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Biomedical subjects

L A Matis

Publications and source records attributed to L A Matis.

At least 73 records · Page 4Linked to original sources
PubMed1988

Expression of two distinct T cell receptor alpha/beta heterodimers by an antigen-specific T cell clone.

A cytochrome c-specific, MHC-restricted T cell clone with two complete rearrangements of the same V beta 1 gene element was shown to express two different TCR alpha/beta heterodimers. Antipeptide antisera specific for TCR C beta 1 and C beta 2 peptides each immunoprecipitated distinct disulfide-linked cell surface heterodimers. The clone was derived from immunized allogeneic chimeric mice, and displayed multiple Ia specificities, including the ability to recognize antigen in association with both I-Ek and I-Es Ia molecules, as well as alloreactivity to the I-Eb molecule. It will be important to determine whether each receptor contributes independently to the overall specificity of the clone.

Animals↗
PubMed1988

Structure and specificity of T cell receptor gamma/delta on major histocompatibility complex antigen-specific CD3+, CD4-, CD8- T lymphocytes.

Analyses of TCR-bearing murine and human T cells have defined a unique subpopulation of T cells that express the TCR-gamma/delta proteins. The specificity of TCR-gamma/delta T cells and their role in the immune response have not yet been elucidated. Here we examine alloreactive TCR-gamma/delta T cell lines and clones that recognize MHC-encoded antigens. A BALB/c nu/nu (H-2d)-derived H-2k specific T cell line and derived clones were both cytolytic and released lymphokines after recognition of a non-classical H-2 antigen encoded in the TL region of the MHC. These cells expressed the V gamma 2/C gamma 1 protein in association with a TCR-delta gene product encoded by a Va gene segment rearranged to two D delta and one J delta variable elements. A second MHC-specific B10 nu/nu (H-2b) TCR-gamma/delta T cell line appeared to recognize a classical H-2D-encoded MHC molecule and expressed a distinct V gamma/C gamma 4-encoded protein. These data suggest that many TCR-gamma/delta-expressing T cells may recognize MHC-linked antigens encoded within distinct subregions of the MHC. The role of MHC-specific TCR-gamma/delta cells in immune responses and their immunological significance are discussed.

Amino Acid Sequence↗
PubMed1988

Self-tolerance alters T-cell receptor expression in an antigen-specific MHC restricted immune response.

The influence of major histocompatibility complex (MHC) gene products on the T-lymphocyte alpha beta receptor (TCR) repertoire is well documented, but how specificity is also generated for a diverse array of foreign peptide antigens is unknown. One proposed mechanism is that the TCR repertoire is selected by the recognition of processed self-antigens bound to MHC molecules. Here, we examine the influence of non-MHC-encoded self-antigens on the TCR repertoire expressed in an antigen-specific immune response. Most pigeon cytochrome c-specific, Ek alpha Ek beta (Ek) Ia-restricted T cells from B10.A mice express a product of the V alpha 11 gene family in association with a V beta 3 gene-encoded protein. We therefore examined V alpha 11 and V beta 3 gene expression in cytochrome c-specific T-cell lines derived from various mouse strains with different non-MHC genetic backgrounds. T cells from several strains failed to express any V beta 3 due to tolerance induced by Mlsc-encoded self-antigens. Variable levels of V alpha 11 messenger RNA (mRNA) were expressed by antigen-specific T cells from all the strains. In one strain V beta 3 was expressed in the relative absence of V alpha 11. These results directly demonstrate that self-tolerance alters TCR gene usage in the immune response to a foreign antigen, and indicate that TCR V alpha and V beta proteins may, in part, be independently selected.

Animals↗
PubMed1988

Two distinct mechanisms account for the immune response (Ir) gene control of the T cell response to pigeon cytochrome c.

Previous experiments have demonstrated that the immune response of MHC congenic mice to pigeon cytochrome c is under Ir gene control. Expression of I-E-encoded gene products influences both the magnitude and fine specificity of the Th cell response to pigeon cytochrome c and phylogenetic derivatives. Results of those experiments implicate both determinant selection and repertoire selection as mechanisms of Ir gene control in this system. In this report we have compared the TCR expressed in pigeon cytochrome c-reactive Th cells from B10.A(I-Ek), B10.A(5R) (I-Eb), and B10.S(9R) (I-Es) mice. The B10.A(5R) strain is a low responder to pigeon cytochrome c, but in response to moth cytochrome c this strain produces T cells which respond to pigeon or moth cytochrome c on B10.A APC. These cells are phenotypically identical to the predominant clonal phenotype seen in the B10.A response to pigeon cytochrome c. In this report, we show that the B10.A and B10.A(5R) pigeon cytochrome c-reactive T cells express essentially identical T cell receptors. These results, coupled with recent studies reporting a relatively low affinity for I-Eb molecules by pigeon cytochrome c peptides compared with moth cytochrome c peptides, strongly argue that the immune response defect in the B10.A(5R) strain is due to a defect in Ag presentation (determinant selection). In contrast, B10.A and B10.S(9R) strains are high responders to pigeon cytochrome c. Both strains produce T cell clones which are capable of responding to cytochrome c presented by either B10.A or B10.S(9R) APC in vitro. We show that, even in T cells with this MHC restriction degeneracy, the TCR expressed in the two strains are different. Because the APC of both strains can clearly present the cytochrome c Ag, we conclude that the differential expression of the TCR in the responses is due to a T cell repertoire selection difference in the two strains. Thus, for the response to one Ag in three MHC congenic strains, there exists evidence that both determinant selection and repertoire selection can be mechanisms of Ir gene control of an immune response.

Amino Acid Sequence↗
PubMed1988

Selection of amino acid sequences in the beta chain of the T cell antigen receptor.

The induction of an immune response in mammals is initiated by specifically reactive T lymphocytes. The specificity of the reaction is mediated by a complex receptor, part of which is highly variable in sequence and analogous to immunoglobulin heavy- and light-chain variable domains. The functional specificity of the T cell antigen receptor is, however, markedly different from immunoglobulins in that it mediates cell-cell interactions via the simultaneous recognition of foreign antigens and major histocompatibility complex-encoded molecules expressed on the surface of various lymphoid and nonlymphoid cells. The relation between the structure of the receptor and its functional specificity was investigated by analyzing the primary sequences of the receptors expressed by a series of T lymphocyte clones specific for a model antigen, pigeon cytochrome c. Within this set of T lymphocyte clones there was a striking selection for amino acid sequences in the receptor beta-chain in the region analogous to the third complementarity-determining region of immunoglobulins. Thus, despite the functional differences between T cell antigen receptors and immunoglobulin molecules, analogous regions appear to be important in determining ligand specificity.

Amino Acid Sequence↗
PubMed1988

Influence of bone marrow-derived Ia-bearing cells on the selection of the T-cell repertoire.

We have presented the results of studies using chimeric animals to examine the role of distinct cell subsets in shaping the TCR repertoire. Examination of specificity and TCR expression in antigen-specific long-term T-cell lines derived from these chimeras suggests that bone marrow-derived APC play a role in the selection of T cells for MHC restriction during development, and also profoundly influence the expansion of the TCR repertoire following antigen priming. An understanding of the molecular mechanisms that govern TCR repertoire maturation may await the development of effective in vitro model systems of T-cell differentiation.

Animals↗
PubMed1988

The influence of MHC gene products on the generation of an antigen-specific T-cell repertoire.

We have previously described the B10.A pigeon cytochrome c-specific response in terms of clonal phenotypes and T-cell receptor (TcR) gene usage. All B10.A T-cell clones studied respond to antigen in association with syngeneic B10.A APCs and cross-react to antigen in association with one or two allogeneic variants of the I-E-encoded MHC molecules. In congenic strains of mice expressing these allogeneic MHC alleles [B10.A(5R) and B10.S(9R)], pigeon cytochrome c-specific T cells exhibit very similar MHC cross-reactivities. Our goal was to determine whether the same MHC cross-reactive T-cell clones were expressed in each appropriate strain, or whether each T-cell repertoire was unique. The results indicate that identical V alpha-J alpha and V beta-J beta combinations were expressed by the major pigeon cytochrome c-specific response phenotype in B10.A and B10.A(5R) mice. Previous functional data supports this overlap in expressed T-cell clones. B10.A and B10.S(9R) mice exhibit similar response phenotypes to pigeon cytochrome c but express distinctly different TcR genes. The results of these studies support the existence of at least two different mechanisms in determining MHC-linked immune response polymorphisms.

Animals↗
PubMed1988

Distinct mechanisms of c-myc and lymphokine gene expression in an antigen specific T cell clone.

Experiments were performed to examine the mechanisms regulating the expression of the c-myc gene and the IL-2 and interferon gamma (IFN-gamma) lymphokine genes in an antigen-specific murine T cell clone. IL-2 and the mitogenic lectin, concanavalin A (Con A), as well as the calcium ionophore ionomycin, in concert with phorbol ester, (PMA) enhanced c-myc gene transcription, but by distinct mechanisms as demonstrated by differential sensitivity to inhibition of protein synthesis and by transcriptional run-off assays using c-myc exon 1 and exon 2 probes. Induction of c-myc expression by IL-2, but not lectin or ionomycin plus phorbol ester, was inhibited in the presence of cycloheximide. IL-2 induced the transcription of both c-myc exons 1 and 2, whereas Con A primarily enhanced exon 1 to exon 2 transcriptional read-through. A direct relationship was observed between the level of early c-myc expression following IL-2 stimulation and the magnitude of the subsequent clonal proliferative response. Lymphokine gene expression was enhanced by Con A, but not by IL-2. Induction of the lymphokine genes in this T cell clone was under predominant post-transcriptional control and was sensitive to protein synthesis inhibition. Therefore, mitogenic lectins induce c-myc and lymphokine gene expression via different pathways.

Animals↗
PubMed1987

Adoptive chemoimmunotherapy of murine leukemia with helper T lymphocyte clones.

Antigen-specific syngeneic noncytolytic helper T lymphocyte clones were investigated for their ability to mediate successful adoptive chemoimmunotherapy (ACIT) of mice with established RBL5 tumors. Clone B10, specific for the viral coat m.w. 70,000 glycoprotein, could be rapidly activated in situ after local transfer with intact tumor cells in syngeneic hosts to produce a delayed-type hypersensitivity reaction. For ACIT, mice bearing 5-day-old tumors received cyclophosphamide followed by transfer of resting helper T lymphocyte clones with or without exogenous interleukin 2 (rIL-2). A single injection of clone B10 was effective in ACIT when followed by a short course of exogenous rIL-2. Alternatively, repeated injections of resting clone were also effective without exogenous rIL-2, suggesting that the major role for rIL-2 was prolongation of clone survival in vivo rather than activation of other effector cells. Clone F12, specific for a component of fetal calf serum, was not effective in ACIT either with or without rIL-2, even when administered under conditions known to result in clone activation. Thus, antigen-specific helper T lymphocyte clones are capable of activation and promotion of antitumor responses after adoptive transfer.

Animals↗
PubMed1987

The molecular basis of alloreactivity in antigen-specific, major histocompatibility complex-restricted T cell clones.

We have studied the relationship between major histocompatibility complex (MHC)-restricted antigen recognition and alloreactivity by examining T cell receptor (TCR) alpha and beta gene expression in cytochrome c-specific, Ek alpha:Ek beta (Ek)-restricted helper T cell clones derived from B10.A mice. The clones could be segregated on the basis of four distinct alloreactivity patterns. Clones cross-reactive for three different allogeneic la molecules (As alpha:As beta [As], Ab alpha:Ab beta [Ab], Ek alpha: Eb beta [Eb]) expressed the same V alpha and V beta gene segments, generating the distinct alloreactive specificities via unique V alpha-J alpha and V beta-D beta-J beta joining events. Ek alpha:Es beta (Es)-alloreactive B10.A clones expressed the same V alpha, J alpha, and V beta segments as an Es-restricted, Ek-alloreactive, cytochrome c-specific, H-2-congenic B10.S(9R) clone. This homology between TCRs mediating allorecognition of la molecules and recognition of the same la molecules as restriction elements associated with nominal antigen suggests that MHC-restricted recognition and allorecognition represent differences in the affinity of the TCR-MHC molecule interaction.

Animals↗
PubMed1987

Antigen-driven T cell clones can proliferate in vivo, eradicate disseminated leukemia, and provide specific immunologic memory.

The aim of the current study was to determine the ability of antigen-driven cloned helper cell independent cytotoxic T lymphocytes (HITc) to proliferate and to survive in vivo and to mediate tumor therapy. The HITc clone utilized (denoted 1.B6) was specifically cytolytic to FBL-3, a syngeneic Friend virus-induced murine leukemia. Activation in vitro (48 hr) with FBL-3 induced secretion of interleukin 2 (IL 2), expression of IL 2 receptors (IL 2R), and in vitro proliferation. These cells could be "rested" for several weeks without stimulation, which resulted in reduced expression of IL 2R; however, restimulation with antigen resulted in reinduction of IL 2R and proliferation. The ability of cloned HITc to proliferate and to survive in vivo was examined in cyclophosphamide (CY) pretreated donor mice congenic for the Thy-1 gene. Adoptively transferred cloned HITc could be found in large numbers, and were widely distributed in vivo 1 wk after transfer. In tumor therapy, 1.B6 cells when injected into a site of tumor (i.p.) and used as an adjunct to CY were effective against disseminated FBL-3. In this circumstance, cloned 1.B6 cells could be recovered from cured mice 125 days after transfer and were shown to specifically lyse tumor and proliferate in vitro in response to FBL-3. Thus as an adjunct to CY, tumor-specific cloned HITc are capable of eradicating disseminated leukemia, persisting long-term in vivo, and providing specific immunologic memory.

Animals↗
PubMed1987

Generation of diversity in T cell receptor repertoire specific for pigeon cytochrome c.

17 T cell clones and 3 T cell lines, specific for pigeon cytochrome c, were analyzed for fine specificity and rearranged T cell receptor (TCR) gene elements. Clones of similar fine specificities were grouped into one of four phenotypes, and correlations between phenotype differences and gene usage could be made. All the lines and clones rearranged a member of the V alpha 2B4 gene family to a limited number of J alpha regions. The beta chain was made up of one of three non-cross-hybridizing V beta regions, each rearranging to only one or two J beta s. The use of alternate V beta regions could be correlated with phenotype differences, which were manifested either as MHC- or MHC and antigen-specificity changes. In addition, the presence of alloreactivity, which defined a phenotype difference, could be correlated solely with the use of an alternate J alpha region. These observations were substantiated by prospective analyses of pigeon cytochrome c-specific T cell lines that were selected for alternate MHC specificity or alloreactivity and were found to express the correlated alpha and beta chain rearrangements. Previously, the TCR DNA sequences from two clones, each representing a variant of one phenotype, showed sequence differences only in the N regions of their TCR genes. Since only these two variants, using identical V alpha-J alpha and V beta-J beta gene elements, were repeatedly observed in this study, we would predict that the junctional diversity differences are selectable. In this T cell response, all the gene elements involved in the generation of diversity appear to be selected, and may therefore be important in the determination of TCR specificity. This high degree of receptor gene selection represents a fundamental difference from the diversity seen in several extensively analyzed antibody responses.

Animals↗
PubMed1986

Distinct signals are required for proliferation and lymphokine gene expression in murine T cell clones.

Experiments were performed to assess the capacity of lectin (Con A), ionomycin, phorbol ester (PMA), and recombinant IL 2 to mediate proliferation as well as the expression of cell surface IL 2 receptors, two lymphokine genes, IL 2 and IFN-gamma, and the c-myc proto-oncogene in cloned T cell populations. Stimulation of T cell clones with recombinant IL 2 resulted in proliferation and sustained expression of the c-myc cellular proto-oncogene, but did not induce the expression of mRNA for the lymphokines IFN-gamma and IL 2. In contrast, stimulation of cloned T cells with lectin alone induced significant IFN-gamma and IL 2 mRNA expression, up-regulation of the number of cell surface IL 2 receptors, and transient c-myc expression. Ionomycin alone was not a sufficient signal for lymphokine mRNA induction. The phorbol ester PMA alone induced neither proliferation nor lymphokine gene expression but potentiated lectin and ionomycin-mediated signals. We also performed experiments to examine whether the T cell response to extracellular stimuli was a function of the activation state of the cell. Reexposure of 48-hr antigen-activated cloned cells to identical stimuli revealed several differences. Low but significant levels of IFN-gamma mRNA were now also reinduced in activated clones cells in response to IL 2 or PMA alone. Activated cells were refractory to reinduction of IL 2 mRNA by any stimulus, which may reflect a physiologic mechanism to limit clonal expansion after antigenic stimulation. This could be partially reversed by restimulation with lectin in the presence of cycloheximide, suggesting a role for a labile protein repressor in the down-regulation of IL 2 mRNA expression. PMA alone induced an IL 2-independent proliferative response. We demonstrate that distinct signals are required for lymphokine gene expression vs cellular proliferation in cloned T lymphocyte populations, and that the capacity of extracellular stimuli to reinduce expression of lymphokine genes or to mediate cell proliferation is altered by prior activation.

Animals↗