Antibody-induced modulation of the CD3/T cell receptor complex causes T cell refractoriness by inhibiting the early metabolic steps involved in T cell activation (original) (raw)
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Journal of Experimental Medicine, 1988
The surface T cell receptor (TCR) for antigen/MHC products is composed of a disulfide a/0 heterodimer noncovalently associated with CD3, a multipolypeptide cell membrane complex (1, 2). In addition, a minor subset of CD3+ cells has recently been shown to express C133-associated molecules different from a/0 molecules, which may represent the putative TCRy gene product (3). T cell activation can be induced in both types of CD3+ cells by the use of lectins (i.e., PHA) or mAbs directed against either the TCR, CD3, or CD2, another surface glycoprotein, which is not physically linked to the CD3/TCR complex (4-6). As previously shown , the interaction between surface receptors and their specific ligands elicits a series of early metabolic events, such as an increase in free cytoplasmic Cat+ concentration ([Ca 2+ ]i) and inositol-3-phosphate (InSP3)t formation. Both events are thought to be fundamental steps in the process by which T lymphocytes are triggered to express their functional programs . We have recently shown that the signal transducing mechanisms operating in CD3+ lymphocytes after stimulation via CD3 and CD2 molecules or with PHA involve activation of the classical inositol-lipid metabolism . An important functional consequence of antibody-induced modulation of the CD3/TCR complex is represented by the T cell refractoriness to any further stimulus. This general refractoriness appears to be caused by an inhibition of the early metabolic steps involved in T cell activation (10) . These results provide evidence for a regulatory role of CD3/TCR complex in the other pathways of T cell activation and suggest the existence of a physical association of the CD3/TCR complex with the transducing machinery used by all other receptors coupled to PIP2 hydrolysis .
Degradation of T Cell Receptor (TCR)CD3- z Complexes after Antigenic Stimulation
2000
Summary T cell activation by specific antigen results in a rapid and long-lasting downregulation of trig- gered T cell receptors (TCRs). In this work, we investigated the fate of downregulated TCR- CD3- z complexes. T cells stimulated by peptide-pulsed antigen-presenting cells (APCs) un- dergo an antigen dose-dependent decrease of the total cellular content of TCR- b , CD3- e ,
Degradation of T cell receptor (TCR)CD3-ζ complexes after antigenic stimulation
The Journal of …, 1997
T cell activation by specific antigen results in a rapid and long-lasting downregulation of triggered T cell receptors (TCRs). In this work, we investigated the fate of downregulated TCR-CD3-complexes. T cells stimulated by peptide-pulsed antigen-presenting cells (APCs) undergo an antigen dose-dependent decrease of the total cellular content of TCR- , CD3-⑀ , and chains, as detected by FACS ® analysis on fixed and permeabilized T-APC conjugates and by Western blot analysis on cell lysates. The time course of CD3-chain consumption overlaps with that of TCR downregulation, indicating that internalized TCR-CD3 complexes are promptly degraded. Inhibitors of lysosomal function (bafilomycin A1, folimycin) markedly reduced chain degradation, leading to the accumulation of chain in large Lamp1 ϩ vesicles. These results indicate that in T cell-APC conjugates, triggered TCRs are rapidly removed from the cell surface and are degraded in the lysosomal compartment.
Int Immunol, 1999
We studied cytotoxic T lymphocyte (CTL) clones expressing cytoplasmic domain-deleted CD3δ and CD3γ chains. These cells retained efficient antigen-specific cytolysis. Because the cytoplasmic domains of native CD3δ and CD3γ chains contain a dileucine-based and a tyrosine-based motif thought to be important for receptor endocytosis, we compared TCR-CD3 down-modulation on the CTL clones expressing or not these domains. We found that antigen-induced TCR-CD3 downmodulation was not dependent on either the CD3δ or CD3γ cytoplasmic domains. This contrasts with phorbol ester-and anti-CD3 mAb (soluble or plastic-coated)-induced TCR-CD3 downmodulation, that are respectively dependent on CD3γ and on either CD3δ or CD3γ cytoplasmic domains, suggesting that differences may exist between the mechanisms of TCR-CD3 downmodulation in response to the three stimuli. TCR-CD3 down-modulation in response to antigen was demonstrated by confocal microscopy to be associated with TCRβ chain internalization, whether CD3δ and CD3γ were native or truncated. Inhibition by the protein tyrosine kinase inhibitor PP1 of TCR-CD3 down-modulation in response to antigen was also similar whether CD3δ and CD3γ cytoplasmic domains were present or not. These properties of receptor down-modulation are discussed with respect to the requirements for TCR engagement on antigen-presenting cells.
International Immunology, 1999
We studied cytotoxic T lymphocyte (CTL) clones expressing cytoplasmic domain-deleted CD3δ and CD3γ chains. These cells retained efficient antigen-specific cytolysis. Because the cytoplasmic domains of native CD3δ and CD3γ chains contain a dileucine-based and a tyrosine-based motif thought to be important for receptor endocytosis, we compared TCR-CD3 down-modulation on the CTL clones expressing or not these domains. We found that antigen-induced TCR-CD3 downmodulation was not dependent on either the CD3δ or CD3γ cytoplasmic domains. This contrasts with phorbol ester-and anti-CD3 mAb (soluble or plastic-coated)-induced TCR-CD3 downmodulation, that are respectively dependent on CD3γ and on either CD3δ or CD3γ cytoplasmic domains, suggesting that differences may exist between the mechanisms of TCR-CD3 downmodulation in response to the three stimuli. TCR-CD3 down-modulation in response to antigen was demonstrated by confocal microscopy to be associated with TCRβ chain internalization, whether CD3δ and CD3γ were native or truncated. Inhibition by the protein tyrosine kinase inhibitor PP1 of TCR-CD3 down-modulation in response to antigen was also similar whether CD3δ and CD3γ cytoplasmic domains were present or not. These properties of receptor down-modulation are discussed with respect to the requirements for TCR engagement on antigen-presenting cells.
Clinical and Experimental Immunology, 2004
The antihuman CD2 MoAb BTI-322 (Lo-CD2a) effectively inhibits T cell responses in vitro to allogeneic cells, which is followed by unresponsiveness to the original stimulator in secondary stimulation. We studied the xenogeneic human antiporcine mixed lymphocyte reaction (MLR), and utilized anti-T cell receptor (TCR) Vβ family antibody-induced cell proliferation to determine the specificity and mechanism. BTI-322 and its humanized version, MEDI-507, effectively inhibited the primary xenogeneic MLR. After suboptimal primary stimulation using lower numbers of xenogeneic stimulator cells, the unresponsiveness in secondary culture was apparent only for xenogeneic stimulator cells of the original SLA haplotype, and not for third-party stimulators or allogeneic cells. The inhibition of primary MLR was not observed for nylon-wool-purified T cells, but was seen after reconstitution of purified T cells with monocytes. Similarly, anti-Vβ family-specific stimulation showed family-specific unresponsiveness in secondary culture. This required the presence of the whole BTI-322 molecule: a F(ab′)2 fragment was not effective. T cells of a distinct Vβ family were depleted after stimulation with an anti-Vβ family-specific antibody and BTI-322. We conclude that the inhibition by BTI-322 of a primary xenogeneic MLR or the response to an anti-TCR Vβ antibody is associated with unresponsiveness upon restimulation, due to activation-associated cell depletion. In this process, the interaction between monocytes and the Fc part of the antibody is involved. This unique characteristic of BTI-322 suggests the potential of the antibody for tolerance induction in vivo, besides the potential use as a T cell depleting agent.
CD3 pathway of T-cell activation
Cellular Immunology, 1988
The role of distinct regions of HLA class I molecules in regulating T-cell activation via the CD3-antigen receptor complex was investigated. Monoclonal antibodies (MoAbs) which recognize monomorphic and polymorphic epitopes on HLA Class I molecules were shown to inhibit T-cell proliferation to OKT3. These MoAbs have differential effects on the synthesis of interleukin-2 (IL-2) and IL-2 receptor expression. Cell cycle analysis demonstrated that these MoAbs function both in inhibiting cell cycle entry (Go-G, shift) and in blocking cell cycle progression (Gi-S shift) of activated T cells. Furthermore, these MoAbs have regulatory effects on the alternate pathway of T-cell activation via the CD2 molecule, T-cell activation induced by PHA, and activation induced by the phorbol ester PMA in conjunction with the calcium ionophore Ionomycin. Thus these MoAbs have different effects depending upon the pathway of T-cell activation. The results indicate that HLA class I molecules are selectively involved in the sequence of intracellular events leading to T-cell activation and proliferation. o 1988 Academic press, Inc.
The Impact of Duration versus Extent of TCR Occupancy on T Cell Activation
Immunity, 2001
wise phosphorylation of CD3/ subunits and subsequent Center for Immunology recruitment of appropriate signaling molecules must University of Minnesota take time to complete, it is reasonable to expect that Minneapolis, Minnesota 55455 the interruption of TCR engagement may prevent correct 2 Basel Institute for Immunology assembly of the signaling complex (Germain and Ste-Grenzacherstrasse 487 fanova, 1999; Kersh et al., 1998a). Kinetic proofreading/ CH-4005 Basel discrimination models predict that TCR interaction with Switzerland ligands exhibiting fast off rates would only permit very 3 Department of Immunology early activation events but not allow the T cell to commit The Scripps Research Institute to later activation events, blunting, or inhibiting the func-La Jolla, California 92037 tional T cell response. By contrast, a more sustained 4 Anthony Nolan Bone Marrow Trust TCR interaction would favor complete T cell activation. The Royal Free Hospital A central concept of these models is that the minimum Hampstead, London NW32QG time required to complete formation of a fully competent United Kingdom signaling complex could enable the TCR to discriminate between
Increased TCR Avidity after T Cell ActivationA Mechanism for Sensing Low-Density Antigen
Immunity, 2001
and form a large cluster at the site of interaction that has been called the immunologic synapse/SMAC (Paul and Seder, 1994; Monks et al., 1998; ; Grakoui et al., 1999). This contact region facilitates directed release of effector molecules from the T cell toward the APC. There have been a variety of estimates of the requirement for multivalent TCR complexes for Johns Hopkins University Baltimore, Maryland 21218 optimal signaling. Recent studies have indicated that as few as two antigen-MHC complexes are sufficient for generating all the qualitative TCR signals and that additional complexes only have quantitative effects on sig-Summary naling (Bachmann et al., 1998; Bachmann and Ohashi, 1999; Cochran et al., 2000).