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D Mathis

Publications and source records attributed to D Mathis.

At least 109 records · Page 6Linked to original sources
PubMed1993

Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease.

How peptide-major histocompatibility complex (MHC) class II complexes are naturally generated is still unknown, but accumulating evidence suggests that unfolding proteins or long peptides can become bound to class II molecules at the dominant determinant before proteolytic cleavage. We have compared the immunogenicity of hen egg-white lysozyme (HEL) in nonobese diabetic (NOD), (NOD x BALB/c)F1, and E(d) alpha transgenic NOD mice. We find that a response to the subdominant ANOD-restricted determinant disappears upon introduction of an E(d) molecule, and is restored when scission of HEL separates this determinant from its adjoining, competitively dominant, E(d)-restricted determinant. This suggests that the E(d) molecule binds and protects its dominant determinant on a long peptide while captured neighboring determinants are lost during proteolysis. These results provide clear evidence for "determinant capture" as a mechanism of determinant selection during antigen processing and a possible explanation for MHC-protective effects in insulin-dependent diabetes mellitus.

Animals↗
PubMed1993

The major histocompatibility complex (MHC) Ea promoter: sequences and factors at the initiation site.

We have analysed the function of sequences in the TATA/initiator region of the promoter of Ea, a class II gene of the Major Histocompatibility Complex. We find that the Ea promoter contains an initiator element with a strong influence on transcription. We also find that the Ea promoter does contain a bona fide TATA box, which can be recognized by the TATA binding protein (TBP), and that TBP is required for transcriptional activity. For activity, TBP must be included within a larger TFIID complex, as Ea transcription in a heat-treated extract can be restored by immunopurified TFIID but not by TBP alone. On the other hand, the TATA motif can be eliminated without significantly affecting either the efficiency or the startsites of transcription. This suggests that TBP, even in this TATA-containing promoter, is held in place by other components of the initiation complex, regardless of its affinity for the underlying DNA.

Animals↗
PubMed1993

Following a diabetogenic T cell from genesis through pathogenesis.

Nonobese diabetic (NOD) mice spontaneously develop a disease very similar to type 1 diabetes in humans. We have generated a transgenic mouse strain carrying the rearranged T cell receptor genes from a diabetogenic T cell clone derived from a NOD mouse. Self-reactive T cells expressing the transgene-encoded specificity are not tolerized in these animals, resulting in rampant insulitis and eventually diabetes. Features of the disease process emphasize two so-called check-points, recognized previously in the NOD and human diseases but easily misinterpreted. Although NOD mice are protected from insulitis and diabetes by expression of the E molecule encoded in the major histocompatibility complex, the transgenics are not, permitting us to exclude some possible mechanisms of protection.

Amino Acid Sequence↗
PubMed1993

Mice lacking TdT: mature animals with an immature lymphocyte repertoire.

In adult animals, template-independent (or N) nucleotides are frequently added during the rearrangement of variable (V), diversity (D), and joining (J) segments of lymphocyte receptor genes, greatly enhancing junctional diversity. Receptor genes from adult mice carrying a mutation in the terminal deoxynucleotidyl transferase (TdT) gene have few N nucleotides, providing proof that this enzyme is essential for creating diversity. Unlike those from normal adults, receptor genes from adult mutant mice show extensive evidence of homology-directed recombination, suggesting that TdT blocks this process. Thus, switch-on of the TdT gene during the first week after birth provokes an even greater expansion of lymphocyte receptor diversity than had previously been thought.

Animals↗
PubMed1993

Another view of the selective model of thymocyte selection.

Thymocyte commitment to the CD4 helper versus CD8 cytotoxic lineage has not been satisfactorily established. Two models have been elaborated: one based on instruction, the other on selection. Most previous results support the instructive model, but our comparison of thymocyte differentiation in MHC class II-, class I- and double-deficient mice provides data challenging it. There exists a significant population of CD4 single positive cells in class II-deficient animals that is intermediate in maturity between CD4+CD8+ and end-stage CD4+CD8- thymocytes and is selected on class I molecules; an equivalent CD8+CD4- population occurs in class I-deficient animals. We propose a selective model entailing two TCR-MHC molecule engagements: the first provokes random down-modulation of either CD4 or CD8 and a degree of differentiation; the second, requiring participation of the appropriate coreceptor, permits end-stage differentiation.

Animals↗
PubMed1993

Mice lacking the MHC class II-associated invariant chain.

The invariant chain (li) has aroused much interest because of its close association with major histocompatibility complex (MHC) class II molecules. Various functions have been proposed for it; several of these have received experimental support, but most have not been definitively proven, owing largely to uncertainties inherent in the experimental systems employed. We have now generated a line of mice devoid of the invariant chain by introducing a drastic mutation into the li gene. Cells from mutant animals show aberrant transport of MHC class II molecules, resulting in reduced levels of class II complexes at the surface, and these do not have the typical compact conformation indicative of tight peptide binding. Consequently, mutant cells present protein antigens very poorly and mutant mice are deficient in producing and at negatively selecting CD4+ T cells.

Animals↗
PubMed1993

The level of N-region diversity in T cell receptors is not pre-ordained in the stem cell.

The alpha beta T cell repertoires of adults and neonates are distinctly different. For example, T cell receptors (TcR) from adult animals have substantial N-nucleotide addition at their V-D-J junctions while those from neonatal animals do not. This dichotomy reflects a rather abrupt change in expression of the terminal deoxynucleotidyl transferase (TdT) gene in thymocytes on day 4 after birth. We have asked whether this change is due to the differentiation of successive waves of stem cells harboring different potentials for TdT expression, a scenario like the one proposed to explain developmental regulation of gamma delta T cell repertoires. Reconstitution of adult severe combined immunodeficiency mice with either fetal liver or adult bone marrow precursors gave rise to T cells with substantial N-region diversity in their TcR, even at the earliest points of reconstitution. It is most likely, then, that the abrupt change in TdT gene expression in day 4 thymocytes is due to an environmentally induced switch-on.

Animals↗
PubMed1993

Environmental modulation of the autonomy of cytotoxic T lymphocytes.

The extent to which one compartment of the immune system depends on another for efficient function is important to establish to fully comprehend disease phenotypes arising from selective immunodeficiency. Just how much the major histocompatibility complex class I-restricted cytotoxic T cell responses depend on class II-restricted T cell help has been controversial. Using the influenza A virus system, we show that mice unable to make class II-restricted T cell responses due to an engineered defect in class II molecule expression are able to mount virtually normal cytotoxic responses when bred under specific-pathogen-free conditions. However, when exposed to the more diverse environmental challenges of a conventional breeding facility, a situation that more closely parallels immunodeficient states in man, they show impaired cytotoxic responses.

Amino Acid Sequence↗
PubMed1993

Graft rejection by T cells not restricted by conventional major histocompatibility complex molecules.

The appropriate crosses of mice lacking conventional major histocompatibility complex (MHC) class I or class II molecules generate single- and double-deficient offspring. These were used as donors for skin grafts across major plus minor, or just minor, histocompatibility differences. Surprisingly, in the two circumstances, there was a rapid rejection of grafts lacking both MHC class I and class II molecules. Rejection was mediated by thymically derived CD4+ T cells of the host. We provide evidence that these T cells recognize an unconventional ligand, capable of activating a pre-formed T cell compartment but incapable of positively selecting it. The existence of this unexpected rejection phenomenon should serve to caution those aiming to engineer "universal donor" cells by simply abrogating expression of MHC class I and class II molecules.

Animals↗
PubMed1993

Major histocompatibility complex class I molecules are required for the development of insulitis in non-obese diabetic mice.

An early step in the development of autoimmune diabetes is lymphocyte infiltration into the islets of Langerhans of the pancreas, or insulitis. The infiltrate contains both CD4+ and CD8+ T cells and both are required for progression to diabetes in non-obese diabetic (NOD) mice. It has been thought that the CD4+ lymphocytes are the initiators of the disease, the islet invaders, while CD8+ cells are the effectors, the islet destroyers. We question this interpretation because NOD mice lacking MHC class I molecules, hence CD8+ T cells, do not display even insulitis when expected.

Animals↗
PubMed1993

Transgenes and knock-outs in autoimmunity.

While there have not been any earth-shattering events during the past year relating to the use of germline manipulation in the study of autoimmunity, several new developments have brought interesting insights into the way the immune system deals (or fails to deal) with autoantigens. Several systems described recently have the potential to help us understand what makes an autoantigen, and what events lead to a pathogenic reaction.

Animals↗
PubMed1992

Regulation of N-region diversity in antigen receptors through thymocyte differentiation and thymus ontogeny.

The random addition of "N nucleotides" by terminal deoxynucleotidyltransferase (TdT) is an important component of the diversity of T-cell receptor genes. We have investigated the expression of TdT during thymocyte differentiation and thymus ontogeny. TdT gene transcripts are confined to immature thymocytes of the cortex, being down-regulated concomitantly with recombination-activating gene transcripts after positive selection of mature medullary T cells. According to in situ hybridization, TdT RNA is absent from the neonatal thymus, but it appears 3 to 5 days after birth, just before the appearance of significant N-region diversity in T-cell receptor junctional sequences but clearly after the thymus attains competence at clonal deletion.

Aging↗
PubMed1992

Evaluation of the functional equivalence of major histocompatibility complex class II A and E complexes.

Most mice display two conventional major histocompatibility complex class II isotypes, A and E. Several A+E- strains have been observed, but never any that are A-E+. Because of this and because of hints from several lines of functional analysis, it has been proposed that the two isotypes might not operate equivalently. This proposition has not been directly testable until now because of the lack of an E-only strain. We report the production of such mice, exploiting previously created class II-transgenic and class II-"knock-out" lines. A+E-, A-E-, and A-E+ littermates have been compared by a number of parameters. We find that E and A molecules are, for the most part, functionally equivalent. However, subtle differences are seen in their ability to engage CD4 molecules on immature thymocytes, and in the profile of receptors on T cells selected into the periphery.

Animals↗
PubMed1992

Intron-exon organization of the NF-Y genes. Tissue-specific splicing modifies an activation domain.

NF-Y is a highly conserved transcription factor which recognizes CCAAT motifs in a variety of genes. We report here the genomic organization of the genes encoding both subunits, which gives interesting clues about the functional organization of the proteins. We also report the existence of isoforms of NF-YA which result from differential splicing. These alternative splicing events map within a glutamine-rich activation domain and show a marked cell- and tissue-specific bias.

Amino Acid Sequence↗
PubMed1992

Evolutionary variation of the CCAAT-binding transcription factor NF-Y.

NF-Y is a CCAAT-specific transcription factor thought to be involved in the regulation of a variety of eukaryotic genes. It shows a striking sequence similarity with the yeast factor HAP2/3. In an attempt to trace back its evolutionary history, we succeeded in isolating NF-Y cDNA clones from a plant and from several species of vertebrates. The patterns of sequence conservation delineate potential functional domains: A central, highly conserved, domain likely responsible for DNA-binding and subunit interaction; more evolutionarily flexible flanking regions, in which variability is clustered, individualizing conserved glutamine or acidic amino-acids putatively involved in protein-protein contacts.

Amino Acid Sequence↗
PubMed1992

Why is clonal deletion of neonatal thymocytes defective?

A major mechanism for establishing tolerance to some murine self antigens is clonal deletion of self reactive T cells in the thymus. This mechanism is responsible for the near absence of T cells displaying particular T cell receptor (TcR) V beta in strains of mice that express the major histocompatibility complex class II E molecule and a protein encoded within the 3' open reading frame (ORF) of certain endogenous mammary tumor viruses (Mtv). However, clonal deletion does not operate in these same strains during the first few days after birth. This defect could be explained by a difference in any (or any combination of) the three elements involved: the T cell, the thymic stromal cell(s) or the antigen. We have explored these different possibilities and have come to the conclusion that a lack of antigen is the most likely explanation. Yet, neonatal and adult thymi have quite similar levels of messenger ribonucleic acid corresponding to Mtv 3' ORF.

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