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Biomedical subjects

D Mathis

Publications and source records attributed to D Mathis.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cellular and molecular changes accompanying the progression from insulitis to diabetes.

Insulin-dependent diabetes mellitus (IDDM) is not a disease of unbridled destruction. The autoimmune attack on pancreatic beta cells has two distinct stages - insulitis and diabetes - and progression of the former to the latter appears to be highly regulated. Identifying the factors controlling this transition has been difficult because it is a complex process that occurs non-universally and asynchronously. We have overcome these difficulties by coupling a simplified TCR transgenic (tg) model of IDDM and the immunosuppressive drug cyclophosphamide (CY). Young BDC2.5 TCR tg mice show insulitis but not diabetes; CY treatment provoked diabetes in 100% of animals with rapid, highly reproducible kinetics. This allowed a detailed temporal analysis of changes in cellular organization and cytokine gene expression within the lesion. The monokines IL-18, IL-12 and TNF-alpha were pivotal, their induction occurring almost immediately and their coordinate action being required for the onset of aggression. Other cytokines with direct toxicity for beta cells, including IL-1 -beta, IL-6 and IFN-gamma, were subsequently induced; in contrast, there was no cellular or molecular evidence of cell contact-mediated mechanisms of beta cell death.

Animals↗
PubMed1999

Inhibition of thymocyte positive selection by natural MHC: peptide ligands.

The 3A9 transgenic mouse line carries the rearranged TCR genes from a T cell hybridoma that recognizes hen egg lysozyme peptide 46-61 in the context of MHC class II Ak molecules. As expected, positive selection of immature 3A9 thymocytes to become mature CD4+ 8- T cells was efficient on the "selecting" CBA (H-2k) genetic background but not on the "non-selecting" C57BL/6 (H-2b) background. Surprisingly, positive selection was also inefficient on the CBA x C57BL/6 F1 background (H-2kb). We present evidence that expression of A(beta)b molecules on thymus epithelium (in conjunction with A(alpha)b or A(alpha)k molecules) inhibits the positive selection of 3A9 thymocytes mediated by A(alpha)k:A(beta)k complexes, in a process evocative of peptide antagonism of mature T cells.

Animals↗
PubMed1999

An influence of CD5 on the selection of CD4-lineage T cells.

Combining CD5-null, MHC-deficient and lineage-specific reporter animals, we have investigated the influence of CD5 on positive selection and the choice of CD4- versus CD8-lineage commitment on broad populations of thymocytes. CD5 has no obvious quantitative effect in wild-type mice. In mice lacking MHC class II molecules, however, increased numbers of transitional, class I-selected CD4+ CD8(int) CD3(hi) cells were positively selected in the absence of CD5. Importantly, they were committed to the CD4 lineage. Our results indicate that CD5 negatively regulates the differentiation of CD4-committed cells in suboptimal conditions, thus perhaps serving to tighten the correlation between restriction of the TCR and lineage choice.

Animals↗
PubMed1999

The arthritogenic T cell receptor and its ligand in a model of spontaneous arthritis.

OBJECTIVE: Spontaneous arthritis in the KRN transgenic mouse model is due to the autoreactivity of the transgenic T cell receptor (TCR) against Ag7 major histocompatibility complex (MHC) molecules, which leads to strong but incomplete clonal deletion. We sought to determine whether other stimuli triggering this receptor might provoke arthritis, whether the apparently systemic reactivity might have some joint-preferential component explaining the paradoxical arthritic phenotype, and whether the transgenic receptor was the only one required or whether other TCRs might be ferried along in a leaky tolerance process. METHODS: Crosses and radiation chimeras involving a panel of transgenic and knockout mouse lines were used. The reactivity of the KRN TCR was tested in carboxyfluorescein diacetate succinimidyl ester-transfer experiments and in crosses with transgenic or inbred mice expressing other molecules that stimulate the KRN receptor (the mls-1a superantigen, the Aalpha(k69)Abeta(k) mutant MHC molecule). The arthritogenic capacity of T cells expressing only the KRN TCR was tested by crossing to recombination-activating gene-knockout mice, and constructing bone marrow chimeras with precursors to these strictly monoclonal T cells. RESULTS: The data show that the KRN TCR itself is the only receptor needed. It needs to be triggered by the Ag7 molecule loaded with self-peptides in order to provoke arthritis, but there is no indication of preferential presentation of joint-derived peptides. CONCLUSION: Arthritis can be generated by systemic recognition of self-MHC-peptide complexes by autoreactive T cells. This triggers B lymphocytes to produce arthritogenic antibodies, without the involvement of joint-specific T cell targets.

Animals↗
PubMed1999

From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins.

Rheumatoid arthritis is a common and debilitating autoimmune disease whose cause and mechanism remain a mystery. We recently described a T cell receptor transgenic mouse model that spontaneously develops a disease with most of the clinical, histological, and immunological features of rheumatoid arthritis in humans. Disease development in K/BxN mice is initiated by systemic T cell self-reactivity; it requires T cells, as expected, but B cells are also needed, more surprisingly. Here, we have identified the role of B cells as the secretion of arthritogenic immunoglobulins. We suggest that a similar scenario may unfold in some other arthritis models and in human patients, beginning with pervasive T cell autoreactivity and ending in immunoglobulin-provoked joint destruction.

Adoptive Transfer↗
PubMed1999

Positive selection of thymocytes induced by gene transfer: MHC class II-mediated selection of CD8 lineage cells.

Recombinant adenovirus vectors are powerful tools for inducing de novo gene expression in vivo. Here we have exploited them to study the specificity of CD4/CD8 lineage commitment during thymocyte positive selection, transferring MHC class II genes directly into thymi of mice deficient in both class I and II molecules. Expression of class II molecules was induced on cortical stroma, provoking the selection of a large population of mature CD4(+)CD8(-) cells, as expected, but also of a significant number of CD4(-)CD8(+) cells. The latter constituted a diverse population, containing both immature precursors and, though less frequent, cells that were mature according to several criteria. CD4(-)CD8(+) cells appeared with the same kinetics as their CD4(+)CD8(-) counterparts, but tended to be more prevalent at early times or when thymocyte reconstitution was only modest. These observations, derived from a dynamic selection system, indicate that CD4/CD8 lineage commitment is not irredeemably linked to the class of MHC molecule driving positive selection, a conclusion most compatible with selective models of commitment.

Adenoviridae↗
PubMed1999

Different modes of pathogenesis in T-cell-dependent autoimmunity: clues from two TCR transgenic systems.

T lymphocytes constantly flirt with reactivity to self peptides, a price they pay for their ability to recognize foreign peptides presented by self-MHC molecules, and autoreactivity in the T compartment occasionally gives rise to autoimmune disease. Pathology from T-cell autoimmunity can manifest itself through radically different strategies, as we have observed recently in two transgenic models. In the BDC2.5 diabetes model, T cells express a transgene-encoded T-cell receptor (TCR) with reactivity against a pancreatic antigen. This leads to a massive, if often controlled, infiltration of the pancreatic islets. Target cell destruction then results from the local consequences of this local immune/inflammatory process. On the other hand, the arthritic manifestations of the KRN transgenic model are indirect: the transgenic TCR confers a broad autoreactivity, through which T cells stimulate B cells to produce arthritogenic immunoglobulins. These molecules are then sufficient to produce the disease, even in the complete absence of any lymphocytes. Although important questions subsist in this model--how the KRN T cells interfere with B-cell tolerance, what the target of arthritogenic IgG is--its implication is that an isolated T-cell dysregulation may manifest itself through an Ig-mediated disease.

Animals↗
PubMed1998

Visualization of CD4/CD8 T cell commitment.

A system to innocuously visualize T cell lineage commitment is described. Using a "knock-in" approach, we have generated mice expressing a beta-galactosidase reporter in place of CD4; expression of beta-galactosidase in these animals appears to be an accurate and early indicator of CD4 gene transcription. We have exploited this knock-in line to trace CD4/CD8 lineage commitment in the thymus, avoiding important pitfalls of past experimental approaches. Our results argue in favor of a selective model of thymocyte commitment, demonstrating a fundamentally symmetrical process: engagement of either class of major histocompatibility complex (MHC) molecule by a differentiating CD4(+)CD8(+) cell can give rise to T cell antigen receptor (TCR)hi thymocytes of either lineage. Key findings include (a) direct demonstration of a substantial number of CD4-committed, receptor/coreceptor-mismatched cells in MHC class II- deficient mice, a critical prediction of the selective model; (b) highly efficient rescue of such "mismatched" intermediates by forced expression of CD8 in a TCR transgenic line, and an explanation of why previous experiments of this nature were less successful-a major past criticism of the selective model; (c) direct demonstration of an analogous, though smaller, population of CD8-committed mismatched intermediates in class I-deficient animals. Finally, we found no evidence of a CD4 default pathway.

Animals↗
PubMed1998

Major histocompatibility complex class II molecules can protect from diabetes by positively selecting T cells with additional specificities.

Insulin-dependent diabetes is heavily influenced by genes encoded within the major histocompatibility complex (MHC), positively by some class II alleles and negatively by others. We have explored the mechanism of MHC class II-mediated protection from diabetes using a mouse model carrying the rearranged T cell receptor (TCR) transgenes from a diabetogenic T cell clone derived from a nonobese diabetic mouse. BDC2.5 TCR transgenics with C57Bl/6 background genes and two doses of the H-2(g7) allele exhibited strong insulitis at approximately 3 wk of age and most developed diabetes a few weeks later. When one of the H-2(g7) alleles was replaced by H-2(b), insulitis was still severe and only slightly delayed, but diabetes was markedly inhibited in both its penetrance and time of onset. The protective effect was mediated by the Abetab gene, and did not merely reflect haplozygosity of the Abetag7 gene. The only differences we observed in the T cell compartments of g7/g7 and g7/b mice were a decrease in CD4(+) cells displaying the transgene-encoded TCR and an increase in cells expressing endogenously encoded TCR alpha-chains. When the synthesis of endogenously encoded alpha-chains was prevented, the g7/b animals were no longer protected from diabetes. g7/b mice did not have a general defect in the production of Ag7-restricted T cells, and antigen-presenting cells from g7/b animals were as effective as those from g7/g7 mice in stimulating Ag7-restricted T cell hybridomas. These results argue against mechanisms of protection involving clonal deletion or anergization of diabetogenic T cells, or one depending on capture of potentially pathogenic Ag7-restricted epitopes by Ab molecules. Rather, they support a mechanism based on MHC class II-mediated positive selection of T cells expressing additional specificities.

Animals↗
PubMed1998

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes.

Evidence has been accumulating that shows that insulin-dependent diabetes is subject to immunoregulation. To determine whether cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is involved, we injected anti-CTLA-4 mAb into a TCR transgenic model of diabetes at different stages of disease. When injected into young mice, months before they would normally become diabetic, anti-CTLA-4 induced diabetes rapidly and essentially universally; this was not the result of a global activation of T lymphocytes, but did reflect a much more aggressive T cell infiltrate in the pancreatic islets. These effects were only observed if anti-CTLA-4 was injected during a narrow time window, before the initiation of insulitis. Thus, engagement of CTLA-4 at the time when potentially diabetogenic T cells are first activated is a pivotal event; if engagement is permitted, invasion of the islets occurs, but remains quite innocuous for months, if not, insulitis is much more aggressive, and diabetes quickly ensues.

Abatacept↗
PubMed1998

The phenotype of H-2M-deficient mice is dependent on the MHC class II molecules expressed.

For a broader view of the role of H-2M as an accessory molecule in antigen presentation, we investigated the degree to which different MHC class II isotypes and alleles depend on H-2M to function in vivo. We generated H-2M-deficient animals expressing Ek/b or Ak molecules in addition to the Ab molecules already present in the mutant strain, and compared the ability of the different MHC class II molecules to present antigen at the cell surface for recognition by T cells, and contribute to positive selection of CD4+ T cells in the thymus. Biochemical analyses were performed to assess MHC class II maturation, and to determine the peptide content of the molecules. In the absence of H-2M, Ek/b molecules contained a more heterogeneous set of class II-associated invariant chain peptides (CLIP) than Ab did, which, unlike Ab-CLIP complexes, were not SDS-stable. Unlike Ab molecules, both Ek/b and Ak efficiently presented exogenously added peptides to T cells in the absence of H-2M. In addition, epitopes from some proteins, especially those known to be invariant chain independent, were presented by Ak molecules in the mutant animals. To our surprise, expression of Ek/b overcame the positive selection defect observed in H-2M-deficient mice expressing Ab alone. In contrast, Ak expression did not augment positive selection of CD4+ T cells in the mutant animals. Some of these findings in vivo contrast significantly with findings from in vitro studies on murine MHC class II molecules in human DM-deficient cell lines.

Amino Acid Sequence↗
PubMed1998

CD4+ T cell responses in mice lacking MHC class II molecules specifically on B cells.

The role of B lymphocytes in initiating and maintaining a CD4+ T cell response has been examined using a variety of strategies, but remains controversial because of weaknesses inherent to each of the approaches. Here, we address this issue by measuring CD4+ T cell priming both in mutant mice devoid of B cells and in chimeric animals lacking major histocompatibility complex class II molecules specifically on B cells. We find that peptide and some protein antigens do not require B cells expressing class II molecules, nor B cells themselves, to efficiently prime. This could be demonstrated by the usual lymph node proliferation assay, a rather indirect in vitro measure of priming, and by a direct ex vivo assay of population expansion and activation marker expression. Interestingly, one protein antigen, conalbumin, could not prime in the absence of B cells, but could in the presence of B cells devoid of class II molecules. This finding constrains the possible mechanisms whereby B lymphocytes contribute to the initiation of a CD4+ T cell response, arguing against the importance of surface immunoglobulin-mediated antigen presentation by B cells.

Amino Acid Sequence↗
PubMed1998

Mice lacking the transcription factor CIITA--a second look.

We have generated a second line of mice lacking a transcription factor thought to be a critical regulator of MHC class II gene expression, CIITA (for class II transactivator). Our and the previously published lines differ in the deletion that was engineered and by the fact that we removed the neomycin-resistance promoter and structural gene via the cre-loxP recombination system. Characterization of our line led to two new findings. First, a substantial number of cells can express class II molecules in the absence of CIITA, albeit at 5-fold reduced levels, most notably dendritic cells in s.c. lymph nodes; therefore, the CIITA gene cannot be an absolute 'master gene' controlling the expression of class II molecules, as had been thought. Second, in contrast to recent results on human cell lines, CIITA is not critically involved in the IFN-gamma-induced up-regulation of MHC class I genes.

Animals↗
PubMed1998

CD4/CD8 lineage commitment: matching fate with competence.

The outcome of positive selection of T lymphocytes is that there is a close match between the lineage adopted by a particular cell (CD4+ or CD8+) and the specificity of the T-cell receptor for the class of Major Histocompatibility Complex molecule recognized. How this match is obtained has been a matter of debate. We review the evidence, from recent and older experiments, that indicates that the process follows a selective logic, rather than an instructive one.

Animals↗
PubMed1998

Interleukin-4 deficiency does not exacerbate disease in NOD mice.

To investigate the role of interleukin (IL)-4 in the regulation of autoimmune diabetes, we crossed the IL-4 knock-out mutation onto the NOD genetic background. This experiment was accelerated by typing for microsatellites linked to known diabetes susceptibility (Idd) loci, and included a control backcross of the wild-type 129/SvJ-derived IL-4 gene, the original target locus. We also crossed the mutation into the BDC2.5 transgenic line, a diabetes model that carries the rearranged T-cell receptor genes from a diabetogenic T-cell clone. The IL-4-null mutation did not accelerate or intensify insulitis in regular NOD mice or in the BDC2.5 transgenic model; it also had no effect on the timing or frequency of the transition to overt diabetes. These data indicate that IL-4 plays no required role in controlling the aggressiveness of murine diabetes.

Alleles↗