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Biomedical subjects

L A Matis

Publications and source records attributed to L A Matis.

At least 37 records · Page 2Linked to original sources
PubMed1996

Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv.

Activation of the complement system contributes significantly to the pathogenesis of numerous acute and chronic diseases. Recently, a monoclonal antibody (5G1.1) that recognizes the human complement protein C5, has been shown to effectively block C5 cleavage, thereby preventing the generation of the pro-inflammatory complement components C5a and C5b-9. Humanized 5G1.1 antibody, Fab and scFv molecules have been produced by grafting the complementarity determining regions of 5G1.1 on to human framework regions. Competitive ELISA analysis indicated that no framework changes were required in the humanized variable regions for retention of high affinity binding to C5, even at framework positions predicted by computer modeling to influence CDR canonical structure. The humanized Fab and scFv molecules blocked complement-mediated lysis of chicken erythrocytes and porcine aortic endothelial cells in a dose-dependent fashion, with complete complement inhibition occurring at a three-fold molar excess, relative to the human C5 concentration. In contrast to a previously characterized anti-C5 scFv molecule, the humanized h5G1.1 scFv also effectively blocked C5a generation. Finally, an intact humanized h5G1.1 antibody blocked human complement lytic activity at concentrations identical to the original murine monoclonal antibody. These results demonstrate that humanized h5G1.1 and its recombinant derivatives retain both the affinity and blocking functions of the murine 5G1.1 antibody, and suggest that these molecules may serve as potent inhibitors of complement-mediated pathology in human inflammatory diseases.

Amino Acid Sequence↗
PubMed1995

Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation.

Prevention of hyperacute xenograft rejection in the pig-to-primate combination has been accomplished by removal of natural antibodies, complement depletion with cobra venom factor, or prevention of C3 activation with the soluble complement inhibitor sCR1. Although these strategies effectively prevent hyperacute rejection, they do not address the relative contribution of early (C3a, C3b) versus late (C5a, C5b-9) activated complement components to xenogeneic organ damage. To better understand the role of the terminal complement components (C5a, C5b-9) in hyperacute rejection, an anti-human C5 mAb was developed and tested in an ex vivo model of cardiac xenograft rejection. In vitro studies demonstrated that the anti-C5 mAb effectively blocked C5 cleavage in a dose-dependent manner that resulted in complete inhibition of both C5a and C5b-9 generation. Addition of anti-C5 mAb to human blood used to perfuse a porcine heart prolonged normal sinus cardiac rhythm from a mean time of 25.2 min in hearts perfused with unmodified blood to 79,296, or > 360 min when anti-C5 mAb was added to the blood at 50 micrograms/ml, 100 micrograms/ml, or 200 micrograms/ml, respectively. In these experiments, activation of the classical complement pathway was completely inhibited. Hearts perfused with blood containing the highest concentration of anti-C5 mAb had no histologic evidence of hyperacute rejection and no deposition of C5b-9. These experiments suggest that the activated terminal complement components C5a and C5b-9, but not C3a or C3b, play a major role in tissue damage in this porcine-to-human model of hyperacute rejection. They also suggest that targeted inhibition of terminal complement activation by anti-C5 mAbs may be useful in clinical xenotransplantation.

Acute Disease↗
PubMed1995

Monoclonal antibodies directed against human C5 and C8 block complement-mediated damage of xenogeneic cells and organs.

The hyperacute rejection (HAR) of xenotransplanted organs is initiated by the deposition of natural antibodies on donor endothelium followed by the activation of the recipient complement system, which rapidly destroys the graft. Studies of the role of activated complement in HAR have suggested that natural antibody as well as early (C3a, C3b) and late (C5a, C5b-9) activated complement components may contribute to cell activation and damage. Attenuation of HAR has been achieved by blockade of C3 activation with soluble CR1 or consumptive depletion of complement with cobra venom factor; however, similar studies using specific inhibitors of terminal complement components have not been described. To address the contribution of C5a and the membrane attack complex (C5b-9, MAC) to complement-mediated xenogeneic cell and organ damage, we utilized functionally blocking monoclonal antibodies directed against the human terminal complement components C5 and C8. Our data show that both anti-C5 and anti-C8 mAbs protect porcine aortic endothelial cells from membrane damage mediated by human C5b-9. Additionally, both the anti-C5 and anti-C8 mAbs blocked complement-mediated generation of membrane prothrombinase activity on porcine aortic endothelial cells challenged with human serum. To test the ability of these antibodies to attenuate antibody and complement-mediated damage of xenogeneic organs, an ex vivo model was developed wherein isolated rat hearts were perfused with human serum in the presence or absence of the anti-C5 and anti-C8 mAbs. Our data demonstrate that mAbs directed against human C5 and C8 prevented organ damage by human serum complement and suggest that these molecules may serve as potent inhibitors of HAR.

Animals↗
PubMed1995

Porcine vascular cell adhesion molecule (VCAM) mediates endothelial cell adhesion to human T cells. Development of blocking antibodies specific for porcine VCAM.

Vascular cell adhesion molecule (VCAM) is expressed on activated endothelial cells and binds to the alpha 4 beta 1 integrin receptor, very late antigen-4 (VLA-4), expressed on human lymphoid cells. Anti-VCAM mAbs have been shown to prolong allograft survival. To explore the role of porcine VCAM (pVCAM) in xenotransplantation, a recombinant secreted form of pVCAM (spVCAM) was expressed in 293-EBNA cells and purified by metal affinity chromatography. A human lymphoid cell line bound to spVCAM in a VLA-4-dependent manner. Using spVCAM as an immunogen, we developed three anti-pVCAM mAbs that reacted with cell surface pVCAM on porcine aortic endothelial cells (PAEC) but not to human VCAM on human umbilical vein endothelial cells. Pairwise interaction analysis indicated that these mAbs recognized distinct epitopes on pVCAM. Two anti-pVCAM mAbs, 2A2 and 3F4, inhibited the binding of Ramos cells to spVCAM, while the third, 5D11, did not. Similarly, mAbs 2A2 and 3F4 inhibited binding of Ramos cells or human peripheral blood T cells to activated PAEC. The extent of inhibition with mAbs 2A2 and 3F4 was comparable to the inhibition obtained with a blocking mAb to human VLA-4. These anti-pVCAM mAbs will provide a means to specifically block pVCAM in a xenograft setting and allow the determination of the role of pVCAM in a primary xenogeneic immune response.

Amino Acid Sequence↗
PubMed1995

Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease.

Activated components of the complement system are potent mediators of inflammation that may play an important role in numerous disease states. For example, they have been implicated in the pathogenesis of inflammatory joint diseases including rheumatoid arthritis (RA). To target complement activation in immune-mediated joint inflammation, we have utilized monoclonal antibodies (mAbs) that inhibit the complement cascade at C5, blocking the generation of the major chemotactic and proinflammatory factors C5a and C5b-9. In this study, we demonstrate the efficacy of a mAb specific for murine C5 in the treatment of collagen-induced arthritis, an animal model for RA. We show that systemic administration of the anti-C5 mAb effectively inhibits terminal complement activation in vivo and prevents the onset of arthritis in immunized animals. Most important, anti-C5 mAb treatment is also highly effective in ameliorating established disease. These results demonstrate a critical role for activated terminal complement components not only in the induction but also in the progression of collagen-induced arthritis and suggest that C5 may be an attractive therapeutic target in RA.

Animals↗
PubMed1995

Identification of Rlk, a novel protein tyrosine kinase with predominant expression in the T cell lineage.

The control of phosphorylation by protein tyrosine kinases represents an important regulatory mechanism in T cell growth, function, and differentiation. We have identified a 62-kDa murine protein tyrosine kinase predominantly expressed within the T cell lineage, which we have termed Rlk (for Resting lymphocyte kinase). rlk mRNA was found to be expressed in the fetal thymus as early as day 13 of embryonic development as well as in adult thymus and mature resting peripheral T cells. The sequence of rlk showed that it is most closely related to the subfamily of cytoplasmic tyrosine kinases that includes the Btk, Itk, and Tec proteins. However, Rlk differs from these kinases by virtue of its unique aminoterminal domain, which lacks a region of pleckstrin homology common to the other members of this protein subfamily. Examination of rlk abundance within different T cell subpopulations revealed preferential expression in Th1 relative to Th2 T cell clones, suggesting a possible role in signal transduction pathways that selectively regulate cytokine production in mature CD4+ T cell subsets. Rlk thus represents a novel cytoplasmic tyrosine kinase with potential functions in intrathymic T cell development and mature T cell signaling.

Amino Acid Sequence↗
PubMed1995

Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.

Complement activation contributes to the systemic inflammatory response induced by cardiopulmonary bypass. At the cellular level, cardiopulmonary bypass activates leukocytes and platelets; however the contribution of early (3a) versus late (C5a, soluble C5b-9) complement components to this activation is unclear. We used a model of simulated extracorporeal circulation that activates complement (C3a, C5a, and C5b-9 formation), platelets (increased percentages of P-selectin-positive platelets and leukocyte-platelet conjugates), and neutrophils (upregulated CD11b expression). to specifically target complement activation in this model, we added a blocking mAb directed at the human C5 complement component and assessed its effect on complement and cellular activation. Compared with a control mAB, the anti-human C5 mAb profoundly inhibited C5a and soluble C5b-9 generation and serum complement hemolytic activity but had no effect on C3a generation. Additionally, the anti-human C5 mAb significantly inhibited neutrophil CD11b upregulation and abolished the increase in P-selectin-positive platelets and leukocyte-platelet conjugate formation compared to experiments performed with the control mAb. This suggests that the terminal components C5a and C5b-9, but not C3a, directly contribute to platelet and neutrophil activation during extracorporeal circulation. Furthermore, these data identify the C5 component as a site for therapeutic intervention in cardiopulmonary bypass.

Antibodies, Monoclonal↗
PubMed1994

Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection.

The serious shortage of human organs available for transplantation has engendered a heightened interest in the use of animal organs (xenografts) for transplantation. However, the major barrier to successful discordant xenogeneic organ transplantation is the phenomenon of hyperacute rejection. Hyperacute rejection results from the deposition of high-titer preformed antibodies that activate serum complement on the luminal surface of the vascular endothelium, leading to vessel occlusion and graft failure within minutes to hours. Although endogenous membrane-associated complement inhibitors normally protect endothelial cells from autologous complement, they are species restricted and thus confer limited resistance to activated xenogeneic complement. To address the pathogenesis of hyperacute rejection in xenotransplantation, transgenic mice and a transgenic pig were engineered to express the human terminal complement inhibitor hCD59. High-level cell surface expression of hCD59 was achieved in a variety of murine and porcine cell types, most importantly on both large vessel and capillary endothelium. hCD59-expressing porcine cells were significantly resistant to challenge with high-titer anti-porcine antibody and human complement. These experiments demonstrate a strategy for developing a pig-to-primate xenogeneic transplantation model to test whether the expression of a human complement inhibitor in transgenic pigs could render xenogeneic organs resistant to hyperacute rejection.

Animals↗
PubMed1994

Molecular and functional analysis of porcine E-selectin reveals a potential role in xenograft rejection.

In this study, we report the molecular and functional characterization of porcine E-selectin. Incubation of porcine endothelial cells with human TNF alpha but not human IL-1 resulted in a marked increase in binding to human neutrophils. In order to confirm that this interaction was mediated by E-selectin, we isolated the full-length porcine E-selectin cDNA which contained an open reading frame encoding 485 amino acids with 75% identity to human E-selectin. Expression or recombinant porcine E-selectin in COS cells resulted in surface expression of the protein and increased binding to human neutrophils. Northern blot analysis showed that treatment of porcine endothelial cells with human TNF alpha but not human IL-1 resulted in high levels of porcine E-selectin mRNA. Taken together, our data establish that porcine E-selectin mediates adhesive interactions between porcine endothelial cells and human leukocytes that may contribute to xenograft rejection.

Amino Acid Sequence↗
PubMed1994

Evidence that activation of human T cells by porcine endothelium involves direct recognition of porcine SLA and costimulation by porcine ligands for LFA-1 and CD2.

In this study we present a comprehensive evaluation of the molecular interactions between human T cells and porcine aortic endothelial cells (PAEC) that contribute to human T cell activation. Binding assays demonstrated that porcine erythrocytes (E) and PAEC express ligand(s) for the human T cell glycoprotein CD2. Prior incubation of human T cells with a blocking monoclonal antibody directed against CD2 (alpha CD2-BL) completely inhibited T cell/E and T cell/PAEC interaction. Xenogeneic mixed lymphocyte reactions (XMLR) revealed that human PBMC, or highly purified T cells were activated by PAEC in the absence of human antigen-presenting cells (APC). Addition of alpha CD2-BL or alpha LFA-1 to these assays inhibited PAEC-mediated human T cell activation. Furthermore, we demonstrated that highly purified human CD4+ and CD8+ T cells proliferated in response to PAEC and that this response was blocked by monoclonal antibodies directed against LFA-1 and CD2. Addition of alpha SLA class I blocked the proliferation of CD8+ but not CD4+ T cells, indicating direct presentation of SLA class I antigens to human T cells. We have recently shown that expression of the human complement inhibitor (CD59) on PAEC (PAEC-LXSNCD59) rendered these cells resistant to human complement-mediated activation and lysis, suggesting that human CD59 expression on PAEC could be an effective therapy for hyperacute rejection (HAR). However, recent studies have shown that in addition to its role as a complement inhibitor, CD59 binds human T cell CD2 and contributes to T cell activation. We therefore examined whether human CD59 expression on PAEC augmented the human antiporcine T cell response. We demonstrated that human T cells do not display increased binding to or activation by PAEC-LXSNCD59 relative to PAEC controls. Taken together, our data establish that PAEC directly stimulate human T cells in vitro and that interactions between the human accessory molecules CD2, LFA-1 and their PAEC surface ligands contribute to human T cell activation. In addition, the expression of human CD59 on porcine donor organs may confer resistance to human complement-mediated HAR without exacerbating the human antiporcine cellular response.

Animals↗
PubMed1994

Ntk: a Csk-related protein-tyrosine kinase expressed in brain and T lymphocytes.

The activity of Src-related protein-tyrosine kinases is repressed by the phosphorylation of a conserved carboxyl-terminal tyrosine by another cytoplasmic protein-tyrosine kinase termed p50csk. In this study, we characterize Ntk, a protein-tyrosine kinase bearing striking similarities to p50csk. Like p50csk, Ntk possesses Src homology 3 and Src homology 2 domains and lacks the consensus tyrosine phosphorylation and myristoylation sites found in members of the Src family. Expression of ntk transcripts was maximal in brain, and was observed at significant levels in thymus and spleen. ntk RNA levels were dramatically reduced upon mitogenic stimulation of normal T lymphocytes and were minimal in transformed T-cell populations. Firm evidence that Ntk is a Csk-related enzyme was provided by the observation that it phosphorylated a Src-related polypeptide on the inhibitory carboxyl-terminal tyrosine. These findings indicate that Ntk is a Csk-related enzyme that may play an inhibitory role in the control of T-cell proliferation.

Amino Acid Sequence↗
PubMed1994

Tissue-specific expression of messenger RNAs encoding endogenous viral superantigens.

The minor lymphocyte stimulating (MLS) superantigens of mice are encoded by open reading frames (ORFs) in the 3' long terminal repeats (LTRs) of endogenous mouse mammary tumor viruses. By stimulating all T cells bearing particular TCR V beta proteins, these viral superantigens (v-SAGs) exert profound effects on T cell development and function. We have examined expression of the 1.7 kb mRNA product predicted to encode v-SAG proteins in different cells and tissues of the immune system. The LTR-ORF mRNA was expressed in activated B cells and activated mature CD8 but not CD4 T cells, consistent with previous functional studies assessing MLS activity in these cell types. Little or no message was detected in thymic epithelial cells, macrophages, or dendritic cells, although low levels could be observed in thymic epithelium after southern hybridization to PCR-amplified cDNA. LTR-ORF mRNA was also expressed in immature CD4-CD8- and CD4+CD8+ thymocytes, suggesting selective down-regulation of expression in the T cell lineage after differentiation to the CD4+ phenotype. Thus, among cells of the immune system, v-SAG encoding mRNA is expressed predominantly within the lymphoid lineage.

Amino Acid Sequence↗
PubMed1994

Interactions of p59fyn and ZAP-70 with T-cell receptor activation motifs: defining the nature of a signalling motif.

The tyrosine-based activation motif is a 20- to 25-amino-acid sequence contained in the cytoplasmic domains of many hematopoietic receptors which is sufficient by itself to reconstitute signalling. This motif is characterized by two YXXL/I sequences separated by approximately 10 residues. The molecular basis of signalling by this motif is unknown. Here we demonstrate that the tyrosine-based activation motif is required and sufficient for association with the tyrosine kinases p59fyn and ZAP-70, suggesting that association with these kinases is a general feature of this motif. Focusing on the single activation motif present in epsilon, we analyzed which residues of the motif were critical for binding of p59fyn and ZAP-70. Surprisingly, we found that no single mutation of any residue of epsilon resulted in the loss of p59fyn association. In contrast, single mutations at five residues of the epsilon activating motif abrogated ZAP-70 binding. Both of the tyrosines and the leucine or isoleucine residues that follow them were critical. The spacing between the tyrosines was also important, as deletion of two residues disrupted binding of ZAP-70, although p59fyn binding was not disrupted. Most of the defined features of the tyrosine activation motif are therefore requirements for ZAP-70 binding. Interestingly, the interaction of ZAP-70 with the motif was dependent on the presence of both ZAP-70 SH2 domains and both of the tyrosine residues in the motif, suggesting that ZAP-70 interacts with two phosphotyrosine residues and that the binding of the two SH2 domains is cooperative. In addition, we demonstrate that the interaction between the tyrosine activation motif is direct and requires prior tyrosine phosphorylation of the motif. We propose that the activation of cells by the tyrosine activating motif occurs in four discrete steps: binding of p59fyn, phosphorylation of the motif, binding of ZAP-70, and activation of ZAP-70 kinase activity.

Amino Acid Sequence↗
PubMed1994

Two distinct protein isoforms are encoded by ntk, a csk-related tyrosine protein kinase gene.

Recently, we and others have cloned cDNAs encoding a second member of the Csk family of inhibitory tyrosine protein kinases, which we have termed Ntk. Intriguingly, the mouse ntk cDNA sequences published by two independent groups differed by the presence or absence of a 136 nucleotide-insert near their 5' ends. In this report, we demonstrate that this 136 nucleotide-sequence likely corresponds to a complete exon in the ntk gene (termed exon 2), and that the two types of cDNAs/transcripts are produced by alternative splicing. Using ribonuclease protection assays, it was also established that brain and lymphoid organs, as well as most hemopoietic cells, predominantly expressed ntk transcripts lacking exon 2. In contrast, selected hemopoietic cell lines, such as the immature myeloid cell lines 32D cl3(G) and WEHI-3B, exclusively possessed exon 2-bearing RNAs. Interestingly, exon 2 introduced a novel in-frame upstream AUG in the ntk transcript, which is in the appropriate context for translation initiation. Evidence was obtained that this AUG is utilized in vivo, and that it extends the amino-terminal sequence of Ntk by 40 amino acids. Indeed, while exon 2-deficient ntk RNAs were translated into a 52 kilodalton (kDa) polypeptide (p52ntk), those bearing exon 2 produced a 56 kDa protein (p56ntk). Furthermore, p56ntk, but not p52ntk, was recognized by an antiserum directed against the novel amino-terminal sequence encoded by exon 2. Additional biochemical characterizations showed that p52ntk and p56ntk were localized to the cytoplasm, and that they partially accumulated in the detergent-insoluble cellular fraction. This last finding suggested that the Ntk proteins can associate with the cytoskeleton. Finally, through linkage analysis of two multilocus crosses, the ntk gene was mapped to Chromosome 10 in the mouse. Taken together, these data showed that ntk, a csk-related tyrosine protein kinase gene, encodes two protein isoforms expressed in distinct cell types. Moreover, they raised the possibility that Ntk may be involved in the regulation of Src-like enzymes in detergent-insoluble cellular compartments.

3T3 Cells↗
PubMed1993

Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling.

Clonal activation of CD4+ and CD8+ T lymphocytes depends on binding of peptide-major histocompatibility complex (MHC) molecule complexes by their alpha/beta receptors, eventually resulting in sufficient aggregation to initiate second messenger generation. The nature of intracellular signals resulting from such T cell receptor (TCR) occupancy is believed to be independent of the specific structure of the ligand being bound, and to vary quantitatively, not qualitatively, with the concentration of ligand offered and the affinity of the receptor for the peptide-MHC molecule complex. In contrast to the expectations of this model, the analysis of the response of a T helper type 1 clone to mutant E alpha E beta k molecules in the absence or presence of a peptide antigen revealed that peptide inhibited the interleukin 2 (IL-2) response to an otherwise allostimulatory mutant form of this MHC class II molecule. The inhibition was not due to competition for formation of alloantigen, it required TCR recognition of peptide-mutant MHC molecule complexes, and it decreased IL-2 production without affecting receptor-dependent IL-3, IL-2 receptor alpha, or size enlargement responses. This preferential reduction in IL-2 secretion could be correlated with the costimulatory signal dependence of this cytokine response, but could not be overcome by crosslinking the CD28 molecule on the T cell. These results define a new class of TCR ligands with mixed agonist/antagonist properties, and point to a ligand-related variation in the quality of clonotypic receptor signaling events or their integration with other signaling processes. It was also found that a single TCR ligand showed greatly different dose thresholds for the elicitation of distinct effector responses from a cloned T cell population. The observations that changes in ligand structure can result in qualitative alterations in the effects of receptor occupancy and that quantitative variations in ligand density can be translated into qualitative differences in T cell responses have important implications for models of intrathymic selection and control of the results of active immunization.

Amino Acid Sequence↗
PubMed1993

Phenotypic and functional analysis of positive selection in the gamma/delta T cell lineage.

Recent evidence suggests that T cells expressing gamma/delta antigen receptors (T cell receptor [TCR]) are subject to positive selection during development. We have shown that T cells expressing a class I major histocompatibility complex (MHC)-specific gamma/delta TCR transgene (tg) are not positively selected in class I MHC-deficient, beta 2-microglobulin (beta 2m) gene knockout mice (tg+ beta 2m-). In this report, we examine phenotypic and functional parameters of gamma/delta positive selection in this transgenic model system. TCR-gamma/delta tg+ thymocytes of mature surface phenotype (heat stable antigen-, CD5hi) were found in beta 2m+ but not in beta 2m- mice. Moreover, subsets of tg+ thymocytes with the phenotype of activated T cells (interleukin [IL]2R+, CD44hi, or Mel-14lo) were also present only in the beta 2m+ mice. Cyclosporine A, which blocks positive selection of TCR-alpha/beta T cells, also inhibited gamma/delta tg+ T cell development. These results support the idea that positive selection of TCR-gamma/delta requires active TCR-mediated signal transduction. Whereas tg+ beta 2m+ thymocytes produced IL-2 and proliferated when stimulated by alloantigen, TCR engagement of tg+ beta 2m- thymocytes by antigen induced IL-2R expression but was uncoupled from the signal transduction pathway leading to IL-2 production and autocrine proliferation. Overall, these results demonstrate significant parallels between gamma/delta and alpha/beta lineage development, and suggest a general role for TCR signaling in thymic maturation.

Animals↗
PubMed1993

Evidence for programmed cell death of self-reactive gamma delta T cell receptor-positive thymocytes.

The negative selection of T cells expressing the gamma delta T cell antigen receptor (gamma delta T cells) was studied using transgenic mice expressing a gamma delta receptor with specificity for an H-2T-linked class I major histocompatibility complex molecule from H-2b mice. The potentially self-reactive gamma delta thymocytes in H-2b/d transgenic mice are larger and have lower levels of gamma delta T cell receptor expression than gamma delta thymocytes from H-2d mice. H-2b/d gamma delta thymocytes do not respond to H-2b antigen-presenting cells, and thus are inactive compared to H-2d gamma delta thymocytes. However, the H-2b/d gamma delta thymocyte population, but not the H-2d gamma delta thymocyte population, undergoes a high rate of programmed cell death when placed in overnight culture. These observations constitute the first direct evidence that self-reactive gamma delta thymocytes undergo programmed cell death. This in vitro programmed cell death of self-reactive gamma delta thymocytes may reflect the clonal deletion process that results in a depletion of gamma delta T cells in the peripheral lymphoid organs of adult H-2b/d mice. We also present evidence that self-reactive gamma delta T cells, similarly to alpha beta T cells, undergo a lesser degree of clonal deletion in neonatal mice compared to adult mice.

Animals↗