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PubMed1990

Abnormal T cells from lpr mice down-regulate transcription of interferon-gamma and tumor necrosis factor-alpha in vitro.

We have studied the ability of isolated T cell subpopulations from the autoimmune mouse MRL/MPJ/lpr/lpr (lpr) to proliferate and to undergo changes in cytokine gene transcription in vitro, in the presence or absence of cytokines. The lpr mouse develops lupus-like symptoms and massive lymphadenopathy due to accumulation of abnormal CD4-/CD8- T lymphocytes, which are unusual in coexpressing Thy1 and B220. FACS-purified B220+/Thy1+ lpr lymph node cells showed little proliferative response to cytokines, even in the presence of PMA, and failed to proliferate in response to stimulation through the CD3/TcR complex. Polymerase chain reaction was used to examine the presence of cytokine gene transcripts in B220-/Thy1+ and B220+/Thy1+ ("abnormal") T cells, before and after in vitro culture. The high level of transcripts of IFN-gamma and TNF-alpha genes observed in freshly isolated B220+/Thy1+ cells decreased after 10 hr of in vitro culture, while levels of TNF-beta, IL-6 and TGF-beta transcripts were maintained. These results suggest that a positive stimulus for IFN-gamma and TNF-alpha gene transcription by lpr B220+/Thy1+ cells may exist in vivo but is removed upon purification of this abnormal T cell subset.

Animals↗

PubMedDate not supplied

Anti-Tumor CC49-zeta CD4 T cells possess both cytolytic and helper functions.

The authors report that the nature of the T-cell-receptor--derived signal in normal CD4+ T cells can induce interleukin-2 (IL-2) secretion or perforin-mediated cytolytic activity. Normal human T cells were genetically modified to express the tumor antigen specific chimeric immune receptor, CC49-zeta. The CC49-zeta chimeric immune receptor is comprised of the intracellular signaling domains of the TCR CD3zeta protein fused to the single chain scFv of the humanized CC49 antibody, which binds the pan-adenocarcinoma tumor antigen TAG-72. Patient-specific T cells genetically modified to express the CC49-zeta receptor have been used in patients with colon cancer. The authors report that both CD4 and CD8 T cells expressing the CC49-zeta receptor mediated the major histocompatibility complex-unrestricted lysis of TAG-72--expressing tumor cells with comparable efficiency. However, although the CC49-zeta receptor mediated target cell lysis, it did not support the production of IL-2, even in the presence of CD28 stimulation. Robust IL-2 secretion and T-cell proliferation were observed when the same CD4 CC49-zeta T cells were stimulated through the CD28 receptor and endogenous T-cell receptor. These results indicate that CD4 T lymphocytes possess the capacity to act as both cytolytic and helper T cells and that this difference in effector function is controlled by the nature of the T-Cell receptor--derived signals.

Antigens, Neoplasm↗

PubMed1999

TCR signaling thresholds regulating T cell development and activation are dependent upon SHP-1.

An examination of thymocytes and peripheral T cells from SHP-1-deficient motheaten mice possessing a transgenic MHC class I-restricted TCR has implicated SHP-1 in regulating TCR signaling thresholds at three checkpoints in T cell development and activation. First, in the population of CD4-CD8- double negative thymocytes, SHP-1 appears capable of regulating signals from TCR complexes that control the maturation and proliferation of double negative thymocytes. Second, the loss of SHP-1 increased the number of CD4+CD8+ double positive thymocytes capable of maturing as TCRhigh single positive thymocytes. Third, the loss of SHP-1 altered the basal level of activation of naive lymph node T cells. Accordingly, SHP-1-deficient lymph node T cells bearing the transgenic TCR demonstrated a hyperresponsiveness to stimulation with cognate peptide. However, the loss of SHP-1 did not alter the cytolytic ability of mature effector cytotoxic T lymphocytes. Together these results suggest that SHP-1 contributes to establishing thresholds for TCR signaling in thymocytes and naive peripheral T cells.

Animals↗

PubMed1996

Identical genetic control of MLC reactivity to different MHC incompatibilities, independent of production of and response to IL-2.

The inbred strain STS/A exhibits a higher proliferative response in the mixed lymphocyte culture (MLC) to stimulator cells of all 11 tested inbred mouse strains with 10 different major histocompatibility complex (MHC) haplotypes, as well as to stimulation with IL-2 than does the strain BALB/cHeA. However, alloantigen-stimulated BALB/c cells produce more IL-2 than STS/A cells. To study the genetic basis of these differences, we used 20 recombinant congenic strains (RCS) of the CcS/Dem series. Each of these CcS/Dem RC strains contains a different subset of about 12.5% of genes from the STS/A strain and the remaining approximately 87.5% of BALB/c origin genes. As a result the multiple non-linked genes responsible for phenotypic differences between BALB/c and STS/A became separated into different CcS/Dem strains. The strain distribution pattern (SD) of high or low MLC response of individual CcS/Dem strains to stimulator cells of four different strains was almost identical, indicating that differences in responsiveness, rather than the alloantigenic difference itself, determine the magnitude of the response, and that the responsiveness to different alloantigens is largely controlled by the same genes. The SDP of IL-2 stimulation was different from that of MLC responsiveness. The differences in the proliferative responses observed among individual CcS/Dem strains were not due to differences in numbers of CD3+, CD4+ or CD8+ cells or to the observed differences in IL-2 production, and hence they likely reflect genetically determined intrinsic properties of T cells. These results show that a set of non-linked genes controls proliferative responses in MLC irrespective of the MHC haplotype of the stimulator cells, and that stimulation with IL-2 and production of IL-2 are controlled by different subsets of genes. Since the genomes of all RCS are extensively characterized by microsatellite markers, they can be used to map the genes controlling proliferative responsiveness to stimulation with alloantigens and IL-2.

Animals↗

PubMed1999

A novel role for HEB downstream or parallel to the pre-TCR signaling pathway during alpha beta thymopoiesis.

TCR gene rearrangement and expression are central to the development of clonal T lymphocytes. The pre-TCR complex provides the first signal instructing differentiation and proliferation events during the transition from CD4-CD8-TCR- double negative (DN) stage to CD4+CD8+ double positive (DP) stage. How the pre-TCR signal leads to downstream gene expression is not known. HeLa E-box binding protein (HEB), a basic helix-loop-helix transcription factor, is abundantly detected in thymocytes and is thought to regulate E-box sites present in many T cell-specific gene enhancers, including TCR-alpha, TCR-beta, and CD4. Targeted disruption of HEB results in a 5- to 10-fold reduction in thymic cellularity that can be accounted for by a developmental block at the DN to DP stage transition. Specifically, a dramatic increase in the CD4low/-CD8+CD5lowHSA+TCRlow/- immature single positive population and a concomitant decrease in the subsequent DP population are observed. Adoptive transfer test shows that this defect is cell-autonomous and restricted to the alpha beta T cell lineage. Introduction of an alpha beta TCR transgene into the HEBko/ko background is not sufficient to rescue the developmental delay. In vivo CD3 cross-linking analysis of thymocytes indicates that TCR signaling pathway in the HEBko/ko mice appears intact. These findings suggest an essential function of HEB in early T cell development, downstream or parallel to the pre-TCR signaling pathway.

Adoptive Transfer↗

PubMed2000

Brain migration disorder and T-cell activation deficiency associated with abnormal signaling through TCR/CD3 complex and hyperactivity of Fyn tyrosine kinase.

In this study we report on a patient affected by a brain migration disorder and a T-cell activation deficiency presumably inherited as an autosomal recessive trait. The immunological evaluation revealed that the mitogen stimulation failed to induce a proper up-regulation of membrane expression of T-cell activation markers, and cell proliferation. This functional impairment was associated with abnormalities of the signal transduction process that follows T-cell receptor stimulation. A constitutive hyperphosphorylation of the Fyn tyrosine kinase was documented. This is the first report on a T-cell signaling abnormality associated with a developmental brain disorder. Whether the alteration of Fyn, which plays a role in both neurological and immunological systems, is responsible for either disorder remains to be elucidated.

Brain Diseases, Metabolic, Inborn↗

PubMed2005

IDEC-131 (anti-CD154), sirolimus and donor-specific transfusion facilitate operational tolerance in non-human primates.

CD154-specific antibody therapy prevents allograft rejection in many experimental transplant models. However, initial clinical transplant trials with anti-CD154 have been disappointing suggesting the need for as of yet undetermined adjuvant therapy. In rodents, donor antigen (e.g., a donor blood transfusion), or mTOR inhibition (e.g., sirolimus), enhances anti-CD154's efficacy. We performed renal transplants in major histocompatibility complex-(MHC) mismatched rhesus monkeys and treated recipients with combinations of the CD154-specific antibody IDEC-131, and/or sirolimus, and/or a pre-transplant donor-specific transfusion (DST). Therapy was withdrawn after 3 months. Triple therapy prevented rejection during therapy in all animals and led to operational tolerance in three of five animals including donor-specific skin graft acceptance in the two animals tested. IDEC-131, sirolimus and DST are highly effective in preventing renal allograft rejection in primates. This apparently clinically applicable regimen is promising for human renal transplant trials.

Animals↗

PubMed2004

Insertion of host-derived costimulatory molecules CD80 (B7.1) and CD86 (B7.2) into human immunodeficiency virus type 1 affects the virus life cycle.

Human immunodeficiency virus type 1 (HIV-1) carries virus-encoded and host-derived proteins. Recent advances in the functional characterization of host molecules inserted into mature virus particles have revealed that HIV-1 biology is influenced by the acquisition of host cell membrane components. The CD28/B7 receptor/ligand system is considered one of the fundamental elements of the normal immune response. Two major cell types that harbor HIV-1 in vivo, i.e., monocytes/macrophages and CD4+ T cells, express the costimulatory molecules CD80 (B7.1) and CD86 (B7.2). We investigated whether CD80 and CD86 are efficiently acquired by HIV-1, and if so, whether these host-encoded molecules can contribute to the virus life cycle. Here we provide the first evidence that the insertion of CD80 and CD86 into HIV-1 increases virus infectivity by facilitating the attachment and entry process due to interactions with their two natural ligands, CD28 and CTLA-4. Moreover, we demonstrate that NF-kappaB is induced by CD80- and CD86-bearing virions when they are combined with the engagement of the T-cell receptor/CD3 complex, an event that is inhibited upon surface expression of CTLA-4. Finally, both CD80 and CD86 were found to be efficiently incorporated into R5- and X4-tropic field strains of HIV-1 expanded in cytokine-treated macrophages. Thus, besides direct interactions between the virus envelope glycoproteins and cell surface constituents, such as CD4 and some specific chemokine coreceptors, HIV-1 may attach to target cells via interactions between cell-derived molecules incorporated into virions and their natural ligands. These findings support the theory that HIV-1-associated host proteins alter virus-host dynamics.

Antigens, CD↗

PubMed2002

Single T cell receptor-mediated recognition of an identical HIV-derived peptide presented by multiple HLA class I molecules.

A dual specific human CTL clone harboring one beta and two inframe alpha transcripts of TCR was previously reported to recognize an HIV Pol-derived nonapeptide (IPLTEEAEL) endogenously presented by both syngeneic HLA-B*3501 and HLA-B*5101. In the current study, a retrovirus-mediated TCR transfer of individual alpha- and beta-chains to TCR-negative hybridoma showed that Valpha12.1 TCR in complex with Vbeta5.6 were responsible for the peptide-specific response in the context of both HLA-B*3501 and HLA-B*5101, confirming single TCR-mediated dual specificity. The second TCR-alpha chain was not somehow expressed on the cell surface. Remarkably, the Valpha12.1/Vbeta5.6 TCR also recognized the same peptide presented by allogeneic HLA class I molecules that share the similar peptide-binding motifs, such as HLA-B*5301 and HLA-B*0702. The sensitivity of peptide recognition by the Valpha12/Vbeta5.6 TCR appeared to be comparable when the peptide was presented by syngeneic and allogeneic HLA class I molecules, with changes in T cell responsiveness caused largely by peptide-binding capacity. Moreover, the CTL clone bearing Valpha12.1/Vbeta5.6 TCR showed substantial cytolytic activity against the peptide-loaded cells expressing HLA-B*3501, HLA-B*5101, HLA-B*5301, or HLA-B*0702, providing further evidence that a single TCR complex can recognize the same peptide presented by a broad range of HLA class I molecules. A TCR with fine specificity for an HIV Ag but broad specificity to multiple HLA molecules may provide an advantage to the generation of allorestricted, peptide-specific T cells, and thus could be a potent candidate for immunotherapy against HIV infection.

Alleles↗

PubMed1996

Catalytic activity of the mouse guanine nucleotide exchanger mSOS is activated by Fyn tyrosine protein kinase and the T-cell antigen receptor in T cells.

mSOS, a guanine nucleotide exchange factor, is a positive regulator of Ras. Fyn tyrosine protein kinase is a potential mediator in T-cell antigen receptor signal transduction in subsets of T cells. We investigated the functional and physical interaction between mSOS and Fyn in T-cell hybridoma cells. Stimulation of the T-cell antigen receptor induced the activation of guanine nucleotide exchange activity in mSOS immunoprecipitates. Overexpression of Fyn mutants with an activated kinase mutation and with a Src homology 2 deletion mutation resulted in a stimulation and suppression of the mSOS activity, respectively. The complex formations of Fyn-Shc, Shc-Grb2, and Grb2-mSOS were detected in the activated Fyn-transformed cells, whereas the SH2 deletion mutant of Fyn failed to form a complex with mSOS. Moreover, tyrosine phosphorylation of Shc was induced by the overexpression of the activated Fyn. These findings support the idea that Fyn activates the activity of mSOS bound to Grb2 through tyrosine phosphorylation of Shc. Unlike the current prevailing model, Fyn-induced activation of Ras might involve the stimulation of the catalytic guanine nucleotide exchange activity of mSOS.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Lack of coreceptor allows survival of chronically stimulated double-negative alpha/beta T cells: implications for autoimmunity.

Lymphoproliferative diseases are characterized by massive accumulation of CD4(-)CD8(-)B220(+) (double-negative [DN]) T cells in peripheral organs. Although evidence indicates these cells are derived from mature autoreactive alpha/beta T cells, the significance of coreceptor downregulation is not known. In this study, we examined the role CD4 coreceptor plays in the survival of repeatedly stimulated T cells. CD4(+/+) and CD4(-/-) T cells from AND T cell receptor (TCR) transgenic mice exhibited similar phenotypes after antigenic stimulation, but the CD4(-/-) T cells survived in much larger numbers than the CD4(+/+) cells upon primary and secondary major histocompatibility complex (MHC)/peptide stimulation. Enhanced survival of CD4(-/-) T cells was due to decreased apoptosis rather than enhanced proliferation. Similarly, circumvention of the CD4/MHC interaction by using a surrogate TCR ligand that does not engage CD4 led to significant enhancement of CD4(+/+) cells than when stimulated with MHC/peptide. Finally, we generated DN B220(+) T cells using an in vitro model system and showed they were more tolerant to chronic stimulation than CD4(+/+) cells. Together, these results indicate that coreceptor engagement controls expansion of normal T cells. In the absence of coreceptor, T cells survive chronic stimulation and express B220 as seen in autoimmune lymphoproliferative diseases.

Animals↗

PubMed1992

Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas.

Immature T cells and some T cell hybridomas undergo apoptotic cell death when activated through the T cell receptor complex, a phenomenon that is probably related to antigen induced negative selection of developing T cells. This activation-induced apoptosis depends on active protein and RNA synthesis in the dying cells, although none of the genes required for this process have previously been identified. Antisense oligonucleotides corresponding to c-myc block the constitutive expression of c-Myc protein in T cell hybridomas and interfere with all aspects of activation-induced apoptosis without affecting lymphokine production in these cells. These data indicate that c-myc expression is a necessary component of activation-induced apoptosis.

Animals↗

PubMed1987

Activation of immature cortical thymocytes through the T11 sheep erythrocyte binding protein.

Two major pathways, the T cell receptor and the T11 alternate pathway, allow for T cell activation. In the human thymus, the T cell antigen receptor complex is reduced or absent on immature thymocytes, whereas the T11 glycoprotein is present at high cell surface density on all thymocytes. To determine whether activation through the T11 pathway induces similar or different changes in mature and immature thymocytes, we fractionated thymocytes according to their surface expression of the T3-T cell receptor (T3/Ti) complex. We report that two populations, one with high and one with low T3/Ti expression, can be activated through the T11 pathway to undergo nuclear activation and express IL 2 receptors. Moreover, in the absence of accessory cells, only the most mature population, expressing high T3 density, could be induced to proliferate, whereas the subset representing immature cortical thymocytes required accessory cells for proliferation. These findings suggest that the cellular microenvironment may have a critical role in regulating the activation of immature cortical thymocytes and that this cell population may not represent "nonfunctional" dead end cells, but rather a valid intermediate in human thymic differentiation.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1993

T cell development in mice that lack the zeta chain of the T cell antigen receptor complex.

The zeta subunit of the T cell antigen receptor complex is required for targeting nascent receptor complexes to the cell surface and for receptor-mediated signal transduction. To examine the significance of the zeta subunit in T cell development, mice deficient for zeta expression were generated by gene targeting. These zeta-/- mice had few CD4+CD8+ thymocytes, and the generation of CD4+ and CD8+ single positive T cells was impaired but not completely abrogated. Peripheral T cells were present but were unusual in that they expressed small amounts of CD5 and few T cell receptors. Thus, zeta chain expression influences thymocyte differentiation but is not absolutely required for the generation of single positive T cells.

Animals↗

PubMed2003

[Extracorporeal immunopharmacological therapy in the treatment of patients with acutely progressing froms of pulmonary tuberculosis].

Extracorporeal immune-pharmacological therapy, involving Diuciphonium, was added to the complex treatment of 46 patients primarily diagnosed as having acutely progressing destructive pulmonary tuberculosis. Investigations showed that this method sped up the regression of clinical and X-ray signs, during 1 to 2 months, and recovered the immune reactivity in 89% of patients. The clinical changes were dynamically compared with those of 50 other patients in another group (including 39 patients with caseous pneumonia), who were treated by small-volume plasmapheresis. Advantages of applying the extracorporeal immune-pharmacological therapy were demonstrated; they comprise: a shorter time needed to arrest the endotoxicosis, a fuller and faster recovery of the main populations and sub-populations of lymphocytes and a less number of fatal outcomes.

Acute Disease↗

PubMed2000

Triggering the TCR complex causes the downregulation of nonengaged receptors by a signal transduction-dependent mechanism.

Downregulation of the TCR complex is believed to be intimately tied to T cell activation, allowing serial triggering of receptors and desensitization of stimulated cells. We studied transfected and transgenic T cells expressing CD3zeta chimeras to demonstrate that ligand engagement of the TCR or chimeras causes comodulation of nonengaged receptors. Comodulation required protein tyrosine kinase activity but not trans-phosphorylation of nonengaged receptors. The TCR appears to be downregulated by at least two mechanisms. One mechanism requires direct engagement, independent of signaling. The second requires signaling and downregulates nontriggered receptors. These results shed new light on the process of TCR downregulation and indicate that the number of downregulated TCRs cannot be assumed to equal the number of engaged receptors.

Animals↗

PubMed1998

Costimulation through CD28 suppresses T cell receptor-dependent activation of the Ras-like small GTPase Rap1 in human T lymphocytes.

Members of the Ras superfamily of small molecular weight GTPases play diverse and critical roles in mediating cellular responses to extracellular stimuli, including mitogenesis, cytoskeletal maintenance and rearrangement, and integrin activation. In T lymphocytes, biochemical and genetic evidence demonstrate that Ras plays an essential role in coupling T cell receptor ligation to signaling cascades required for T cell proliferation and development. Recent observations that C3G, a guanine nucleotide exchange factor specific for the Ras-related GTPase Rap1, is recruited into tyrosine-phosphorylated protein signaling complexes in activated T cells have suggested that Rap1 may also play a role in T cell activation. Utilizing a recently developed technique for detection of endogenous, GTP-bound Rap1, we have found that Rap1, but not Rap2, is transiently activated following T cell receptor stimulation of normal human T lymphocytes. Increases in intracellular calcium is both necessary and sufficient to induce Rap1 activation. Remarkably, costimulation of T cells with mitogenic anti-CD28 antibody completely abolished T cell receptor-dependent activation of Rap1. This report demonstrates a potential role for Rap1 in T cell receptor signaling and suggests inactivation of Rap1 as a candidate target of CD28-dependent costimulatory signals required for T cell antigen responsiveness.

CD28 Antigens↗

PubMed1990

Maturational arrest from CD4+8+ to CD4+8- thymocytes in a mutant strain (LEC) of rat.

A mutant strain (LEC) of rats was found to have a novel defect in T cell maturation, that is, arrest of differentiation from CD4+8+ to CD4+8- but not to CD4-8+ thymocytes. FACS analyses demonstrated a deficiency in the CD4+8- T cell subset in the thymus and a marked decrease in CD4+ T cells in peripheral lymphoid organs. Expression of the T cell receptor (TCR)/CD3 complex in CD4+8+ and CD4-8+ thymocytes of LEC rats was normal. Expression of class II major histocompatibility complex (MHC) in the thymus of LEC rats was also the same as that of normal rats. These results indicate that maturational arrest occurs only in the transition pathway from CD4+8+ to CD4+8- thymocytes, and that this mutation can not be attributed to the default of expression of either TCR/CD3, CD4, or class II MHC antigen. Consequently, dysfunction of helper T cells was observed in LEC rats, while killer T cells and B cells functioned normally. Although the complete identification of the origin of this mutation requires further studies, it is hoped that such investigations will throw light on the mechanism of positive selection.

Animals↗