Stimulation and proliferation of CD4<sup>+</sup> peripheral blood T lymphocytes induced by an anti‐CD4 monoclonal antibody

Carrel, Stefan; Moretta, Alessandro; Pantaleo, Giuseppe; Tambussi, Giuseppe; Isler, Patrick; Perussia, Bice; Cerottini, Jean‐Charles

doi:10.1002/eji.1830180303

Cited by 66 publications

(14 citation statements)

References 55 publications

(4 reference statements)

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“…Contrasting data have been reported on the ability of CD4 to induce increases in [Ca'+], [27,47,481. Different anti-CD4 mAb were used in these experiments, raising the question of the role of distint CD4 epitopes in inducing calcium flux.…”

Section: Cd4 Epitopes Differ In Their Abillity To Induce Calcium Fluxmentioning

confidence: 67%

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Distinct signaling properties identify functionally different CD4 epitopes

et al. 1995

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The CD4 coreceptor interacts with non-polymorphic regions of major histocompatibility complex class II molecules on antigen-presenting cells and contributes to T cell activation. We have investigated the effect of CD4 triggering on T cell activating signals in a lymphoma model using monoclonal antibodies (mAb) which recognize different CD4 epitopes. We demonstrate that CD4 triggering delivers signals capable of activating the NF-AT transcription factor which is required for interleukin-2 gene expression. Whereas different anti-CD4 mAb or HIV-1 gp120 could all trigger activation of the protein tyrosine kinases p56lck and p59fyn and phosphorylation of the Shc adaptor protein, which mediates signals to Ras, they differed significantly in their ability to activate NF-AT. Lack of full activation of NF-AT could be correlated to a dramatically reduced capacity to induce calcium flux and could be complemented with a calcium ionophore. The results identify functionally distinct epitopes on the CD4 coreceptor involved in activation of the Ras/protein kinase C and calcium pathways.

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Section: Cd4 Epitopes Differ In Their Abillity To Induce Calcium Fluxmentioning

confidence: 67%

“…B66.6 anti-CD4 mAb [27] was a gift of 0. Acuto and BMA031 mAb [28] was kindly provided by R. Kurrle.…”

Section: Antibodies and Gpl20mentioning

confidence: 99%

Distinct signaling properties identify functionally different CD4 epitopes

et al. 1995

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“…Depending on how the assay is done, CD4 and CD8 can be shown to deliver both positive and negative signals in cultured cells (2,5,16,33,39,48,50). However, because the cytoplasmic domains of both CD4 and CD8, with which p56Ick interacts, have been shown to be important in the activation of several T-cell lines by antigen (39,50), it appears likely that pS6Ick can participate in positive signaling under some circumstances.…”

Section: Resultsmentioning

confidence: 99%

Cross-linking of T-cell surface molecules CD4 and CD8 stimulates phosphorylation of the lck tyrosine protein kinase at the autophosphorylation site.

Luo¹,

Sefton²

1990

Mol. Cell. Biol.

155

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pS6kk, a lymphocyte-specific tyrosine protein kinase, binds to the cytoplasmic tails of the T-cell surface molecules CD4 and CD8. Cross-linking of CD4 expressed on the surface of murine thymocytes, splenocytes, and CD4+ T-cell lines induced tyrosine phosphorylation of p56kk dramatically. Cross-linking of CD8 stimulated tyrosine phosphorylation of p56kk strongly in murine L3 and GA4 cells, slightly Tyr-394 was the predominant site of increased tyrosine phosphorylation in two leukemic cell lines. In the other two cell lines, the phosphorylation of both Tyr-394 and an inhibitory site, Tyr-505, was found to increase. In contrast to cross-linking with antibodies, no striking increase in the tyrosine phosphorylation of ps6ck was stimulated by antigenic stimulation. Therefore, the effect of antibody-induced aggregation of CD4 and CD8 on the tyrosine phosphorylation of p56kk differs, at least quantitatively, from what occurs during antigen-inducedIck is a member of the src family of genes that encode cytoplasmic protein tyrosine kinases. Its product, p561ck, is expressed almost exclusively in lymphoid cells and tissues (6,22,28,41,47). Like other protein tyrosine kinases, p56'ck is thought to play a role in the generation of growth regulatory signals. p561ck binds to the cytoplasmic tails of the T-cell surface molecules CD4 and CD8 in both human and murine T cells (35,38,43,50). Its association with CD4 and CD8 suggests that it may play a role in a signal transduction pathway during T-cell activation or T-cell maturation.CD4 and CD8 bind to class II and class I major histocompatibility proteins, respectively, during antigen-induced T-cell activation (8,11,(30)(31)(32) and during T-cell maturation (9, 21, 37). In addition to increasing adhesion between T cells and antigen-presenting cells, several lines of evidence suggest the involvement of CD4 and CD8 in transducing growth regulatory signals. It has been demonstrated that a truncated form of CD4 that is missing the cytoplasmic domain is less effective than wild-type CD4 at enhancing interleukin-2 production by T cells (39). In addition, studies with CD8a', a form of CD8 lacking most of the cytoplasmic tail, have demonstrated that the cytoplasmic domain of CD8 is also required for antigen-induced T-cell activation (50). The cytoplasmic domains of CD4 and CD8 are therefore likely to be involved in positive signaling during T-cell activation.Since it is the cytoplasmic tails of CD4 and CD8 with which p561ck interacts (38, 50), the inability of these truncated forms of CD4 and CD8 to enhance T-cell activation by antigen suggests that p561ck is involved in positive signaling during T-cell activation.Evidence for negative signaling through CD4, however, * Corresponding author.comes from the observation that treatment of cells with anti-CD4 antibody, such as GK1.5, blocks Ca2" influx at an early stage of T-cell activation (33, 40) and inhibits both antigen-stimulated and lectin-induced interleukin-2 production (2, 33, 48). It is possible, therefore, that pS6lck can also pla...

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“…In early studies, anti-CD4 mAbs were found capable to induce either cell depletion [26] or functional inactivation of T cells [27,28], although activation of T-cell functions was also reported[29]. These divergent effects may explain the inconsistency in the clinical efficacy of different anti-CD4 mAbs particularly in the treatment of rheumatoid arthritis, namely a promising initial efficacy in open anti-CD4 trials [30,31], subsequent discouraging double-blind clinical trials (reviewed in [32]), and, finally, a revitalization of the anti-CD4 treatment notion with new, humanized anti-CD4 mAbs [33].…”

Section: ) Anti-cd4 Antibodies In Clinical Practice: Beyond Immune Smentioning

confidence: 99%

Protective versus pathogenic anti-CD4 immunity: insights from the study of natural resistance to HIV infection

et al. 2009

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HIV-1 exposure causes several dramatic unbalances in the immune system homeostasis. Here, we will focus on the paradox whereby CD4 specific autoimmune responses, which are expected to contribute to the catastrophic loss of most part of the T helper lymphocyte subset in infected patients, may display the characteristics of an unconventional protective immunity in individuals naturally resistant to HIV-1 infection. Reference to differences in fine epitope mapping of these two oppositely polarized outcomes will be presented, with particular reference to partially or totally CD4-gp120 complex-specific antibodies. The fine tuning of the anti-self immune response to the HIV-1 receptor may determine whether viral exposure will result in infection or, alternatively, protective immunity.Along this line, an efficacious anti-HIV strategy can rely on the active (i.e., through immunization) or passive targeting of cryptic epitopes of the CD4-gp120 complex, including those harboured within the CD4 molecule. Such epitopes are expected to be safe from genetic drift and thus allow for broad spectrum of efficacy. Moreover, since these epitopes are not routinely exposed in uninfected individuals, they are expected to become targets of neutralizing antibodies or other specifically designed molecules only after viral exposure, with a predictable low impact in terms of potentially harmful anti-CD4 self-reactivity.The experimentum naturae of naturally resistant individuals indicates a strategy to design innovative strategies to neutralize HIV-1 by acting on the sharp edge between harmful and protective self-reactivity.

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Stimulation and proliferation of CD4⁺ peripheral blood T lymphocytes induced by an anti‐CD4 monoclonal antibody

Cited by 66 publications

References 55 publications

Distinct signaling properties identify functionally different CD4 epitopes

Distinct signaling properties identify functionally different CD4 epitopes

Cross-linking of T-cell surface molecules CD4 and CD8 stimulates phosphorylation of the lck tyrosine protein kinase at the autophosphorylation site.

Protective versus pathogenic anti-CD4 immunity: insights from the study of natural resistance to HIV infection

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Stimulation and proliferation of CD4+ peripheral blood T lymphocytes induced by an anti‐CD4 monoclonal antibody

Cited by 66 publications

References 55 publications

Distinct signaling properties identify functionally different CD4 epitopes

Distinct signaling properties identify functionally different CD4 epitopes

Cross-linking of T-cell surface molecules CD4 and CD8 stimulates phosphorylation of the lck tyrosine protein kinase at the autophosphorylation site.

Protective versus pathogenic anti-CD4 immunity: insights from the study of natural resistance to HIV infection

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Stimulation and proliferation of CD4⁺ peripheral blood T lymphocytes induced by an anti‐CD4 monoclonal antibody