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PubMed2005

Signaling for NKT cell development: the SAP-FynT connection.

New studies demonstrate a critical role for the adaptor protein SAP (SLAM-associated protein) during NKT cell development. By connecting homotypic SLAM family receptor interactions with the FynT Src kinase, SAP may integrate a set of long-standing yet seemingly disparate observations characterizing NKT cell development. In fact, SAP-dependent signaling may underlie the development of multiple unconventional T cell lineages whose thymic selection relies on homotypic interactions between hematopoietic cells.

Animals↗
PubMed2006

Mechanisms imposing the Vbeta bias of Valpha14 natural killer T cells and consequences for microbial glycolipid recognition.

Mouse and human natural killer T (NKT) cells recognize a restricted set of glycosphingolipids presented by CD1d molecules, including self iGb3 and microbial alpha-glycuronosylceramides. The importance of the canonical Valpha14-Jalpha18 TCR alpha chain for antigen recognition by NKT cells is well recognized, but the mechanisms underlying the Vbeta8, Vbeta7, and Vbeta2 bias in mouse have not been explored. To study the influences of thymic selection and the constraints of pairing with Valpha14-Jalpha18, we have created a population of mature T cells expressing Valpha14-Jalpha18 TCR alpha chain in CD1d-deficient mice and studied its recognition properties in vitro and in vivo. Transgenic cells expressed a diverse Vbeta repertoire but their recognition of endogenous ligands and synthetic iGb3 was restricted to the same biased Vbeta repertoire as expressed in natural NKT cells. In contrast, alpha-GalCer, a synthetic homologue of microbial alpha-glycuronosylceramides, was recognized by a broader set of Vbeta chains, including the biased NKT set but also Vbeta6, Vbeta9, Vbeta10, and Vbeta14. These surprising findings demonstrate that, whereas Vbeta8, Vbeta7, and Vbeta2 represent the optimal solution for recognition of endogenous ligand, many Vbeta chains that are potentially useful for the recognition of foreign lipids fail to be selected in the NKT cell repertoire.

Animals↗
PubMed1991

Genetics of Coxsackie B3 (CVB3) myocarditis.

The pathogenic T cell responsible for myocarditis following CVB3 infection differs between BALB/c and DBA/2 mice. Since these two strains are identical at the major histocompatibility (MHC) loci (both H-2d), our aim was to investigate the genetic basis for this difference in T cell immunity, as well as the tissue origin responsible. As previously described, DBA/2 mice are protected from developing myocarditis by CD4+ T cell depletion; BALB/c CUM mice could be protected by CD8+ depletion. TxBM DBA/2 mice were irradiated and reconstituted with thymus and bone marrow cells of either DBA/2 or BALB/c CUM origin. These mice were then tested for susceptibility to CVB3 myocarditis following specific T cell depletion. These studies demonstrated that the pathogenic mechanism is inherent in the bone marrow of the animal and does not reflect thymic selection during T cell ontogeny. Further studies involving C.D2 mice, which are BALB/c AnPt mice congenic with DBA/2, were performed to analyse the susceptibility pattern following specific T cell depletion and virus infection. Analysis of BALB/c AnPt and congenics revealed a pattern consistent with the DBA/2 strain, and not the BALB/c CUM strain. This indicates that the differences in immune pathogenicity lie within subfamilies of BALB/c mice, making information on strain origin important when comparing experimental results in this system.

Animals↗
PubMed1997

Developmentally regulated expression of peanut agglutinin (PNA)-specific glycans on murine thymocytes.

Intrathymic maturation of T lymphocytes is characterized by variable expression of O-linked Gal beta 1,3GalNAc glycans reactive with peanut agglutinin (PNA) lectin. Recent studies on human thymocytes show that conversion from PNA+ to PNA- phenotype is correlated with increased expression of alpha 2,3 O-linked sialyltransferase (ST), which sialylates Gal beta 1,3GalNAc glycans, masking their binding sites for PNA. Interestingly, alpha 2,3 O-linked ST expression is highest within the regions of the thymus containing the most immature and most mature thymocyte subsets, suggesting that PNA-specific glycans are intermittently masked by sialylation during thymic selection processes. Here, we studied expression of PNA receptors on developing thymocytes in the murine system using thymocytes from both normal mice and transgenic mice that are genetically arrested at the early phases of T cell development. Our results confirm and extend recent findings in the human system by showing that murine T cells sequentially progress from PNAlo-->PNAhi-->PNAlo stages during their differentiation within the thymus. In addition, our data demonstrate that a similar set of polypeptides is variably masked by sialylation throughout T cell development.

Animals↗
PubMed1994

Involvement of protein kinase C-epsilon in glucocorticoid-induced apoptosis in thymocytes.

Apoptosis is induced in immature thymocytes by physiological peak levels of glucocorticoid hormones, especially in murine and rat cells. Endogenous glucocorticoids may have some role in thymic selection. Glucocorticoid-induced thymocyte apoptosis appears to be dependent on protein kinase C (PKC), since it is inhibited by PKC inhibitors. PKC is a family of closely related enzymes, consisting of Ca(2+)-dependent (PKC-alpha, -beta I, -beta II, and -gamma) and Ca(2+)-independent (PKC-delta, -epsilon, -eta (L), -theta, -zeta, and -lambda) isozymes. In the present study, we analyzed the role of PKC in glucocorticoid-induced apoptosis in murine thymocytes and found that glucocorticoid selectively induces an increase in Ca(2+)-independent PKC activity in the particulate fraction of immature thymocytes but not in that of mature T cells. The increase as well as the apoptosis was inhibited by actinomycin D, cycloheximide, or the glucocorticoid receptor antagonist, RU 38486. Immunoblotting studies revealed the selective translocation of PKC-epsilon from the cytosolic fraction to the particulate fraction upon glucocorticoid treatment. These results suggest that glucocorticoid-induced apoptosis in immature thymocytes involves glucocorticoid receptor-mediated and selective activation of PKC-epsilon through de novo synthesis of macromolecules.

Animals↗
PubMed1997

B7 blockade prevents activation-induced cell death of thymocytes.

Although both B7 and its counter-receptor CD28 are expressed in the thymus, the role of B7 in thymic selection is not clear. We investigated the role of B7 in intrathymic deletion of antigen-specific T cells using a TCR transgenic model specific for antigen ovalbumin (OVA) and H-2Ad. Intraperitoneal injection of OVA induced apoptosis of thymocytes and drastic reduction of thymocyte numbers. This was significantly inhibited by co-injection of CTLA-4-Ig which blocks B7 co-stimulation. Deletion of T cells in the thymus following i.p. injection of OVA was associated with T cell pre-activation as demonstrated by T cell proliferation and cytokine production. Injection of CTLA-4-Ig blocked all these activation events and rescued thymocytes from activation-induced cell death. These results demonstrate that B7 is required for the activation-induced cell death of MHC class II-restricted thymocytes in vivo.

Animals↗
PubMed2003

Transforming growth factor-beta- and Activin-Smad signaling pathways are activated at distinct maturation stages of the thymopoeisis.

Members of the transforming growth factor (TGF)-beta family play pivotal roles in the control of differentiation, proliferation and tolerance in peripheral T cells. Recently, they have been implicated in thymic selection, but their role is so far not well characterized. In the present study, we demonstrate that specific thymocyte populations are under the influence of either the TGF-beta and/or Activin pathway, and transduce signals into the nucleus via phosphorylated Smad2 (pSmad2). Thymocytes in the medulla and in the subcapsular zone expressed nuclear translocated pSmad2, a hallmark of active TGF-beta/Activin receptor signaling. When analyzed at the cellular level, the pSmad2(+) cells were confined to the double-negative (DN) and single-positive (SP) subpopulations. Moreover, the most immature DN thymocytes (CD44(+)CD25(-) and CD44(+)CD25(+)) expressed higher levels of pSmad2 compared to the more mature DN. In vitro stimulation demonstrated that pure CD44(+)CD25(-), CD44(+)CD25(+) and CD44(+)CD25(+) thymocytes respond to ActivinA, while the mature CD4(+) and CD8(+) SP thymocytes respond to TGF-beta stimulation measured as enhanced phosphorylation of Smad2. Double staining of pSmad2(+) cells with either the Activin type I receptor, ALK4, or the TGF-beta type I receptor, ALK5, demonstrated that pSmad2(+) DN cells exhibited high levels of immunoreactivity to ALK4 and moderate levels of immunoreactivity to the TGF-beta-responsive ALK5 receptor. In sharp contrast, the SP pSmad2(+) cells were predominately ALK5(+). Collectively, our results demonstrate that early and late thymocytes express pSmad2 in the nuclei in vivo. The functional experiments in vitro suggest that members of the TGF-beta family (TGF-beta or Activin) may play important non-redundant roles during different stages of thymopoiesis.

Activin Receptors, Type I↗
PubMed2004

Development of TCRB CDR3 length repertoire of human T lymphocytes.

The third complementarity-determining region (CDR3) of TCR interacts directly with antigenic peptides bound to grooves of MHC molecules. Thus, it is the most critical TCR structure in launching acquired immunity and in determining fates of developing thymocytes. Since length is one of the components defining the CDR3 heterogeneity, the CDR3 length repertoires have been studied in various T cell subsets from humans in physiological and pathological conditions. However, how the CDR3 length repertoire develops has been addressed only by a few reports, including one showing that CDR3 of CD4 thymocytes becomes shorter during thymic development. Here, we explored multiple regulations on the development of the TCRB CDR3 length repertoires in the thymus and the peripheral blood. CDR3 length spectratyping was employed to examine thymocyte and peripheral T cell populations for their CDR3 length repertoires. We have found that repertoire distribution patterns depend on use of the BV gene. The BV-dependent patterns were shaped during thymic selections and maintained in the peripheral blood. Differences in the mean CDR3 length among different BV subsets were seen throughout lymphocyte development. We also observed that CDR3 was shortened in both CD4 and CD8 thymocytes. Of note, the degrees of the shortening depended on the CD4/CD8 lineage and on use of the BV gene. When expansions of peripheral T cell clones are negligible, no obvious difference was seen between mature thymocytes and peripheral lymphocytes. Thus, the TCRB CDR3 length repertoires are finely tuned in the thymus before the lymphocytes emigrate into the peripheral blood.

Adolescent↗
PubMed2004

Changes in sensitivity of peripheral lymphocytes of autoimmune gld mice to FasL-mediated apoptosis reveal a mechanism for the preferential deletion of CD4-CD8-B220+ T cells.

During thymic selection 'mis-selected' CD8(+) T cells exit to the periphery where they are deleted by a Fas/FasL-mediated mechanism, presumably as a result of activation by self-antigens. In the absence of functional FasL, as is the case in autoimmune gld mice, these 'mis-selected' T cells develop into unique Thy1(+)CD4(-)CD8(-) TCRalphabeta(+)B220(+) lymphocytes [abnormal double negative T (DN T) cells]. Using bioactive FasL-bearing vesicles [FasL vesicle preparation (FasL VP)], we were able to induce acute apoptosis in freshly isolated lymphocytes and to demonstrate that peripheral lymphocytes of gld mice become more sensitive to the FasL-mediated apoptosis as they age. Furthermore, flow cytometric analyses indicated that within this peripheral lymphocyte population, the abnormal DN T cells were preferentially eliminated. The exquisite sensitivity of these abnormal DN T cells is attributed to their increased membrane Fas expression with a concomitant reduction of cytosolic FLIP(L). Our data support the hypothesis that specific components of the Fas-mediated apoptotic pathway are modulated in favor of the elimination of auto-reactive T cells as well as those CD8(+) T cells that are 'mis-selected' in the thymus and escape to the periphery.

Animals↗
PubMed1995

How are class II MHC genes turned on and off?

Fragments of foreign antigen are detected by CD4+ helper T cells via the T cell receptor for antigen in the context of major histocompatibility complex (MHC) class II molecules. Very few cells normally express class II MHC molecules, and these cells play critical roles in antigen presentation and in the thymic selection of T lymphocytes before their exit into the periphery. Because of the central role the class II MHC molecules play in immune system function, it is not surprising that the lack of expression of these molecules results in a severe combined immunodeficiency disorder (called bare lymphocyte syndrome) and that the aberrant expression of the molecules is frequently observed in the target organs of various autoimmune disorders (e.g., multiple sclerosis and rheumatoid arthritis). Because both classes of disease could conceivably be treated by molecular approaches targeted at either restoring or inhibiting expression of class II MHC genes, there has been an intense effort during the past decade to elucidate the regulatory mechanisms of class II MHC genes. An analysis of recent advances in this effort is provided in this review article.

Animals↗
PubMed1997

Pathogenesis and treatment of Sjögren's syndrome.

The criteria for diagnosis of primary Sjögren's syndrome continue to be controversial, leading to confusion in clinical practice and in the research literature. Among Sjögren's syndrome patients who fulfill the European criteria, only 15% of those would fulfill the San Diego criteria. This difference in disease classification leads to difficulty in evaluating clinical trials and in elucidating pathogenetic mechanisms, because different patient populations are evaluated. As a result of the ease and safety of minor salivary gland biopsy, Sjögren's syndrome serves as a prototype model to study the immunopathogenic features of a human organ-specific autoimmune disease. Critical features of pathogenesis include: 1) failure to "delete" autoimmune T cells at the level of thymic selection; 2) "homing" of autoimmune lymphocytes to salivary and lacrimal glands via high endothelial venules; 3) clonal expansion of autoimmune T cells in the glands; 4) upregulation of major histocompatibility antigens and adhesive molecules by epithelial cells in the glands; 5) secretion of proinflammatory cytokines by both lymphocytes and epithelial cells; 6) decreased neural innervation of the glands; 7) failure of residual glandular tissue express secretory functions; and 8) failure to remove autoimmune T cells by normal mechanisms of apoptosis. Each of these steps is regulated by cell-matrix interactions, cytokine and growth factor secretion, cell membrane receptor stimulation, "second" signals in the cytoplasm, and nuclear transcription factors. Recent studies on each of these steps in Sjögren's syndrome have suggested their role in pathogenesis and, consequently, their potential as sites for therapeutic intervention.

Antibodies, Viral↗
PubMed2003

Aspects of early lymphoid commitment.

In the past year, significant progress has been realized in understanding the molecular underpinnings of commitment to the lymphoid pathways of differentiation. Several new approaches of phenotypic identification have revealed early stages of lymphoid commitment, and recent new studies have provided additional information regarding the central role of Notch receptors and their ligands and modulators as important regulators of the T/B lineage decision. The identification of PU.1 as a transcriptional regulator of the interleukin-7 receptor has established one mechanism by which PU.1 regulates lymphoid development. Finally, two studies have provided insight into the mechanisms of thymic selection. Still to be resolved, however, is the question of whether the T lineage is specified in bone marrow or only after migration of multipotent progenitors to the thymus.

Animals↗
PubMed2006

Humanized transgenic mice expressing HLA DR4-DQ3 haplotype: reconstitution of phenotype and HLA-restricted T-cell responses.

Many autoimmune conditions have close genetic linkages to particular human histocompatibility leukocyte antigen (HLA) class II genes. With the aim of establishing a murine model of autoimmune disease, we have generated an HLA DR4-DQ3 haplotype transgenic (Tg) mouse that expresses a 440-kb yeast artificial chromosome harbouring DRA, DRB1*040101, DRB4*010301, DQA1*030101, DQB1*0302 and all the internal regulatory segments. This Tg mouse line was crossed to human CD4 (hCD4) Tg mice and endogenous class II knockout mice (I-A(o/o) and I-E(o/o)) lines to generate a DR4-DQ3.hCD4.IAE(o/o) Tg line. The Tg DR and DQ molecules are expressed on the physiological cell types in these animals, i.e. on most B cells (>85%), dendritic cells (DCs) and macrophages but not on T cells, with levels of expression comparable with those of human B cells (where DR > DQ expression). The DR4/DQ3 transgenes fully reconstituted the CD4 T-cell compartment, in both the thymus and the periphery, and the analysis of the T-cell receptor repertoire in the Tg mice confirmed that these class II molecules were able to mediate thymic selection of a broad range of Vbeta families. HLA DR4- and DQ3-restricted T-cell responses were elicited following immunization with known T-cell determinants presented by these molecules. Furthermore, the DR4-DQ3-restricted CD4(+) T cells conferred protective antibody-mediated immunity against an otherwise lethal infection with Salmonella enterica var. typhimurium. These new DR4-DQ3 Tg mice should prove to be valuable tools for dissecting the importance of this class II haplotype in autoimmune disorders like rheumatoid arthritis.

Animals↗
PubMed1986

Lymphocyte population kinetics in the mouse.

In a normal dynamic equilibrium, at least half of the peripheral T-cell pool is constituted by lymphocytes which have divided 24-48 h previously, and are therefore rapidly renewed. The renewal of peripheral T cells occurs partly by influx of cells from the thymus and, more importantly, by cell division at the periphery. The cyclic pattern of decay observed for T cells after HU treatment suggests the presence of progenitor-descendent relationships within the peripheral T-cell pool. Peripheral progenitors must contain both cycling and non-cycling cells to account for cell recovery after HU administration in ATx mice. T-cell production at the periphery involves both organized (spleen or lymph nodes) as well as non-organized lymphoid tissue (GALT). The latter may in fact provide the major contribution. Expansion of mature T lymphocytes contributes to clonal persistence at the periphery and to the choice of T-cell repertoires. The importance of post-thymic selection of T-cell repertoires is suggested by the considerable expansion potential revealed by peripheral T cells.

Animals↗
PubMed1987

Functional and molecular aspects of human T lymphocyte activation via T3-Ti and T11 pathways.

Two pathways of human lymphocyte activation are known to exist on T-lineage cells. The first involves the T-lymphocyte receptor for antigen (T3-Ti) which operates in conjunction with gene products of the MHC complex and is a molecular complex composed of 5 polypeptide chains. Both the 49KD alpha and 43KD beta chains are immunoglobulin-like and thus contain variable domains responsible for ligand binding. In contrast, the 20-25KD T3 gamma, delta and epsilon chains are monomorphic structures presumably involved in transmembrane signalling. The alpha and beta subunits are disulfide bonded to each other and held in noncovalent association with the T3 chains. The second pathway involves the 50KD T11 sheep erythrocyte binding protein. The T11 pathway is operational during early intrathymic ontogeny, prior to T3-Ti receptor expression. Under physiologic conditions, T3-Ti and T11 pathways appear to function in series with T11, representing a more "nuclear proximal" structure. However, each pathway, independently of the other, can activate the phosphoinositol cascade and lead to elevation in cytosolic free calcium. The latter is critical for transcriptional activation of the endogenous IL-2 gene. The ability of the T3-Ti complex to regulate T11-mediated activation is discussed with reference to its possible role in thymic selection.

Antigens, Surface↗
PubMed1992

No requirement for p56lck in the antigen-stimulated clonal deletion of thymocytes.

Activation of protein-tyrosine kinases (PTKs) is required for signal transduction during T cell activation, although the pathway used during thymic selection is unknown. An in vitro system was established in which T cell receptor transgenic thymocytes underwent clonal deletion in response to peptide antigen. The effects of two PTK-specific inhibitors, herbimycin A and genistein, on the clonal deletion of immature thymocytes and the activation of mature thymocytes were examined. Clonal deletion occurred while T cell activation was inhibited and when no p56lck activity was evident. Thus, p56lck is not required for the antigen-stimulated step of clonal deletion of immature thymocytes, and negative selection proceeds via a distinct pathway.

Animals↗
PubMed1989

Developmental biology of T cell receptors.

T cell receptors are the antigen-recognizing elements found on the effector cells of the immune system. Two isotypes have been discovered, TCR-gamma delta and TCR-alpha beta, which appear in that order during ontogeny. The maturation of prothymocytes that colonize the thymic rudiment at defined gestational stages occurs principally within the thymus, although some evidence for extrathymic maturation also exists. The maturation process includes the rearrangement and expression of the T cell receptor genes. Determination of these mechanisms, the lineages of the cells, and the subsequent thymic selection that results in self-tolerance is the central problem in developmental immunology and is important for the understanding of autoimmune diseases.

Animals↗
PubMed1999

Inactivation of misselected CD8 T cells by CD8 gene methylation and cell death.

Misselected CD8 cells that express T cell receptors (TCRs) that do not recognize class I major histocompatibility complex (MHC) protein can emerge from thymic selection. A postthymic quality control mechanism that purges these cells from the repertoire is defined here. The failure of mature CD8 cells to simultaneously engage their TCR and CD8 coreceptor triggers an activation process that begins with inhibition of CD8 gene expression through remethylation and concludes with up-regulation of surface Fas and Fas ligand and cellular apoptosis. Thus, inhibition of a death signal through continued TCR-CD8 coengagement of MHC molecules is a key checkpoint for the continued survival of correctly selected T cells. Molecular defects that prevent delivery of the death signal to mistakenly selected T cells underlie the expansion of double-negative T cells, which is the cellular signature of a subset of systemic autoimmune diseases.

Adoptive Transfer↗