction of xenograft tolerance and in the treatment of immunodeficiency diseases.
Cell Mol Biol (Noisy-le-grand) 2001 Feb
PMID:Maturation and function of mouse T-cells with a transgenic TCR positively selected by highly disparate xenogeneic porcine MHC. 1129 57

The interaction of interleukin-2 (IL-2) with its receptor (IL-2R) critically regulates the T-cell immune response, and the alpha chain CD25/IL-2Ralpha is required for the formation of the high-affinity receptor. Tissue-specific, inducible expression of the IL-2Ralpha gene is regulated by at least three positive regulatory regions (PRRI, PRRII, and PRRIII), but none responded to CD28 engagement in gene reporter assays although CD28 costimulation strongly amplifies IL-2Ralpha gene transcription. By DNase I hypersensitivity analysis, we have identified a novel TCR-CD3- and CD28-responsive enhancer (CD28rE) located 8.5 kb 5' of the IL-2Ralpha gene. PRRIV/CD28rE contains a functional CRE/TRE element required for CD28 signaling. The T-cell-specific, CD28-responsive expression of the IL-2Ralpha gene appears controlled through PRRIV/CD28rE by cooperation of CREB/ATF and AP-1 family transcription factors.
Mol Cell Biol 2001 Jul
PMID:Novel CD28-responsive enhancer activated by CREB/ATF and AP-1 families in the human interleukin-2 receptor alpha-chain locus. 1141 31

Antigen recognition by alphabeta T lymphocytes is mediated via the multisubunit TCR complex consisting of invariant CD3gamma,delta,epsilon and zeta chains associated with clonotypic TCRalpha and beta molecules. Charged amino acids located centrally within the TCRalpha transmembrane region are necessary and sufficient for assembly with the CD3deltaepsilon heterodimer. Previously, we have shown that deletion of 6-12 amino acids from the carboxy terminus of the TCRalpha-chain dramatically abrogates surface TCR expression, suggesting that the distal portion of the TCRalpha transmembrane region contains information that regulates the assembly and/or intracellular transport of TCR complexes. We have examined in more detail the molecular basis for reduced TCR expression in T cells bearing truncated TCRalpha chains. We found that in contrast to wild-type (wt), variant TCRalpha proteins missing the last nine C-terminal amino acids did not associate with core CD3gamma,delta,epsilon chains and were not assembled into disulphide-linked alphabeta heterodimers. The stability of newly synthesised wt and variant TCRalpha molecules was similar, showing that the abrogated surface TCR expression was not a consequence of impaired protein survival. Nevertheless, truncated TCRalpha chains still assembled with the chaperon protein calnexin in the endoplasmic reticulum, indicating that the distal portion of the TCRalpha transmembrane region is not essential for calnexin interaction. These data document a role for the distal portion of the TCRalpha transmembrane region in the assembly of TCR complexes and provide a molecular basis for reduced TCR expression in cells bearing truncated TCRalpha chains.
Mol Immunol 2001 Aug
PMID:Importance of the T cell receptor alpha-chain transmembrane distal region for assembly with cognate subunits. 1156 19

N-substituted benzamides are compounds that have recently been reported to inhibit nuclear factor-kappaB (NF-kappaB) activity and induce apoptosis in a pre-B cell line. In this study, we focused on the effects of N-substituted benzamides on transcriptional regulation in Jurkat T cells. We used a model system where the cells can be stimulated either through TCR/CD28 or by treatment of the cells with PMA and ionomycin to induce transcription factors typical for T lymphocyte activation. Treatment of the Jurkat cells with procainamide did not influence the transcription factor profile of stimulated cells, while treatment with a derivative having an acetyl group in position 4 of the aromatic ring inhibited NF-kappaB and nuclear factor of activated T cells (NFAT) activity. Declopramide, which contains a chloride in position 3 of the aromatic ring, was inactive in this system, whereas also the acetylated derivative of this compound inhibited NF-kappaB and NFAT activity. In contrast, the transcriptional activity and nuclear expression of activator protein 1 induced by TCR/CD28 stimulation or PMA and ionomycin treatment was enhanced by the acetylated variants of the N-substituted benzamides. Finally, we investigated the effect of N-substituted benzamides on intact promoters for two genes central in immune regulation; the CD40 ligand (CD40L) and IL-2 promoters. The transcriptional activity of the CD40L promoter as well as surface expression of the CD40L induced by signaling through TCR/CD28 was inhibited by addition of acetylated N-substituted benzamides, while the transcriptional activity of the IL-2 promoter was enhanced. Taken together, these data indicate that derivatives of N-substituted benzamides are potential drug candidates for quantitative as well as qualitative modulation of immune functions.
Mol Immunol 2001 Aug
PMID:N-substituted benzamides inhibit nuclear factor-kappaB and nuclear factor of activated T cells activity while inducing activator protein 1 activity in T lymphocytes. 1156 20

Human T cell leukemia virus type I (HTLV-I) env-pX transgenic rats (env-pX rats) develop chronic destructive arthritis resembling rheumatoid arthritis in humans. Immunological characteristics were compared with those of collagen-induced arthritis (CIA). Rheumatoid factor was present in some env-pX rats regardless of the development of arthritis, but not in nontransgenic rats with CIA. All rats with CIA produced anti-type II collagen (IIC) antibody, but never so in env-pX rats with naturally occurring arthritis. Although expansions of oligoclonal T cells were evident in the affected joints, no particular clone was shown to infiltrate into the arthritic lesions in env-pX rats. In contrast to CIA, in which clonal expansions of IIC-specific T cells are implicated, locally expanded T cell clones against various antigens of the joints may play pathogenetic roles in the arthritis seen in env-pX rats. However, complementarity-determining region 3 of the TCR Vbeta gene of T cells accumulating at the affected joints in env-pX rats contained the GGA amino acid sequence, which was reported to be a conserved motif in HTLV-I env-pX transgenic mice with arthritis. These findings suggest that common antigen(s) might be recognized by T cells accumulating at sites of arthritis in both transgenic rats and mice.
Exp Mol Pathol 2002 Feb
PMID:Clonotypic analysis of T cells accumulating at arthritic lesions in HTLV-I env-pX transgenic rats. 1178 23

In typical cases of infectious mononucleosis (IM), lymphoid tissue is rarely submitted for pathological examination. When lymphoid tissues from IM cases are examined, the histological appearance of IM may be difficult to distinguish from malignant lymphoma. The purpose of this study was to address the utility of clinical molecular assays for T and B cell clonality in distinguishing IM from lymphoid malignancy. DNA was recovered from paraffin-embedded archival lymphoid tissues of 18 cases of IM and 13 control cases representing other reactive lymphoid hyperplasias. T cell receptor gamma (TCR-gamma) and immunoglobulin heavy chain (IgH) gene rearrangements were assayed using our standard clinical polymerase chain reaction procedures targeting each of the four functional variable (V) families and the three joining (J) families of the TCR-gamma gene, and framework III of the IgH gene, respectively. In 17 of 18 cases of IM, no monoclonal T or B cell populations were detectable. One case, the only spleen specimen in the study, had an oligoclonal pattern of TCR-gamma rearrangements. The control cases representing other reactive hyperplasias also lacked monoclonality. The assays used were sensitive to clonal populations as small as 5% of cells. In this case series, no monoclonal lymphoid populations were identified in any case of IM. This finding suggests that molecular studies are useful in distinguishing IM from lymphoid neoplasms.
J Mol Diagn 2002 Feb
PMID:Lymphoid tissues from patients with infectious mononucleosis lack monoclonal B and T cells. 1182 86

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autosomal recessive disease caused by mutations in the AIRE gene. Here we have produced knock-out mice for the Aire gene. The Aire-/- mice develop normally; however, autoimmune features of APECED in Aire-/- mice are evident, including multiorgan lymphocytic infiltration, circulating autoantibodies and infertility. The distribution of B and T cells and thymic maturation as well as activation of T cells appear normal, while the TCR-Vbeta repertoire is altered in peripheral T cells of Aire-/- mice. When mice are challenged with immunization, the peripheral T cells of Aire-/- mice have a 3-5-fold increased proliferation. These findings suggest that the Aire gene is not necessary for normal T cell education and development, while a defect in immune response detected in challenged Aire-/- mice underlines the crucial role of AIRE/Aire in maintaining homeostatic regulation in the immune system.
Hum Mol Genet 2002 Feb 15
PMID:Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. 1185 72

T lymphocytes play a central role in the pathogenesis of a large number of human conditions including autoimmunity and graft rejection. Although T cells are key players in mounting immune responses, the assessment of T cell repertoires has yet to find an important role in clinical decision making. In this review, we discuss the "immunoscope" technique and its potential diagnostic role in a variety of clinical scenarios. This is an RT-PCR based approach that subdivides a bulk T cell population (i. e. from blood, lymph, spleen, or tissue) into approximately 2800 groups based upon rearranged variable beta (Vbeta)/joining beta (Jbeta) gene segments and the resulting length of the T cell receptor's (TCR's) third complementarity determining region (CDR-3). This extensive subdivision, or focusing, allows clonal expansions to be directly observed. Such a fine-tuned analysis has revealed previously unappreciated aspects of the T cell repertoire. For instance, an antigen-specific immune response can be divided into both public and non-public components. The non-public repertoire contains the majority of the expanding T cells which are unique to the individual (private), or shared by only some (semi-private), while "public" T cells can be found responding to the antigenic determinant in every individual. Although they are often a minority of the response, the public T cell repertoire seems to play a more important role in defining, as well as driving, the overall immune phenotype in the animal. Immunoscope analysis has identified public and non-public responses in human pathologies, such as multiple sclerosis. The ability to characterize the driver T cells dictating the state of immunity/autoimmunity in individual patients will be an important step towards understanding autoimmunity and designing effective treatment for a variety of conditions including rheumatoid arthritis and multiple sclerosis. We review the current literature involving public and non-public repertoires and discuss the prospect that immunoscope analysis may play a central role in the study and perhaps the management of human autoimmune diseases, and cancer.
Curr Mol Med 2001 Jul
PMID:Molecular characterization of the T cell repertoire using immunoscope analysis and its possible implementation in clinical practice. 1189 78


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