Do CD4 and CD8 control T-cell activation via a specific tyrosine protein kinase?

doi:10.1016/0167-5699(89)90322-8

Immunology Today

Volume 10, Issue 6, June 1989, Pages 189-192

Immunology Today

https://doi.org/10.1016/0167-5699(89)90322-8 Get rights and content

Abstract

The CD4 and CD8 glycoproteins play an important role in T-cell activation by binding to major histocompatibility complex (MHC) class II or class I molecules, respectively, and stabilizing their interactions with the T-cell receptor-CD3 complex during antigen presentation. Recent evidence suggesting that the cytoplasmic domains of CD4 and CD8 are physically, and perhaps functionally, linked to the T-cell specific tyrosine protein kinase, p56^lck, adds a new dimension to our current understanding of their physiological function. Based on these and other recent findings, Tomas Mustelin and Amnon Altman present a working hypothesis that defines a novel role for CD4 or CD8 in regulating T-cell activation, and perhaps other processes, such as thymic repertoire selection and human immunodeficiency virus (HIV)-induced immunosuppression.

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Citation Excerpt :
Elevated phosphorylation at early time points and decreased phosphorylation in later time points was also observed on CD3ε, -δ, -γ, and -ζ chains (supplemental Fig. S7) and ZAP-70 (supplemental Fig. S6B) in SLP-76 Y3F mutant cells. Phosphorylation of ITAM domains on the ε, δ, γ, and ζ CD3 subunits by Lck is key to the initiation of signaling cascades that characterize T-cell activation (50–55). In Y3F mutant cells, elevated phosphorylation at early time points and decreased phosphorylation at later time points were observed on Tyr149 and Tyr160 of the CD3δ chain (Q value < 0.05).
SRC homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is a cytosolic adaptor protein that plays an important role in the T-cell receptor–mediated T-cell signaling pathway. SLP-76 links proximal receptor stimulation to downstream effectors through interaction with many signaling proteins. Previous studies showed that mutation of three tyrosine residues, Tyr¹¹², Tyr¹²⁸, and Tyr¹⁴⁵, in the N terminus of SLP-76 results in severely impaired phosphorylation and activation of Itk and PLCγ1, which leads to defective calcium mobilization, Erk activation, and NFAT activation. To expand our knowledge of the role of N-terminal phosphorylation of SLP-76 from these three tyrosine sites, we characterized nearly 1000 tyrosine phosphorylation sites via mass spectrometry in SLP-76 reconstituted wild-type cells and SLP-76 mutant cells in which three tyrosine residues were replaced with phenylalanines (Y3F mutant). Mutation of the three N-terminal tyrosine residues of SLP-76 phenocopied SLP-76-deficient cells for the majority of tyrosine phosphorylation sites observed, including feedback on proximal T-cell receptor signaling proteins. Meanwhile, reversed phosphorylation changes were observed on Tyr¹⁹² of Lck when we compared mutants to the complete removal of SLP-76. In addition, N-terminal tyrosine sites of SLP-76 also perturbed phosphorylation of Tyr⁴⁴⁰ of Fyn, Tyr⁷⁰² of PLCγ1, Tyr²⁰⁴, Tyr³⁹⁷, and Tyr⁶⁹ of ZAP-70, revealing new modes of regulation on these sites. All these findings confirmed the central role of N-terminal tyrosine sites of SLP-76 in the pathway and also shed light on novel signaling events that are uniquely regulated by SLP-76 N-terminal tyrosine residues.
Spatiotemporal control of cyclic AMP immunomodulation through the PKA-Csk inhibitory pathway is achieved by anchoring to an Ezrin-EBP50-PAG scaffold in effector T cells
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A variety of immunoregulatory signals to effector T cells from monocytes, macrophages and regulatory T cells act through cyclic adenosine monophosphate. In the effector T cell, the protein kinase A (PKA) type I isoenzyme localizes to lipid rafts during T cell activation and modulates directly the proximal events that take place after engagement of the T cell receptor. The most proximal target for PKA phosphorylation is C-terminal Src kinase (Csk), which initiates a negative signal pathway that fine-tunes the T cell activation process. The A kinase anchoring protein Ezrin colocalizes PKA and Csk by forming a supramolecular signaling complex consisting of PKA, Ezrin, Ezrin/radixin/moesin (ERM) binding protein of 50 kDa (EBP50), phosphoprotein associated with glycosphingolipid-enriched membrane microdomains (GEMs) (PAG) and Csk.
Arsenic interferes with the signaling transduction pathway of T cell receptor activation by increasing basal and induced phosphorylation of Lck and Fyn in spleen cells
2008, Toxicology and Applied Pharmacology
Arsenic is known to produce inhibition as well as induction of immune cells proliferative responses depending on the doses as one of its mechanisms of immunotoxicity. Here we evaluate the effect of arsenic exposure on the activation of splenic mononuclear cells (SMC) in male CD57BL6N mice. Intra-gastric exposure to arsenic (as sodium arsenite) for 30 days (1, 0.1, or 0.01 mg/kg/day), reduced the proportion of CD4+ cells and the CD4+/CD8+ ratio in the spleen, increasing the proportion of CD11b+ cells. Arsenic exposure did not modify the proportion of B cells. SMC showed an increased level of phosphorylation of lck and fyn kinases (first kinases associated to TCR complex when activated). Although normal levels of apoptosis were observed on freshly isolated SMC, an increase in apoptotic cells related with the increase in phosphorylation of lck and fyn was observed when SMC were activated with Concanavalin-A (Con-A). Arsenic exposure reduced the proliferative response of SMC to Con-A, and also reduced secretion of IL-2, IL-6, IL-12 and IFNγ. No effect was observed on IL-4, and IL-10 secretion. The same effects were observed when SMC of exposed animals were activated with anti-CD3/CD28 antibodies for 24 h, but these effects were transitory since a recovery, up to control levels or even higher, were observed after 72 h of stimulation. This study demonstrates that repeated and prolonged exposure to arsenic alters cell populations and produces functional changes depending on the specific activation pathway, and could be related with the phosphorylation status of lck and fyn kinases.
A weak Lck tail bite is necessary for lck function in T cell antigen receptor signaling
2007, Journal of Biological Chemistry
Src family kinases are suppressed by a “tail bite” mechanism, in which the binding of a phosphorylated tyrosine in the C terminus of the protein to the Src homology (SH) 2 domain in the N-terminal half of the protein forces the catalytic domain into an inactive conformation stabilized by an additional SH3 interaction. In addition to this intramolecular suppressive function, the SH2 domain also mediates intermolecular interactions, which are crucial for T cell antigen receptor (TCR) signaling. To better understand the relative importance of these two opposite functions of the SH2 domain of the Src family kinase Lck in TCR signaling, we created three mutants of Lck in which the intramolecular binding of the C terminus to the SH2 domain was strengthened. The mutants differed from wild-type Lck only in one to three amino acid residues following the negative regulatory tyrosine 505, which was normally phosphorylated by Csk and dephosphorylated by CD45 in the mutants. In the Lck-negative JCaM1 cell line, the Lck mutants had a much reduced ability to transduce signals from the TCR in a manner that directly correlated with SH2-Tyr(P)⁵⁰⁵ affinity. The mutant with the strongest tail bite was completely unable to support any ZAP-70 phosphorylation, mitogen-activated protein kinase activation, or downstream gene activation in response to TCR ligation, whereas other mutants had intermediate abilities. Lipid raft targeting was not affected. We conclude that Lck is regulated by a weak tail bite to allow for its activation and service in TCR signaling, perhaps through a competitive SH2 engagement mechanism.
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The discovery that a single amino acid substitution in the PTPN22 protein tyrosine phosphatase can predispose to so many autoimmune diseases (see chapters 2 and 3), even when present in a single copy, raises many questions regarding the broader significance of this observation. Is there something unique about PTPN22 or are genetic variants of other protein tyrosine phosphatases likely also associated with autoimmune disease? If so, will polymorphisms in other phosphatases be found in the same spectrum of diseases? Are protein tyrosine phosphatases like PTPN22 good drug targets for the treatment of human autoimmunity? In this review, I offer some basis for thinking about these questions.
Apoptosis of CD4<sup>+</sup> T cells induced after contact with HIV1-infected or non-infected macrophages
1997, Research in Virology
The hallmark of human immunodeficiency virus type 1 (HIV1) infection is the relentless destruction of CD4⁺ T lymphocytes. Indirect cell killing mechanisms are thought to play an outstanding role in lymphocyte depletion. One such proposed mechanism is the induction of apoptosis through cross-linking of the CD4 receptor by anti-CD4 antibodies or by the HIV1 envelope protein expressed at the surface of infected cells. Here we provide evidence that apoptosis is triggered in CD4⁺ lymphoblastoid cells (MT4) following cocultivation with monocyte-derived macrophages (MDMs) productively infected with the monocytotropic isolate HIV1 PAR. Blocking virus replication by AZT abrogates apoptosis of MT4 cells. Infected MDMs do not transmit virus infection to target cells. DNA nucleosomal fragmentation occurs at 46–66 h after starting cocultures. It is inhibited by the addition of neutralizing anti-gp120 monoclonal antibody (mAb), implying that the gp120/CD4 interaction triggers the apoptotic process. Cocultivating with MDMs, either infected or not, in the presence of anti-CD4 mAb Leu-3a, also leads to MT4 cell death, with DNA fragmentation being detected at 24–40 h. Leu-3a induced apoptosis does not require cross-linking of CD4 by anti-immunoglobulin, showing that MDMs provide an alternative to conventional cross-linking. Both the infected and the non-infected MDMs were found to stimulate ³H-thymidine incorporation in cocultivated MT4 cells.
La diminution du nombre des lymphocytes T4 est la caractéristique majeure de l'infection par le virus de l'immunodéficience humaine (VIH) Une hypothèse actuelle est que cette diminution ressort de mécanismes létaux dits indirects dans la mesure où les cellules qui meurent ne sont pas les cellules infectées. Le pontage du récepteur CD4 serait l'un de ces mécanismes. Il est montré ici que les cellules de la lignée établie MT4 (CD4⁺) co-cultivées avec des macrophages infectés par l'isolat monocytotrope VIH1 PAR subissent un processus de mort cellulaire par apoptose. Ce processus est inhibé lorsque la réplication virale est bloquée par le traitement des macrophages par l'AZT. Les cellules MT4 qui meurent par apoptose meurent sans être infectées. L'apoptose est décelée entre 46 et 66 heures de coculture. Elle est inhibée par les anticorps monoclonaux anti-gp120 clone 110-A et 110-B, ce qui montre qu'elle est déclenchée par l'interaction gp120/CD4. Les cellules MT4 co-cultivées avec des macrophages non infectés en présence d'anticorps monoclonal anti-CD4 (Leu-3a) sont également le siège d'un processus d'apoptose qui se produit entre 24 et 40 heures, et en l'absence de pontage du site CD4 par des anti-immunoglobulines. Les macrophages, infectés ou non, stimulent l'incorporation de la thymidine tritiée dans les cellules MT4.

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^☆: This is Publication Number 57711MM from the Department of Immunology, Research Institute of Scripps Clinic, 10666 North Torrey Pines Road, La Jolla, CA 92037. The work reported herein was supported, in part, by US PHS grants CA35299 and AR35411, a Leukemia Society of America, Inc. Scholarship (AA), the Finska Läkaresällskapet, J.W. Perklens Stiftelse, Duodecim and the Ella and Georg Ehrnrooth Foundation.

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rostrumDo CD4 and CD8 control T-cell activation via a specific tyrosine protein kinase?☆

Abstract

J. Biol. Chem.

Cell

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

Cell

Immunol. Today

Immunol. Today

J. Biol. Chem.

Virology

Science

Science

J. Immunol.

Nature

Science

Nature

EMBO J.

Mol. Cell. Biol.

rostrum
Do CD4 and CD8 control T-cell activation via a specific tyrosine protein kinase?☆