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PubMed1997

Long-lasting adenovirus transgene expression in mice through neonatal intrathymic tolerance induction without the use of immunosuppression.

The major barrier to the clinical application of adenovirus gene therapy for diseases that require stable transgene expression is the immunogenicity of recombinant adenovirus, which ordinarily limits the duration of its effects to a period of about 2 weeks. We postulated that tolerance to adenovirus could be induced and transgene expression could be prolonged if T lymphocytes underwent thymic selection in the presence of adenovirus antigens. Mice were inoculated in the thymus with a recombinant adenovirus containing the lacZ marker gene during the neonatal period at a time before T-cell maturation had occurred. When the virus was administered intravenously to these mice in adulthood, they were found to have an impaired adenovirus-specific cytotoxic T-lymphocyte response which allowed prolonged hepatic lacZ expression, for up to 260 days. The ability to achieve unresponsiveness to a recombinant adenovirus after inoculation of the thymus in neonates extends the paradigm of intrathymic tolerance induction. Furthermore, this model will enable the study of stable adenovirus transgene expression in vivo without the use of immunosuppression and ultimately may have clinical utility.

Adenoviridae↗
PubMed2005

The genetics of psoriasis and autoimmunity.

Psoriasis is an inflammatory/autoimmune disease and, as with many autoimmune diseases, is associated with alleles from the major histocompatibility complex (MHC). With psoriasis and autoimmune disease, the penetrance of the MHC-associated alleles is never 100%, even for monozygotic twins. This may be because development requires additional environmental and/or genetic modifiers or requires specific T-cell receptor arrangements. Families segregating single or multilocus susceptibility alleles other than the MHC have also been reported. Overlapping genetic locations of loci for different autoimmune diseases have been known for several years and are starting to reveal common genes or genetic variants. These include genes normally involved in preventing spontaneous T-cell activation or proliferation, immune synapse formation, or cytokine production via pathways such as those mediated by NFkappaB and those involved in thymic selection. Autoimmunity may also involve dysregulation of genes or pathways regulated by the RUNX family of transcription factors. RUNX is involved in hematopoietic cell development, development of T cells in the thymus, chromatin remodeling, and gene silencing. Hence, its effect on cells of the immune system may be due to variable changes in gene expression and could account for variable body surface involvement and waxing and waning of disease.

Autoantibodies↗
PubMed2005

Toward an understanding of NKT cell biology: progress and paradoxes.

Natural killer T (NKT) cells constitute a conserved T cell sublineage with unique properties, including reactivity for a synthetic glycolipid presented by CD1d, expression of an invariant T cell antigen receptor (TCR) alpha chain, and unusual requirements for thymic selection. They rapidly produce many cytokines after stimulation and thus influence diverse immune responses and pathogenic processes. Because of intensive research effort, we have learned much about factors promoting the development and survival of NKT cells, regulation of their cytokine production, and the means by which they influence dendritic cells and other cell types. Despite this progress, knowledge of the natural antigen(s) they recognize and their physiologic role remain incomplete. The activation of NKT cells paradoxically can lead either to suppression or stimulation of immune responses, and we cannot predict which will occur. Despite this uncertainty, many investigators are hopeful that immune therapies can be developed based on NKT cell stimulation.

Animals↗
PubMed1993

Gamma/delta cells.

Before TCR rearrangements, T cell progenitors are committed not only to the alpha beta and gamma delta T cell lineage but also to various subsets of both lineages. In the mouse, distinct gamma delta T cell subsets can develop in the fetal thymus, the adult thymus, or independently of a thymus, probably in intestinal epithelia. The two subsets that develop in the fetal thymus home to and are maintained throughout adult life in the skin and the mucosa of the uterus, vagina, and tongue. They are monospecific. This unusual restriction in receptor repertoires is the result of severe limitations in the generation of diversity in the fetal progenitors of these subsets and the thymic selection. After birth, one gamma delta T cell subset appears in the blood, spleen, and lymph nodes and one in the intestinal epithelia. The receptor repertoires of these subsets are characterized by the preferential usage of particular V gamma gene segments and extensive junctional diversity. Several murine and human gamma delta T cell clones have been shown to recognize classical MHC class I and class II proteins or MHC class I-like proteins, and in very few cases the presented peptides are known. We suspect that the various murine gamma delta T cell subsets interact with different antigen presenting cells which utilize different antigen presenting proteins and reside in different tissues. The function of gamma delta T cells remains unknown. Preliminary results of experiments with gene knock out mice which lack either alpha beta T cells or gamma delta T cells or both suggest that gamma delta T cells do not function as helper cells in humoral immune responses but may complement alpha beta T cells in the defense against various microorganisms.

Animals↗
PubMed1999

Superantigens are presented by and activate thymocytes from infants.

A high percentage of human fetal and postnatal thymocytes express MHC class II molecules. This raises the possibility that human thymocytes in early life are able to present peptides to other immature T cells and thereby initiate thymic selection of these cells. Here we address this question by exposing newly harvested infant thymocytes to superantigen (Sag) which binds to the T-cell receptor and to MHC class II chains outside the peptide binding groove. The results show that the thymocytes are able to present Sag and to be activated to proliferation as well as apoptosis by Sag presented by other thymocytes. The absence of responses to Sag with mutations in class II binding sites showed that class II molecules were necessary for the responses, and very low expression of class II molecules on CD4-8- cells indicates that the demonstrated T-cell/T-cell interactions are confined to T-cell receptor-positive CD4+8+, CD4+8-, and CD4-8+ cells. These latter subsets were shown to be able to present Sag to each other. These findings suggest that class II+ thymocytes may participate in the selection of self-restricted T cells during a critical period in the shaping of the human immune system.

Antigen Presentation↗
PubMed2005

Thymocyte stimulation by anti-TCR-beta, but not by anti-TCR-alpha, leads to induction of developmental transcription program.

Anti-T cell receptor (aTCR) antibody (Ab) stimulation of T cells results in TCR down-modulation and T cell activation. Differences in the effect of anti-alpha-chain and beta-chain Ab have been reported on thymocytes. Anti-beta-chain Ab but not anti-alpha-chain reagents cause long-term TCR down-modulation. However, both types of Ab result in TCR cross-linking and activate early steps in signal transduction. In this study, we show that TCR internalization and calcium flux, hallmarks of T cell activation, are similar with aValpha and aVbeta treatment. Therefore, we have compared the gene expression profiles of preselection thymocytes stimulated with these reagents. We find that aValpha treatment does not cause any significant change in gene expression compared with control culture conditions. In contrast, aVbeta stimulation results in numerous changes in gene expression. The alterations of expression of genes known to be expressed in thymocytes are similar to changes caused by positive thymic selection, suggesting that the expression of some of the genes without known roles in thymocyte development and of novel genes whose expression is found to be altered may also be involved in this process.

Animals↗
PubMed2005

E2F1-/- C57BL/6 mice overexpressing a human Bcl-2 transgene in B cells develop a mild autoimmune syndrome.

Bcl-2, besides having an anti-apoptotic function, delays cell cycle progression at G1 to S. Overexpression of Bcl-2 in B cells induces an autoimmune syndrome (AIS) in pro-autoimmune genetic backgrounds. E2F1, a member of the E2F transcription factors, controls cell cycle, but it also induces cell death. E2F1(-/-) mice show an altered negative thymic selection but a conserved peripheral tolerance. As a consequence, these mice do not develop autoimmunity. Our aim was to evaluate whether deregulation of both apoptosis and cell cycle alters the mechanisms of tolerance and induces an AIS. C57BL/6 E2F1(-/-) mice were crossed with C57BL/6 mice overexpressing a human Bcl-2 transgene in B cells to obtain E2F1(-/-) hbcl-2 Tg mice. These mice were followed for up to 15 months of age with bleedings every three months to obtain serum and whole blood. The production of an AIS was assessed by quantitation of serum anti-DNA antibodies, renal light microscopy, and direct immunofluorescence in search of immunoglobulin deposits. E2F1(-/-) hbcl-2 Tg mice developed an AIS characterized by anti-DNA autoantibody production with renal damage observed after the 9th month of age. The lesions consisted mainly on cellular proliferation and mesangial deposits, compatible with a mesangial glomerulonephritis. The composition of deposits was predominantly of IgA, followed by IgM and IgG. Despite the development of renal damage, the AIS observed did not induce an accelerated mortality. The coexistence of an altered B cell apoptosis, together with the lack of E2F1, induces a mild AIS in the non-autoimmune background of C57BL/6 mice.

Animals↗
PubMed2004

MHC class II gene expression is not induced in HPIV3-infected respiratory epithelial cells.

The major histocompatibility complex (MHC) class II transactivator (CIITA) typically is required for both constitutive and inducible expression of MHC class II genes. However, transcription of class II MHC genes has been observed in specific cell types (e.g., thymic epithelial cells) in CIITA-deficient mice as well as in specific situations (e.g., following viral infections or in natural killer [NK]/target cell interaction). These observations have been interpreted by some to indicate that a CIITA-independent pathway of class II gene expression might be germane to processes such as the acquisition of tolerance during thymic selection or in the evasion of immune surveillance by a subset of viruses. One of the most striking examples of CIITA-independent, inducible class II gene expression has involved the de novo expression of class II MHC molecules on respiratory epithelial cells following infection by human parainfluenza virus type 3 (HPIV3). We report here that despite careful analysis using multiple techniques, we have been unable to detect HPIV3-dependent, CIITA-independent (or CIITA-dependent) induction of class II MHC genes. Thus, whereas there may still be an intriguing role for CIITA-independent gene expression in facets of the immune response, this is unlikely to manifest in the analysis of HPIV3 infection of respiratory epithelial cells.

Animals↗
PubMed1996

Functions of CD40 and its ligand, gp39 (CD40L).

Initially, a role for the interaction between CD40, expressed on B cells, and gp39 (CD40L), expressed on activated T cells, has been defined in humoral immunity. CD40-CD40L interaction is an essential signal for B cell proliferation, expression of activation markers, immunoglobulin production, and isotype switching. CD40-CD40L interaction is also required for formation of B memory cells and germinal centers, and signaling through CD40 prevents apoptosis of germinal center B cells. Defective expression of CD40L in humans leads to an inability to produce isotypes other than IgM (hyper IgM syndrome), and to an absence of germinal centers. More recent evidence indicates an expansion of the role of the CD40-CD40L axis in cellular interactions beyond antibody formation. Induced expression of CD40 on monocytes can lead to CD40L-activated monocyte effector mechanisms. In addition, CD40-CD40L interactions are crucially involved in development of autoimmune disease in a number of animal models. CD40-CD40L interactions also impact on growth regulation of certain carcinomas. Manipulation of CD40L has also been used to develop novel strategies for long-term antigen-specific tolerization of peripheral T cells. Finally, the CD40-CD40L axis is involved in thymic selection. Following is a comprehensive overview of CD40L-CD40 interactions in physiological and pathogenic cellular responses and a discussion of the therapeutic ramifications of these interactions.

Animals↗
PubMed2005

Signaling pathways involved in glucocorticoid-induced apoptosis of thymocytes.

This review synthesizes recent insights on the signaling pathways triggered by glucocorticoids during apoptosis of thymocytes. Thymocyte apoptosis is a complex process, which is involved in thymic selection. Even if the main partners are identified, there still remain dark zones on the whole pathway and notably on the crosstalk between each signaling cascade. Glucocorticoids trigger thymocyte apoptosis by enhancing cyclin-dependent kinase 2 activity, downregulating the expression of antiapoptotic Bcl-2 proteins, and upregulating that of proapoptotic Bcl-2 proteins. These events result in mitochondrial alterations and subsequent caspase activation. Proteasome intervenes at various levels of the signaling cascades--for instance, degrading the glucocorticoid receptor or caspase inhibitory proteins. Changes in intracellular K+ and Ca2+ concentrations are involved in caspase and endonulease activation. All these effects are dependent on macromolecular synthesis. The only known non-genomic effect of glucocorticoids is an early production of sphingolipids (ceramide and sphingosine), which are involved in caspase activation independent of mitochondrial alterations. Externalization of phosphatidylserine, a process mediating phagocytosis of dying thymocytes, depends on pathways that diverge from those leading to nuclear apoptosis.

Animals↗
PubMed1999

Identification of peptides from autoantigens GAD65 and IA-2 that bind to HLA class II molecules predisposing to or protecting from type 1 diabetes.

Type 1 diabetes is a T-cell-mediated disease in which presentation of autoantigens to CD4+ T-cells is thought to play a crucial role. Polymorphism of HLA class II genes accounts for 50% of the genetic risk of contracting type 1 diabetes. HLA-DQ and -DR molecules predisposing to or protecting from type 1 diabetes have been identified, but the molecular basis controlling these associations is as yet undefined. Apart from distinct thymic selection of autoreactive T-cells by susceptible and protective HLA molecules, exclusive presentation of autoantigenic peptides by type 1 diabetes-predisposing HLA molecules or, alternatively, induction of regulatory T-cells by protective alleles are potential mechanisms for modification of type 1 diabetes risk by HLA polymorphism. As a first step in exploring the role of HLA molecules in autoantigen-specific cellular responses in type 1 diabetes, we have screened peptides covering the sequence of two major autoantigens targeted by humoral and cellular immune responses, GAD65 and islet associated-2 (IA-2), for binding to class II molecules. We developed a sensitive novel competition binding assay allowing us to measure peptide binding on intact cells to 10 HLA-DR and 4 HLA-DQ molecules. For all tested alleles, multiple peptides binding with high affinity were identified. We report clustering of binding peptides in the COOH-terminal regions of GAD65 and IA-2, as well as highly promiscuous binding patterns of some peptides. Our results demonstrate that most peptides derived from the GAD and IA-2 autoantigens can bind to both type 1 diabetes-predisposing and type 1 diabetes-protective HLA molecules, although some exceptions were observed. The binding inventory presented here for GAD and IA-2 peptides can be useful for mapping natural epitopes and predicting peptide-specific responses induced by preventive immunization.

Alleles↗
PubMed2003

Diabetes protection and restoration of thymocyte apoptosis in NOD Idd6 congenic strains.

Type 1 diabetes in the nonobese diabetic (NOD) mouse is a multifactorial and polygenic disease. The NOD-derived genetic factors that contribute to type 1 diabetes are named Idd (insulin-dependent diabetes) loci. To date, the biological functions of the majority of the Idd loci remain unknown. We have previously reported that resistance of NOD immature thymocytes to depletion by dexamethazone (Dxm) maps to the Idd6 locus. Herein, we refine this phenotype using a time-course experiment of apoptosis induction upon Dxm treatment. We confirm that the Idd6 region controls apoptosis resistance in immature thymocytes. Moreover, we establish reciprocal Idd6 congenic NOD and B6 strains to formally demonstrate that the Idd6 congenic region mediates restoration of the apoptosis resistance phenotype. Analysis of the Idd6 congenic strains indicates that a 3-cM chromosomal region located within the distal part of the Idd6 region controls apoptosis resistance in NOD immature thymocytes. Together, these data support the hypothesis that resistance to Dxm-induced apoptosis in NOD immature thymocytes is controlled by a genetic factor within the region that also contributes to type 1 diabetes pathogenesis. We propose that the diabetogenic effect of the Idd6 locus is exerted at the level of the thymic selection process.

Aging↗
PubMed1995

T cell development in CD3-zeta mutant mice.

Increasing evidence points to multiple pathways of T lymphocyte development. The well characterized thymus-dependent pathway gives rise to T cells bearing TCR alpha beta heterodimers and either CD4 or CD8 alpha beta co-receptors. T cells of this lineage populate peripheral lymphoid compartments including lymph nodes, spleen, skin, and Peyer's patches. By comparison, factors which govern extrathymic T cell development are poorly understood. A variety of experiments have shown that intestinal intraepithelial lymphocytes (IELs) develop outside of the thymic environment, e.g., in the gut of nude, SCID, and beta 2m-/- mutant mice, and after transplanting bone marrow or fetal liver cells into irradiated thymectomized adult mice. This review focuses on the role of the CD3-zeta subunit in the development of both thymically and extrathymically derived T cells as determined by gene-targeting experiments in mice. Data from these and other T cell-related mutations continue to define crucial stages in thymocyte differentiation. Most interestingly, CD3-zeta mutant mice contain a unique population of intestinal IELs that develops independently of thymic selective processes and expresses a novel TCR/CD3 complex.

Animals↗
PubMed1993

Post-thymectomy organ-specific autoimmunity: enhancement by cyclosporine A and inhibition by IL-2.

It has previously been shown that the administration of cyclosporine A to newborn mice results in the development of autoimmunity later in life. It has been proposed that the neonatal administration of cyclosporine A results in altered thymic selection or inhibition of the development of suppressor cells. In the present study, treatment of day 3 thymectomized C3H/HeN mice with cyclosporine A (20 mg/kg/day) for 9 d post surgery increased the prevalence of antigastric autoantibodies. In contrast, the administration of IL-2 (300-600 Units/g/day) for 7 days after thymectomy inhibited the development of antigastric antibodies. We hypothesize that CsA may act by causing transient lymphokine abnormalities in the extrathymic environment during the first few weeks of life which lead to the development of antigastric antibodies. In contrast to the inhibition of development of antigastric antibodies, the administration of a similar course of IL-2 produced only a transient suppression of diabetes in NOD mice. These results and other data suggest that diabetes in NOD mice is probably due to a different immunologic defect.

Animals↗
PubMed2026

Beyond Canonical Neoantigens: Emerging Technologies for Identification of Noncanonical Antigens and Implications for Personalized Cancer Vaccines.

Over the past decade, advances in sequencing technologies and computational pipelines enabled the development of personalized cancer vaccines (PCVs). Current PCV strategies primarily target cancer neoantigens generated by non-synonymous DNA mutations, which can result in altered amino acid sequences capable of eliciting tumor-specific immune responses. More recently, a distinct class of tumor-specific antigens (TSA), termed noncanonical or cryptic antigens, has emerged as an additional source of immunogenic targets. Unlike canonical neoantigens, noncanonical antigens typically cannot be identified by tumor/normal whole-exome sequencing, as they do not arise from classical DNA mutations. Instead, they are often associated with less well recognized and/or aberrant processes in the pathways from DNA to human leukocyte antigen (HLA)-presented peptides. Examples include transposable elements, circular RNA, translation of alternative open reading frames and/or long non-coding RNA, among others. Emerging evidence suggests that noncanonical antigens represent a substantial portion of the tumor-specific immunopeptidome and, similar to canonical neoantigens, are absent during thymic selection and can evade central tolerance and elicit T cell responses. Technological advances have increasingly facilitated the identification of noncanonical antigens. Long-read RNA sequencing reveals noncanonical transcripts by improving transcriptome assembly, while ribosome profiling provides genome-wide maps of actively translated regions, facilitating the discovery of peptides from aberrant translation events. Specialized molecular approaches enable enrichment and sequencing of circular RNAs, and immunopeptidomics using mass spectrometry allows for direct characterization of HLA-presented peptides. Together, these technological advances have led to an increasing interest in prioritizing and targeting noncanonical antigens in the next generation of PCVs. This review provides an overview of the diverse origins of TSAs beyond classical neoantigens and discusses emerging approaches that may enable the integration of these antigens in future clinical trials.

circular RNA↗
PubMed2001

Absence of CD43 fails to alter T cell development and responsiveness.

Genetic elimination of CD43 has been associated with increased T cell adhesiveness and T cell hyperresponsiveness to mitogens and alloantigens. Therefore, we investigated whether T cell development was perturbed in CD43-deficient mice by breeding CD43(null) mice with male Ag (Hy)-specific TCR-transgenic mice. Neither positive nor negative thymic selection of male Ag-specific T cells were affected by CD43 status. Furthermore, we did not observe a substantial or consistent hyperresponsive pattern in HY-CD43(null) lymph node cells compared with littermate HY-CD43(+/-) lymph node cells upon analysis of in vitro T cell stimulation with male Ag or mitogen. These observations challenged original conclusions associating absence of CD43 with T cell hyperresponsiveness and led us to re-examine this association. Reported phenotypes of CD43(null) mice have been based on mice with a mixed 129xC57BL/6 genetic background. To exclude a possible influence of genetic background differences among individual mice we analyzed CD43(null) littermates that had been back-bred onto the C57BL/6 background for seven to eight generations. We found that CD43(+) and CD43(null) littermates with the C57BL/6 background exhibited no differences in response to mitogen or alloantigen, thereby establishing that T cell hyperresponsiveness is not a general correlate of CD43 absence.

Animals↗
PubMed2001

Functional evidence that conserved TCR CDR alpha 3 loop docking governs the cross-recognition of closely related peptide:class I complexes.

The TCR recognizes its peptide:MHC (pMHC) ligand by assuming a diagonal orientation relative to the MHC helices, but it is unclear whether and to what degree individual TCRs exhibit docking variations when contacting similar pMHC complexes. We analyzed monospecific and cross-reactive recognition by diverse TCRs of an immunodominant HVH-1 glycoprotein B epitope (HSV-8p) bound to two closely related MHC class I molecules, H-2K(b) and H-2K(bm8). Previous studies indicated that the pMHC portion likely to vary in conformation between the two complexes resided at the N-terminal part of the complex, adjacent to peptide residues 2-4 and the neighboring MHC side chains. We found that CTL clones sharing TCR beta-chains exhibited disparate recognition patterns, whereas those with drastically different TCRbeta-chains but sharing identical TCRalpha CDR3 loops displayed identical functional specificity. This suggested that the CDRalpha3 loop determines the TCR specificity in our model, the conclusion supported by modeling of the TCR over the actual HSV-8:K(b) crystal structure. Importantly, these results indicate a remarkable conservation in CDRalpha3 positioning, and, therefore, in docking of diverse TCRalphabeta heterodimers onto variant peptide:class I complexes, implying a high degree of determinism in thymic selection and T cell activation.

Amino Acid Sequence↗
PubMed2002

Activation of APCs through CD40 or Toll-like receptor 9 overcomes tolerance and precipitates autoimmune disease.

Some autoreactive T cells normally escape thymic selection and persist in the periphery. This is true of myelin-reactive CD4(+) T cells, the effectors of experimental autoimmune encephalomyelitis (EAE) in laboratory animals and the presumed mediators of multiple sclerosis in humans. Nonetheless, most individuals do not succumb to autoimmune disease. There is growing evidence that while peripheral APCs stimulate immune responses against foreign Ags in the setting of tissue destruction and "danger," they actually maintain tolerance against self Ags under steady state conditions. We hypothesized that tolerance against candidate autoantigens could be reversed by activation of APCs via CD40 or Toll-like receptor 9 signaling. Adult SJL mice injected i.p. with a peptide fragment of proteolipid protein (a candidate autoantigen in multiple sclerosis) emulsified in IFA fail to mount lymphoproliferative or cytokine responses and are protected from EAE upon subsequent challenge with the Ag combined with adjuvants. Here we report that tolerized proteolipid protein-specific lymph node cells regain the ability to divide, differentiate along a Th1 lineage, and transfer EAE when reactivated in the presence of agonistic Abs against CD40 or CpG oligonucleotides. The effects of both anti-CD40 and CpG oligonucleotides are dependent upon induction of IL-12. Our findings suggest two mechanisms to explain the well-documented association between infectious illnesses and flare-ups of multiple sclerosis. Microbial pathogens could 1) release molecules that bind Toll-like receptors, and/or 2) stimulate microbe-specific T cells to express CD40 ligand, thereby licensing APCs that bear both microbial and autoantigens to break tolerance.

Abatacept↗