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L A Matis

Publications and source records attributed to L A Matis.

At least 19 recordsLinked to original sources
PubMed1992

Mechanism of self-tolerance of gamma/delta T cells in epithelial tissue.

The present study examined mechanisms of tolerance for T cell receptor gamma/delta (TCR-gamma/delta) cells. Using a transgenic (Tg) model, we demonstrate that although alloantigen (Ag)-specific TCR-gamma/delta cells are deleted in the thymus and spleen of Ag-bearing mice, intraepithelial lymphocytes (IELs) expressing normal levels of the Tg TCR were present. However, Tg+ IELs from Ag-bearing mice were unresponsive to activation. Furthermore, self-reactive Tg+ IELs decreased in number over time. Thus, in epithelial tissue, Tg TCR-gamma/delta cells are eliminated subsequent to and most likely as a result of the induction of clonal anergy.

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PubMed1991

Profound alteration in an alpha beta T-cell antigen receptor repertoire due to polymorphism in the first complementarity-determining region of the beta chain.

Amino acid residues that are critical in maintaining the framework structure of immunoglobulin heavy- and light-chain variable (V) regions are strongly conserved in the V alpha and V beta proteins of the alpha beta T-cell antigen receptor (TCR alpha beta). Consequently, it has been proposed that TCR alpha beta has a conformation similar to that of an immunoglobulin Fab fragment and that the regions of the TCR homologous to the three immunoglobulin complementarity-determining regions (CDRs 1, 2, and 3) bind to the peptide antigen-major histocompatibility complex (MHC) molecule ligand. A single amino acid substitution in the predicted CDR1 of the V beta 3 protein of certain mouse strains dramatically altered TCR alpha beta usage in an antigen-specific MHC-restricted immune response but did not abrogate V beta 3 specificity for the superantigens minor lymphocyte stimulatory locus (Mls)c and staphylococcal enterotoxin A (SEA). The results confirm the importance of the V beta CDR1 in antigen-MHC molecule recognition, supporting the Fab-like structural model of TCR alpha beta, and provide further evidence that conventional antigen-MHC recognition and superantigen recognition are mediated by distinct regions of the TCR beta chain. They also suggest that allelic polymorphism may be a significant source of diversity in the TCR repertoire.

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PubMed1991

Requirement for positive selection of gamma delta receptor-bearing T cells.

The alpha beta and gamma delta T cell receptors for antigen (TCR) delineate distinct T cell populations. TCR alpha beta-bearing thymocytes must be positively selected by binding of the TCR to major histocompatibility complex (MHC) molecules on thymic epithelium. To examine the requirement for positive selection of TCR gamma delta T cells, mice bearing a class I MHC-specific gamma delta transgene (Tg) were crossed to mice with disrupted beta 2 microglobulin (beta 2M) genes. The Tg+beta 2M- (class I MHC-) offspring had Tg+ thymocytes that did not proliferate to antigen or Tg-specific monoclonal antibody and few peripheral Tg+ cells. This is evidence for positive selection within the gamma delta T cell subset.

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PubMed1991

Junctional sequences influence the specificity of gamma/delta T cell receptors.

T lymphocytes bearing the gamma/delta T cell receptor (TCR-gamma/delta) express a limited number of germline variable gene segments, generating receptor sequence diversity primarily through junctional mechanisms. To examine the role of V(D)J junctional sequences in antigen recognition by TCR-gamma/delta, we derived an alloreactive murine TCR-gamma/delta+ T cell line, LKD1, specific for the I-Ad class II major histocompatibility complex (MHC) molecule, and compared its receptor with that expressed by a previously characterized class II MHC alloreactive T cell line, LBK5, specific for I-Ek,b,s Ia molecules. Both LKD1 and LBK5 express receptors encoded by rearranged V gamma 1.2J gamma 2 and V delta 5D delta 2J delta 1 gene elements, differing in sequence only in the V(D)J junctional regions of the gamma and delta genes. These results demonstrate that junctionally encoded sequences corresponding to the putative third complementarity determining region can influence the antigen specificity of TCR-gamma/delta.

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PubMed1991

Control of self-reactivity in the intestine.

In the intestine maintenance of self-tolerance may involve tissue-specific self-Ags, APCs, 'second signals', and extrathymic pathways of T cell maturation. These factors combine to create a unique environment where autoimmune tissue destruction is prevented despite local inflammatory influences. In this review we summarize our findings using a TCR-gamma delta transgenic model where self-tolerance was maintained by clonal deletion for cells localizing to peripheral lymphoid tissue and by clonal anergy for cells localizing to the intraepithelial compartments. Several possible explanations exist for these results but in general, these findings have implications for the maintenance of self-tolerance of normal TCR-alpha beta and TCR-gamma delta IELs in epithelial tissues such as the intestine.

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PubMed1991

Repertoire development and ligand specificity of murine TCR gamma delta cells.

During the past several years, we have been studying the circulating TCR gamma delta cells expressed in peripheral lymphoid tissues. Biochemical and molecular characterization of the TCR gamma delta heterodimers present on these TCR gamma delta cells identified 3 TCR gamma proteins, V gamma 2-C gamma 1, V gamma 1.2-C gamma 2, and V gamma 1.1-C gamma 4. In addition, at least 6 different V delta gene products (V delta 2,4,5,6,V alpha 10, V alpha 11) are expressed in peripheral lymphoid tissue. Nucleotide sequence analysis has revealed a great deal of junctional diversity present among the different V gamma and V delta proteins. Thus, compared to other nonlymphoid tissues (e.g., skin), this population of TCR gamma delta cells appears quite extensive. The development and specificity of TCR gamma delta cells has been pursued by two approaches. First, different TCR gamma delta cells clones were generated which recognize MHC-encoded gene products. One clone recognizes an unconventional TL-encoded antigen, whereas others have been shown to recognize either classical MHC class I or class II antigens. The TCR gamma delta receptor genes have been cloned from the TL-specific TCR gamma delta cell and used to construct transgenic mice to examine the development of TCR gamma delta cells. Although the Tg+ TCR gamma delta cells are tolerized by thymic clonal tolerance similar to TCR alpha beta cells, the epithelial Tg+ TCR gamma delta cells are subjected to non-deletional tolerance (anergy). A second approach towards examining the development of TCR gamma delta cells has been to compare the repertoire of TCR gamma delta splenocytes in a variety of inbred and MHC-congenic strains of mice using subset-specific anti-murine TCR gamma delta mAb. The percentage of individual subsets of splenic TCR gamma delta cells differ widely between different inbred strains of mice due to both MHC- and TCR-encoded genetic differences. In summary, these studies provides a basis for understanding and determining the ligand(s) of the TCR gamma delta heterodimer and the factors which shape the peripheral TCR gamma delta repertoire.

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PubMed1991

Specificity of gamma delta receptor bearing T cells.

T cells expressing the gamma delta receptor heterodimer can recognize a broad array of different antigens, including classical and non-classical major histocompatibility complex (MHC) proteins, MHC-like CD1 antigens, and bacterial antigens such as the mycobacterial heat shock proteins and staphylococcal enterotoxins. Reactivity to self antigens including autologous stress proteins implicates TCR gamma delta T cells in autoimmune disease. It is as yet unclear whether the responses of gamma delta T cells specific for soluble proteins are restricted by conventional or non-classical MHC molecules. Correlations of TCR gamma delta usage with specificity suggest that, like TCR alpha beta, sequences encoded within both the V regions and the V(D)J junctions are important in determining receptor specificity.

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PubMed1990

In vivo induction of anergy in peripheral V beta 8+ T cells by staphylococcal enterotoxin B.

We have developed a model of peripheral in vivo T cell tolerance that is induced by administration of the protein superantigen staphylococcal enterotoxin B (SEB). Rather than activating V beta 8+ T cells, in vivo administration of SEB induced in them a profound state of anergy. This was shown by their failure to proliferate to subsequent in vitro restimulation with SEB or to anti-V beta 8 antibodies. This unresponsiveness was V beta 8 specific since T cells from SEB-immunized mice responded normally to other antigens. 8 d after SEB administration, there was no reduction in the number of V beta 8+ T cells or in the intensity of V beta 8 T cell receptor (TCR) expression. Although a portion of the V beta 8+ T cells from SEB-primed mice were able to express interleukin 2 receptors (IL-2Rs), they failed to proliferate in response to exogenous IL-2, indicating they were defective in their IL-2 responsiveness. 2-4 wk after SEB administration, there was a reduction of approximately 50% in the number of V beta 8+ cells in immunized compared with control animals. There was, however, no reduction in the level of TCR expression on the remaining V beta 8+ cells. These data demonstrate that proteins that activate T cells in vitro in a V beta-specific manner can induce a state of anergy in peripheral T cells in vivo and may possibly further mediate clonal deletion in a portion of the tolerized cells.

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PubMed1990

Molecular analysis of the influences of positive selection, tolerance induction, and antigen presentation on the T cell receptor repertoire.

Immunization of both B10.A and B10.S(9R) mice with pigeon cytochrome c (pcc) elicits T cells capable of proliferating to pcc presented on I-E major histocompatibility complex (MHC) molecules. The T cell receptor (TCR) repertoire used by pcc-specific T cells from these two strains is markedly different, even for T cells recognizing very similar antigen/MHC complexes. Our current studies have been directed toward explaining this differential expression between MHC congenic strains of TCR gene elements capable of recognizing similar ligands. Analysis of the TCR repertoire of pcc-specific T cells from F1[B10.A x B10.S (9R)]----parent radiation chimeras has demonstrated that much of this difference is a result of the positive selection of T cells for MHC restriction specificity. Further analysis of T cell lines from F1 mice and from radiation chimeras stimulated in vitro with pcc on both B10.A and B10.S(9R) antigen-presenting cells has provided clear-cut examples of the influence of positive selection, tolerance induction and of both in vivo and in vitro antigen presentation on the shaping of the TCR repertoire for a protein antigen. This is the first molecular analysis of how positive selection, tolerance induction, and antigen presentation can combine to mold the TCR repertoire.

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PubMed1990

Self-reactive gamma delta T cells are eliminated in the thymus.

The genes encoding a gamma delta T-cell receptor specific for a major histocompatibility complex class I molecule encoded by the TIa locus have been inserted into the mouse germ line. In mice that do not express the TIa-encoded determinant, transgenic gamma delta T cells are a functional component of the CD4-CD8- 'double-negative' T cells in the thymus and peripheral lymphoid organs. In mice that express the TIa-encoded determinant, there are no transgenic gamma delta T cells in peripheral lymphoid organs, and there are no thymocytes expressing normal levels of the transgenic gamma delta T-cell receptor.

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PubMed1990

The molecular basis of T-cell specificity.

Studies of TCR expression in antigen-specific immune responses have provided a large body of information correlating the primary structure of the TCR with specificity. Much has been learned regarding the mechanisms for the generation of TCR diversity and the selection of TCR V elements in immune responses. However, the exact nature of the trimolecular complex found during the TCR/antigen/MHC interaction awaits the structural characterization of the TCR by crystallography. Just as describing the three-dimensional structure of MHC molecules and defining their putative antigen-binding site have made it possible to interpret with fresh insight the wealth of functional data regarding antigen/MHC binding and alloreactivity, similar characterization of the TCR structure will allow more definitive interpretation of all the current data with respect to TCR usage in antigen-specific immune responses. It should also facilitate the study of the molecular basis of positive and negative TCR selection during thymic ontogeny. Finally, the identification of T-cell superantigens and their ability to stimulate T cells on the basis of TCR V beta expression alone has defined a new and distinct type of TCR/ligand interaction. The fact that bacterial products such as staphylococcal and streptococcal toxins as well as the mitogenic moiety produced by some mycoplasma are included within this class of antigens suggests that TCR recognition of superantigens may have major clinical significance. It is important to determine the structural basis of T-cell activation by these antigens.

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PubMed1989

Thymic requirement for clonal deletion during T cell development.

During T cell differentiation, self tolerance is established in part by the deletion of self-reactive T cells within the thymus (negative selection). The presence of T cell receptor (TCR)-alpha beta + T cells in older athymic (nu/nu) mice indicates that some T cells can also mature without thymic influence. Therefore, to determine whether the thymus is required for negative selection, TCR V beta expression was compared in athymic nu/nu mice and their congenic normal littermates. T cells expressing V beta 3 proteins are specific for minor lymphocyte stimulatory (Mlsc) determinants and are deleted intrathymically due to self tolerance in Mlsc+ mouse strains. Here it is shown that V beta 3+ T cells are deleted in Mlsc+ BALB/c nu/+ mice, but not in their BALB/c nu/nu littermates. Thus, the thymus is required for clonal deletion during T cell development.

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PubMed1989

The influence of self-MHC and non-MHC antigens on the selection of an antigen-specific T cell receptor repertoire.

We have examined the influence of self-Ag on TCR expression and specificity in the immune response to the Ag pigeon cytochrome c. Previous work has shown that most Ek-restricted cytochrome c-specific T cells from B10 background mice express TCR alpha beta-heterodimers encoded by V beta 3 and V alpha 11 genes, but that T cells expressing V beta 3 proteins are eliminated due to self-tolerance in Mls-2a mouse strains. Thus, EK-restricted cytochrome c-specific T cells from Mls-2a mice fail to express any V beta 3. In the current study the influence of self-MHC and non-MHC Ag on TCR usage in the immune response to cytochrome c was further examined. First, it was demonstrated that the absence of V beta 3 expression in Mls-2a mice does not alter Ir gene function. Specifically, Mls-2a/Eb haplotype V beta 3- [C3H.SW x B10.A(5R)]F1 mice were high responders to cytochrome c despite the fact that previous structure function analyses have shown a very close correlation between Eb-restricted cytochrome c recognition and V beta 3 expression. This demonstration of the plasticity of TCR expression suggests that relatively few Ir gene defects result from tolerance induced by self-Ag. We also examined differences in V alpha 11 expression among cytochrome c-specific T cells from various H-2k haplotype mouse strains. In particular, the low level of expression of V alpha 11 in cytochrome c-specific T cells from C57BR (H-2k) mice was shown not to be due to self-tolerance. Rather, evidence for limited strain polymorphism of V alpha 11 genes, plus the fact that cytochrome c-specific T cells from F1 hybrids between H-2k, Mls-2b identical C57BR and B10.BR mice express high levels of V alpha 11, suggested the possibility that the variable V alpha 11 usage in the cytochrome c-specific responses of these two strains reflected differences in positive selection during ontogeny by non-MHC non-Mls self-Ag.

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PubMed1989

Structure and specificity of a class II MHC alloreactive gamma delta T cell receptor heterodimer.

Two distinct CD3-associated T cell receptors (TCR alpha beta and TCR gamma delta) are expressed in a mutually exclusive fashion on separate subsets of T lymphocytes. While the specificity of the TCR alpha beta repertoire for major histocompatibility complex (MHC) antigens is well established, the diversity of expressed gamma delta receptors and the ligands they recognize are less well understood. An alloreactive CD3+CD4-CD8- T cell line specific for murine class II MHC (Ia) antigens encoded in the I-E subregion of the H-2 gene complex was identified, and the primary structure of its gamma delta receptor heterodimer was characterized. In contrast to a TCR alpha beta-expressing alloreactive T cell line selected for similar specificity, the TCR gamma delta line displayed broad cross-reactivity for multiple distinct I-E-encoded allogeneic Ia molecules.

Animals↗
PubMed1989

Phenotypic and functional analysis of murine CD3+,CD4-,CD8- TCR-gamma delta-expressing peripheral T cells.

Murine CD3+,CD4-,CD8- peripheral T cells, which express various forms of the TCR-gamma delta on their cell surface, have been characterized in terms of their cell-surface phenotype, proliferative and lytic potential, and lymphokine-producing capabilities. Three-color flow cytofluorometric analysis demonstrated that freshly isolated CD3+,CD4-, CD8- TCR-gamma delta lymph node cells were predominantly Thy-1+,CD5dull,IL-2R-,HSA-,B220-, and approximately 70% Ly-6C+ and 70% Pgp-1+. After CD3+,CD4-,CD8-splenocytes were expanded for 7 days in vitro with anti-CD3-epsilon mAb (145-2C11) and IL-2, the majority of the TCR-gamma delta cells expressed B220 and IL-2R, and 10 to 20% were CD8+. In comparison to CD8+ TCR-alpha beta T cells, the population of CD8+ TCR-gamma delta-bearing T cells exhibited reduced levels of CD8, and about 70% of the CD8+ TCR-gamma delta cells did not express Lyt-3 on the cell surface. Functional studies demonstrated that splenic TCR-gamma delta cells proliferated when stimulated with mAb directed against CD3-epsilon, Thy-1, and Ly-6C, but not when incubated with an anti-TCR V beta 8 mAb, consistent with the lack of TCR-alpha beta expression. In addition, activated CD3+,CD4-,CD8- peripheral murine TCR-gamma delta cells were capable of lysing syngeneic FcR-bearing targets in the presence of anti-CD3-epsilon mAb and the NK-sensitive cell line, YAC-1, in the absence of anti-CD3-epsilon mAb. Finally, activated CD3+, CD4-,CD8-,TCR-gamma delta+ splenocytes were also capable of producing IL-2, IL-3, IFN-gamma, and TNF when stimulated in vitro with anti-CD3-epsilon mAb.

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PubMed1989

Helper-independent CD8+ cytotoxic T lymphocytes express IL-1 receptors and require IL-1 for secretion of IL-2.

The purpose of this study was to examine the role of IL-1 on the activation of CD8+/CD4- class I-restricted helper cell-independent cytolytic T cell (HITc) clones known to produce IL-2 and proliferate in vitro after Ag stimulation with a Friend retrovirus-induced leukemia (FBL). The functional role of IL-1 in Ag-specific proliferation and IL-2 secretion was assessed by stimulating the T cell clones with FBL either in the presence or absence of macrophages (M phi), rIL-1, or rIL-2. Resting cloned HITc cells, purified from residual accessory cells, failed to proliferate in response to FBL alone, but proliferated in response to FBL plus M phi, rIL-1 or rIL-2. Stimulation with FBL alone in the absence of M phi or IL-1 was sufficient for induction of IL-2R expression, and rendered cells responsive to IL-2, but M phi or IL-1 were also required to induce production of IL-2. The activity of IL-1 was further examined by measuring the binding of [125I]rIL-1 alpha, which demonstrated that resting cloned HITc cells expressed IL-1R that increased in number after activation with Ag. This expression of IL-1R and requirement for IL-1 by CD8+ HITc was surprising because previous studies examining T cell populations after mitogen stimulation have not detected IL-1R on the CD8+ population. Therefore, the role of IL-1 in the activation of CD8+ CTL that do not secrete IL-2 after activation was assessed. By contrast to HITc, CD8+ CTL required exogenous IL-2 to proliferate in vitro and did not express IL-1R. These data demonstrate that the subset of CD8+ T cells responsible for IL-2 production express IL-1R and that triggering this receptor with IL-1 after Ag stimulation results in the production of IL-2 and subsequent proliferation.

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