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H Spits

Publications and source records attributed to H Spits.

At least 109 records · Page 6Linked to original sources
PubMed1991

Human T cell receptor gamma delta + T cells.

TCR gamma delta + T cells represent a minority of CD3+ T cells in many species including man. The molecular structure of the TCR gamma and delta loci in man is well understood. The gamma and delta loci contain V, D, J and C gene segments. These segments do not rearrange randomly but in a coordinated, ordered fashion during thymic development. Therefore, the structure of gamma and delta genes of early fetal TCR gamma delta + thymocytes differ drastically from those in postnatal TCR gamma delta + thymocytes. In contrast to postnatal TCR gamma delta + thymocytes, early fetal-TCR gamma delta + produce substantial levels of IL-4 and IL-5 and the possibility is discussed that the early fetal TCR gamma delta + cells are involved in development of TCR gamma delta + cells. In man, unlike in mouse, no preferential homing of early fetal TCR gamma delta + cells has been observed so far. Mature human peripheral TCR gamma delta + cells can recognize a great variety of cell surface antigens including 'classical' and 'non-classical' MHC antigens, immunoglobulins and other undefined antigens. In addition, TCR gamma delta + can recognize bacterial products. So far, no class of antigens has been defined that is preferentially recognized by TCR gamma delta + T cells and the function of these cells remains elusive.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1990

Mycobacterium leprae-specific T cells from a tuberculoid leprosy patient suppress HLA-DR3-restricted T cell responses to an immunodominant epitope on 65-kDa hsp of mycobacteria.

The polar tuberculoid type (TT) of leprosy, characterized by high T cell reactivity to Mycobacterium leprae, is associated with HLA-DR3. Surprisingly, DR3-restricted low T cell responsiveness to M. leprae was found in HLA-DR3-positive TT leprosy patients. This low responsiveness was specifically induced by M. leprae but not by M. tuberculosis and was seen only in patients and not in healthy controls. We studied this patient-specific, M. leprae-induced, DR3-restricted low T cell responsiveness in depth in one representative HLA-DR3-positive TT leprosy patient by using T cell clones. From this patient two types of T cell clones were obtained: one type was cross-reactive with M. tuberculosis and recognized an immunodominant epitope (amino acids 3 to 13) on the 65-kDa heat shock protein (hsp) the other type was M. leprae specific and reacted to a protein other than the 65-kDa one. To examine whether these M. leprae-specific T cell clones were responsible for the DR3-restricted low responsiveness to M. leprae, we tested them for the ability to suppress the proliferation of the DR3-restricted, 65-kDa, hsp-reactive clones. The DR3-restricted, M. leprae-specific T cells completely suppressed the proliferative responses of DR3-restricted, cross-reactive T cell clones to the 65-kDa hsp from the same patient as well as from other individuals. Also, DR3-restricted responses to an irrelevant Ag were suppressed by the M. leprae-specific T cell clones. However, no suppression of non-DR3-restricted T cell responses was seen. Although the mechanism must still be elucidated, this M. leprae-induced, DR3-restricted immunosuppression may at least partly explain the observed DR3-associated low T cell responsiveness in TT leprosy patients.

Bacterial Proteins↗
PubMed1990

Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1.

Cytokine synthesis inhibitory factor (CSIF; interleukin-10), a product of mouse TH2 T cell clones that inhibits synthesis of cytokines by mouse TH1 T cell clones, exhibits extensive sequence similarity to an uncharacterized open reading frame in the Epstein-Barr virus BCRF1. Recombinant BCRF1 protein mimics the activity of interleukin-10, suggesting that BCRF1 may have a role in the interaction of the virus with the host's immune system.

Animals↗
PubMed1990

Human T cell leukemia virus type I prevents cell surface expression of the T cell receptor through down-regulation of the CD3-gamma, -delta, -epsilon, and -zeta genes.

Infection and transformation by human T cell leukemia virus type I (HTLV-I) up-regulates expression of several inducible genes including those coding for cytokines involved in the proliferation of normal and leukemic T cells. We demonstrate that HTLV-I can also shut off expression of the CD3-gamma, delta, epsilon, and zeta genes that code for the constant elements of the TCR for Ag. In addition, the T cell-specific CD3-epsilon enhancer was found to be inactive in a HTLV-I-infected T cell clone. This HTLV-I-infected T cell clone (827-p19-II) that could be cultured in the absence of IL-2 lacked the CD3 proteins but did express the TCR-alpha and -beta proteins intracellularly. In the absence of the CD3-gamma, delta, epsilon, and zeta polypeptide chains the disulfide bridged TCR-alpha/beta heterodimer was not formed and the Ag receptor did not appear at the cell surface. These results allowed two major conclusions: first, HTLV-I infection has an effect on the T cell specific regulatory elements that coordinately regulate CD3-gamma, delta, epsilon, and zeta expression and second, the CD3-gamma, delta, epsilon, and zeta proteins are necessary for formation and routing the variable TCR-alpha/beta (or -gamma/delta) heterodimer to the human T cell surface.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1990

A distinct wave of human T cell receptor gamma/delta lymphocytes in the early fetal thymus: evidence for controlled gene rearrangement and cytokine production.

The rearrangement and expression of human T cell receptor (TCR)-gamma and -delta gene segments in clonal and polyclonal populations of early fetal and postnatal human TCR-gamma/delta thymocytes were examined. The data suggest that the TCR-gamma and -delta loci rearrange in an ordered and coordinated fashion. Initial rearrangements at the TCR-delta locus join V delta 2 to D delta 3, and initial rearrangements at the TCR-gamma locus join downstream V gamma gene segments (V gamma 1.8 and V gamma 2) to upstream J gamma gene segments associated with C gamma 1. These rearrangements are characterized by minimal junctional diversity. At later times there is a switch at the TCR-delta locus such that V delta 1 is joined to upstream D delta gene segments, and a switch at the TCR-gamma locus such that upstream V gamma gene segments are joined to downstream J gamma gene segments associated with C gamma 2. These rearrangements are characterized by extensive junctional diversity. Programmed rearrangement explains in part the origin of discrete subpopulations of peripheral blood TCR-gamma/delta lymphocytes that have been defined in previous studies. In addition, cytokine production by early fetal and postnatal TCR-gamma/delta thymocyte clones was examined. Fetal thymocyte clones produced significant levels of IL-4 and IL-5 following stimulation, whereas postnatal thymocyte clones did not produce these cytokines. Thus, these cell populations may represent functionally distinct subsets as well.

Amino Acid Sequence↗
PubMed1990

Cytotoxic activity and lymphokine production of T cell receptor (TCR)-alpha beta+ and TCR-gamma delta+ cytotoxic T lymphocyte (CTL) clones recognizing HLA-A2 and HLA-A2 mutants. Recognition of TCR-gamma delta+ CTL clones is affected by mutations at positions 152 and 156.

TCR-gamma delta+ CTL clones were generated from CD4-CD8- T cells that were stimulated twice with the cell line JY. Either IL-2 or IL-4 was used as growth factor. A number of TCR-gamma delta+ clones were found to lyse the stimulator cell line JY. Two of these clones secreted N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester serine esterase activity after stimulation with JY cells. The cytotoxic activity of these two clones was blocked by a mAb specific for HLA-A2. Moreover, these two TCR-gamma delta+ clones selectively lysed human fibroblast line M1 and murine P815 cells transfected with DNA fragments encoding HLA-A2 but not those transfected with HLA-B7 encoding DNA, indicating that these clones recognize HLA-A2. Analysis of the recognition of HLA-A2 by using target cells transfected with mutated HLA-A2 encoding genes revealed that the nature of the amino acid at position 152 of the molecule is critical for recognition of the TCR-alpha beta+ as well as the TCR-gamma delta+ CTL clones since replacement of Val for Ala at that position resulted in abrogation of recognition of one TCR-gamma delta+ and one TCR-alpha beta+ clone and substitution of Val for Glu affected recognition of all clones. Substitution of Leu for Trp at position 156 abrogated recognition by one TCR-gamma delta+ and one TCR-alpha beta+ T cell clone, but recognition by the other clones was not changed. All clones were able to secrete IL-2, IFN-gamma, and GM-CSF but not IL-4 after activation.

Clone Cells↗
PubMed1990

Host-reactive CD4+ and CD8+ T cell clones isolated from a human chimera produce IL-5, IL-2, IFN-gamma and granulocyte/macrophage-colony-stimulating factor but not IL-4.

In the present study, we investigated the lymphokine production patterns in a series of CD4+ and CD8+ host-reactive T cell clones isolated from PBL of a SCID patient, who was immunologically reconstituted by two allogeneic fetal liver and thymus transplantations 13 years ago. We demonstrate that these donor-derived T cell clones, specifically reacting with the MHC Ag expressed on the recipient cells, do not produce IL-4 and do not express IL-4 mRNA upon Ag or polyclonal stimulations. In contrast, CD4+ tetanus toxin-specific T cell clones isolated from the same patient and having the same HLA phenotype produced normal amounts of IL-4 upon activation. These data suggest that the failure to produce IL-4 is a specific characteristic of these host-reactive clones and is not due to a genetic defect of the transplanted cells. Furthermore, different modes of activation resulted in simultaneous production of IL-5, IL-2, IFN-gamma, granulocyte/macrophage-CSF, and transcription of the TNF-beta gene by the host-reactive clones, indicating that the lack of IL-4 production is not related to the mode of activation. The finding that some of these clones produce significant levels of IL-5 but no IL-4 indicates that the IL-4 and IL-5 genes are not always coexpressed in activated human T cells.

Antigens, CD↗
PubMed1990

Reactivity of cloned, expressed human Fc gamma RIII isoforms with monoclonal antibodies which distinguish cell-type-specific and allelic forms of Fc gamma RIII.

We have isolated and expressed a cDNA encoding human NK cell Fc gamma RIII. The NK cell cDNA differs from the neutrophil Fc gamma RIII cDNA by a number of point mutations and encodes an additional 21 amino acids at its C-terminus. When transiently expressed neutrophil and NK cell Fc gamma RIII were digested with N-glycanase, deglycosylated neutrophil Fc gamma RIII had a more rapid electrophoretic mobility than NK cell Fc gamma RIII, as is observed for the human Fc gamma RIII isoforms on normal cells. The neutrophil and NK cell Fc gamma RIII isoforms apparently result from cell-type specific expression of different forms of Fc gamma RIII mRNA. A TaqI RFLP was also found for human Fc gamma RIII. Monoclonal antibodies which have been used to distinguish the neutrophil and NK cell Fc gamma RIII isoforms and the NA1 and NA2 alleles of human neutrophil Fc gamma RIII were employed to study the expression of two Fc gamma RIII cDNA clones derived from neutrophils and NK cells. Fc gamma RIII encoded by the neutrophil-derived cDNA reacts with the monoclonal antibody CLBgran11, while the NK-cell Fc gamma RIII cDNA expresses the Fc receptor which carries an antigenic determinant recognized by the antibody GRM1. Characterization of hybrid Fc gamma RIII constructed by interchange of restriction fragments between the neutrophil and NK cell cDNAs allowed localization of antigenic determinants recognized by the monoclonal antibodies.

Alleles↗
PubMed1989

Antigen-specific, but not natural killer, activity of T cell receptor-gamma delta cytotoxic T lymphocyte clones involves secretion of N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester serine esterase and influx of Ca2+ ions.

Analysis of Ag specificity of TRC-gamma delta+ T cells in humans has been hampered by the fact that cloned lines of these cells expanded in IL-2 generally display high NK-like cytotoxic activity. A TCR-gamma delta+ CTL clone, isolated in IL-4, strongly lysed a specific stimulator cell, the EBV-transformed cell line JY, but failed to lyse K562 and other target cells sensitive for NK cell activity. Subsequent culture of this clone (CD124) in IL-2 induced high cytotoxic activity against the NK sensitive target cells. K562 cells were unable to induce the secretion of N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester [(BLT)-serine esterase] or influx of Ca2+ ions in clone CD124 cultured in either IL-4 or IL-2. In contrast, JY cells induced high BLT-serine esterase secretion and an increase of cytosolic Ca2+ levels. By using a combination of a 51Cr-release assay and a BLT-serine esterase secretion assay, the reactivity of clone CD124 against a limited number of target cells was analyzed. CD124 which expresses HLA-A2 and -B7, recognized an Ag shared by JY (HLA-A2; B7; C blank; DR4,6) and one haplotype expressed by the cell line SPS (HLA-A1; B14; Cw6; DR4). The only specificity shared by SPS and JY was HLA-DR4. However, clone CD124 failed to lyse 5 other HLA-DR4+ target cells. The cytotoxic activity of clone CD124 was inhibited by the class I MHC specific mAb W6/32 and the anti-beta 2m mAb A88, but not, or only marginally, by the anti HLA-DQ mAb SPV-L3 or the anti-HLA-DR mAb 135. These data strongly suggest that clone CD124 recognizes a class I MHC Ag different from HLA-A, -B, or -C.

Antibodies, Monoclonal↗
PubMed1989

IL-4 induces LFA-1 and LFA-3 expression on Burkitt's lymphoma cell lines. Requirement of additional activation by phorbol myristate acetate for induction of homotypic cell adhesions.

LFA-1 and LFA-3 expression is absent or low on Burkitt's lymphoma cell lines and low on the EBV-transformed B cell line UD61. Incubation of cells of BL2 and of UD61 with various concentrations of IL-4 resulted in induction of LFA-1 and LFA-3 expression in a dose dependent fashion. This effect was already observed after 16 h of incubation whereas maximal expression was obtained after 72 h. Induction of LFA-1 and LFA-3 expression seemed to be specific for IL-4, because IL-1, IL-2, IL-3, IFN-alpha, IFN-gamma and a low m.w. B cell growth factor were ineffective. LFA-1 and LFA-3 induction by IL-4 was blocked specifically by an anti-IL-4 antiserum. Induction of LFA-1 expression by IL-4 was furthermore confirmed at the specific LFA-1 beta-chain mRNA level. IL-4 was unable to induce LFA-1 expression on EBV-transformed lymphoblastoid cell lines of two LFA-1-deficient patients. BL2 grows as single cells, but induction of LFA-1 and LFA-3 expression by IL-4 was insufficient to induce homotypic cell adhesions and required PMA as a second signal. PMA alone did not induce LFA-1 antigen expression and was unable to induce adhesions between BL2 cells in the absence of IL-4 in 22 h assays. Addition of PMA to BL2 cells that expressed LFA-1 Ag upon incubation with IL-4 resulted in aggregate formation within 30 min. Adhesions between BL2 cells induced by IL-4 in combination with PMA were blocked by anti-LFA-1 beta or anti-LFA-1 alpha-chains mAb. In addition, these mAbs dispersed preformed aggregates of BL2 cells. Our results indicate that IL-4 can induce the adhesion molecules LFA-1 and LFA-3 on B cell lines, but that an additional activation signal provided by PMA was required for the induction of homotypic cell adhesions.

Antibodies, Monoclonal↗
PubMed1989

Antigen specific and MHC nonrestricted cytotoxicity of T cell receptor alpha beta+ and gamma delta+ human T cell clones isolated in IL-4.

IL-4 has been shown to act as a growth factor for human T cells. In addition, IL-4 can enhance CTL activity in MLC, but blocks IL-2 induced lymphokine activated killer cell activity in PBL. In our study, the cloning efficiencies, Ag-specific CTL activity and non-MHC-restricted cytotoxicity of CTL clones generated in IL-2 were compared to those generated in IL-4. In a first experiment, T cells were stimulated with the EBV-transformed B cell line JY and cloned 7 days later with feeder cells and either IL-2 or IL-4. In a second experiment, stimulation of the T cells was carried out in the presence of IL-2 plus anti-IL-4 antibodies or IL-4 plus anti-IL-2 antibodies in order to block the effects of IL-4 and IL-2, respectively, produced by the feeder cells. Although the cloning efficiencies in the second experiment were lower than those obtained in the first experiment, the cloning efficiencies obtained with IL-2 or IL-4 were similar in both experiments. The overall proportion of TCR alpha beta+ T cell clones cytotoxic for the stimulator cell JY established in IL-2 or IL-4 were comparable. A striking difference between the clones obtained in IL-2 or IL-4 was that a large proportion of the clones obtained in IL-4 expressed CD4 and CD8 simultaneously, whereas none of the clones isolated in IL-2 were double positive. Also gamma delta+ T cell clones could be established with IL-4 as a growth factor. TCR gamma delta+ T cell clones isolated in either IL-2 or IL-4 were CD4-CD8- or CD4-CD8+, but the proportion of CD4-CD8+ clones isolated in IL-4 was higher. Interestingly, one TCR gamma delta+ clone isolated in IL-2 was CD4+CD8-. Most of the TCR alpha beta+ and TCR gamma delta+ CTL-clones isolated in IL-2 lysed the NK cell sensitive target cell K562. In contrast, only a small proportion of the TCR alpha beta+ or TCR gamma delta+ CTL clones isolated in IL-4, lysed K562. One TCR gamma delta+ T cell clone (CD-124) isolated in IL-4 and subsequently incubated in IL-2 acquired lytic activity against K562.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Line↗
PubMed1989

Introduction of T cell receptor (TCR)-alpha cDNA has differential effects on TCR-gamma delta/CD3 expression by PEER and Lyon-1 cells.

A TCR heterodimer composed of a TCR gamma-chain and a TCR delta-chain was found to be expressed in association with CD3 by a small population of human peripheral blood T cells, thymocytes, and certain leukemic T cell lines. The leukemic T cell lines PEER and Lyon-1 express such a TCR-gamma delta/CD3 complex at the cell surface. In addition, PEER and Lyon-1 cells transcribe a productively rearranged TCR-beta gene. Introduction of TCR alpha-chain cDNA of human or murine origin resulted in cell surface expression of a TCR-alpha beta/CD3 complex on PEER and Lyon-1 cells. The expression of the TCR-gamma delta/CD3 complex on PEER cells was not affected by introduction of TCR-alpha cDNA. In contrast, introduction of a TCR-alpha cDNA and expression of the TCR-alpha beta/CD3 complex in Lyon-1 cells resulted in the disappearance of the TCR-gamma delta/CD3 complex. These data were confirmed by indirect immunofluorescence, at the protein level and by gene expression analysis. Triggering of the TCR-alpha beta/CD3 complexes by anti-CD3 mAb or anti-TCR mAb resulted in increased internal Ca2+ levels, indicating that these receptors were functional in signal transduction. These results indicate that, besides TCR gene rearrangements, membrane expression of TCR-alpha beta heterodimers may be important in regulating TCR-gamma delta cell surface expression.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1989

Human T cell leukemia/lymphoma virus type I infection of a CD4+ proliferative/cytotoxic T cell clone progresses in at least two distinct phases based on changes in function and phenotype of the infected cells.

The effect of human T cell leukemia/lymphoma virus type I (HTLV-I) infection on the function and the phenotype of a human proliferating/cytotoxic T cell clone, specific for tetanus toxin, was investigated. During the period after infection, two distinct phases were observed, based on growth properties, phenotype, and functional activity of the infected cells. Phase I HTLV-I infected cells (0 to about 150 days after infection) proliferated in an IL-2-dependent way, but without the requirement for repetitive antigenic stimulation. No differences in expression of the CD2, CD3, CD4, Tp103, and CD28 Ag between these cells and the parental cells could be demonstrated, with the exception of the expression of IL-R p55 and HLA-DR Ag, which were constitutively expressed on the phase I cells. The phase I HTLV-I-infected cells, as well as the parental 827 cells reacted with a mAb specific for an epitope on the variable part of the TCR beta-chain, indicating that the TCR was not altered after HTLV-I infection. Like the parental clone, the phase I cells proliferated in response to tetanus toxin, but the tetanus toxin-specific response of the phase I cells did not require the presence of APC. Results of experiments, in which the levels of intracellular Ca2+ were measured, indicated that HTLV-I cells can acquire the capability to process Ag and present that to themselves. Phase I HTLV-I-infected T cells had lost their cytotoxic activity which was likely to be due to an effect on the lytic machinery rather than on Ag recognition by the TCR, inasmuch as it was found that phase I HTLV-I-infected T cells did no longer contain N-alpha-benzyloxy-L-lysine thiobenzylester-serine esterase activity. Furthermore, it was found that phase I HTLV-I-infected T cells had a diminished capacity to form conjugates with target cells. From a period of about 200 days after HTLV-I infection, phase II cells emerged that proliferated strongly in the absence of IL-2 and that had lost all functional activity. These cells did not express the CD3/T cell receptor complex on their surface. Phase I as well as phase II HTLV-I-infected cells were targets for CTL raised in the autologous donor.

Antigen-Presenting Cells↗
PubMed1989

The role of Ca2+ and Mg2+ in the cytotoxic T lymphocyte reaction and in the secretion of N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester-serine esterase by human T cell clones.

Human T cell clones contain enzymes that can cleave the substrate N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester (BLT). All CTL clones tested in this study secreted BLT-serine esterase activity, whereas only one of three tested non-cytolytic T cell clones secreted this enzymatic activity upon Ag-specific activation. BLT-serine esterase secretion could also be induced by the Fc gamma+ target cell Daudi in the presence of mAb specific for the TCR/CD3 complex, CD2, or the T cell activation Ag Tp 103. In addition, anti-CD3 and a mitogenic combination of anti-CD2 mAb, induced secretion of BLT-serine esterase in the absence of target cells, whereas anti-Tp 103 failed to do so. The secreted BLT-serine esterase activity induced by the various ligands was inhibited by the serine esterase inhibitors PMSF and m-ABA, but not by N-alpha-p-tosyl-L-lysine chloromethyl ketone. Significant BLT-serine esterase activity was induced by target cells or soluble anti-CD3 in the absence of extracellular Ca2+ ions, provided that extracellular Mg2+ ions were present. The cytotoxic activities by the human CTL clones were completely blocked under these conditions. All ligands that induced BLT-serine esterase secretion in the absence of extracellular Ca2+, induced a transient rise of intracellular Ca2+. Soluble anti-CD3 mAb did not induce a transient rise in intracellular Ca2+ or secretion of BLT serine esterase in CTL preincubated for 2 h with 5 mM EGTA. These findings indicate that mobilization of intracellular Ca2+ in human CTL clones is required for induction of secretion of BLT-serine esterase.

Antibodies, Monoclonal↗
PubMed1989

Diversity and organization of human T cell receptor delta variable gene segments.

Previous studies of the human TCR-delta gene identified a single commonly used V delta segment, denoted V delta 1. To better understand the extent of the human TCR-delta V gene repertoire, TCR-delta transcripts and gene rearrangements were examined in a new panel of cloned human TCR-gamma/delta lymphocytes. Through this analysis we identified and determined the structures of two new V delta segments, denoted V delta 2 and V delta 3. These V delta segments are different from previously characterized V alpha segments, supporting the notion that the human V delta and V alpha repertoires are distinct. Examination of V gamma gene segment usage in these cells reveals that the V delta 2 gene segment is used in conjunction with the V gamma 2 gene segment. Blot hybridization indicates that the V delta 2 gene segment lies between V delta 1 and D delta-J delta-C delta, and within 100 kb of the latter. Analysis of genomic clones indicates that the V delta 3 gene segment lies in an inverted orientation, approximately 2 kb 3' of C delta. This implies that rearrangement of V delta 3 to D delta-J delta-C delta occurs by inversion. Together with previous mapping studies, these results indicate that human V delta segments are dispersed, rather than clustered, within the TCR-alpha/delta locus. The analysis of rearrangements in polyclonal thymocyte DNA suggests that there may be a limited number of additional V delta gene segments yet to be characterized.

Amino Acid Sequence↗
PubMed1989

Interplay between the TCR/CD3 complex and CD4 or CD8 in the activation of cytotoxic T lymphocytes.

Interactions between CTL and target cells occur in the absence of specific antigen recognition and precede subsequent interaction of the TCR with its specific antigen. This antigen-independent adhesion progresses through two different pathways, one involving the interaction of CD2 with LFA-3 on the target cell, the second the interaction of LFA-1 with ICAM-1. Such antigen-independent adhesions are critical for the activation of T cells via the TCR. Also, CD4 and CD8 can serve as adhesion molecules by binding to monomorphic determinants expressed on class II and class I MHC antigens, respectively, on the target cells, but compared to LFA-1 and CD2 antigens their contribution to conjugate formation is minor. CD4 and CD8 are required for effective T-cell activation in situations where the intrinsic affinity of the TCR or antigen expression is low, suggesting that CD4 and CD8 enhance the avidity of T cells for target cells by binding to class II and class I antigen, respectively. However, CD4 and CD8 are also involved in post-binding events that lead to CTL activation and subsequent lysis of the target cells. On the other hand, blocking of anti-TCR/CD3 mAb-induced CTL reactivity by anti-CD4/CD8 mAbs does not necessarily involve an interference with the binding of CD4 and CD8 to their respective ligands and it has been proposed that the TCR and CD4 or CD8 form functional complexes that are required for optimal T-cell activation. It is still unclear whether blocking by anti-CD4/CD8 mAbs is based on the prevention of complex formation of the TCR with CD4 or CD8, since formation of such complexes has yet to be demonstrated. The alternative hypothesis, that anti-CD4/anti-CD8 mAbs can directly confer negative regulatory signals to the CTL is not supported by our studies with antibody-directed lysis mediated by a CD4+, CD8+ CTL clone. Anti-CD4/CD8 mAbs can also inhibit T-cell cytotoxicity induced by other T-cell surface activation antigens such as CD2 or Tp103. In these situations, the triggering may involve signals transferred via CD3 requiring functional CD3/CD8 or CD3/CD4 complexes. Although most studies investigating the sequence of events leading to T-cell activation are carried out with CTL, preliminary data indicate that the same mechanisms described here for CTL activation are probably also valid for the interactions of T-helper cells with APC or B cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗