Regulation of Lck activity by CD4 and CD28 in the immunological synapse

Holdorf, Amy D.; Lee, Kyeong-Hee; Burack, W. Richard; Allen, Paul M.; Shaw, Andréy S.

doi:10.1038/ni761

Cited by 200 publications

(181 citation statements)

References 45 publications

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“…Investigators found that CD28 co-stimulation maintained the activation of the Src-family tyrosine kinase Lck, which can be recruited to transmit TCR signaling. 19 In contrast, in CD28-deficient T cells, Lck phosphorylation was rapidly diminished in that study. 19 Furthermore, CD28-induced Lck activation leads to phosphorylation of STAT3, whereas inhibition of Lck activity, or JAK/STAT3 signaling, blocks STAT3 phosphorylation and downstream cytokine production.…”

Section: Introductionmentioning

confidence: 69%

“…19 In contrast, in CD28-deficient T cells, Lck phosphorylation was rapidly diminished in that study. 19 Furthermore, CD28-induced Lck activation leads to phosphorylation of STAT3, whereas inhibition of Lck activity, or JAK/STAT3 signaling, blocks STAT3 phosphorylation and downstream cytokine production. 20 Nevertheless, how CD28 activation may affect NKG2D expression on CD8 C T cells has yet to be reported.…”

Section: Introductionmentioning

confidence: 69%

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Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

Batth

Xia

et al. 2016

OncoImmunology

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The natural killer (NK) group 2D (NKG2D) receptor, which displays on mouse and human NK cells, activates CD8 C T cells and small subsets of other T cells. NKG2D C CD8 C T cells play critical roles in both innate and adaptive immunity upon engagement with NKG2D ligands to eliminate tumor and infected cells. Despite the important role of NKG2D C CD8 C T cells in immune surveillance, the mechanisms of how NKG2D expression on CD8 C T cells is regulated remain poorly defined. We treated mouse and human CD8 C T cells with CD80 recombinant protein, plus a pharmacologic model with small molecular inhibitors to determine which signaling pathway leads to NKG2D regulation on CD8 C T cells. This study revealed that CD28 activation gives rise to sustained NKG2D expression on both mouse and human CD8 C T cells in a signal transducer and activator of transcription 3 (STAT3) phosphorylation-dependent manner. Further, we found that CD28 activation stimulated sustained activation of the tyrosine kinase Lck, which recruits and triggers Janus kinase/STAT3 signaling to phosphorylate STAT3, and in turn increases NKG2D expression. Moreover, NKG2D induction on CD8 C T cells exerts cytolytic activity against target tumor cells in vitro, as well as significantly improves the antitumor therapeutic effects in vivo in an NKG2D-dependent manner. Taken together, these results elucidated a novel mechanism of NKG2D regulation by phosphorylated STAT3 (pSTAT3) on CD8 C T cells upon CD28 activation. This mechanism may shed light on the effectiveness of CD80-based, NKG2D-dependent antitumor immunotherapy.

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Section: Introductionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 69%

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

Batth

Xia

et al. 2016

OncoImmunology

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“…Although the CD4 molecule does not appear to be involved in the initial recognition by the TCR of specific peptide-MHC complexes, its association at the synapse is essential in allowing activation of Ag-specific T cells, probably by augmenting the T cell contact with the APC and by facilitating receptor cross-linking at the contact junction. As a matter of fact, a recent study has demonstrated that CD4 allows efficient recruitment of p56 lck and the transient autophosphorylation of lck at the synapse (55). In light of these experiments, it can be inferred that in our system, either monomeric or dimeric forms of CD4 are being recruited to the engaged TCR/Ag/MHC complexes.…”

Section: Discussionmentioning

confidence: 86%

CD4 Dimers Constitute the Functional Component Required for T Cell Activation

Moldovan

Yachou

Lévesque³

et al. 2002

The Journal of Immunology

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The CD4 molecule plays a key role in the development and activation of helper T cells. Dimerization and oligomerization is often a necessary step in the function of several cell surface receptors. Herein, we provide direct biochemical evidence confirming the presence of CD4 as dimers in transfected cells from hemopoetic and fibroblastic origin as well as in primary T cells. Such dimers are also observed with murine CD4 confirming selective pressure during evolution to maintain such a structure. Using a series of point mutations, we have precisely mapped the dimerization site at residues K318 and Q344 within the fourth extracellular domain of CD4. These residues are highly conserved and their mutation results in interference with dimer formation. More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. These data strongly suggest that CD4 dimerization is necessary for helper T cell function.

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“…Cross-linking of CD3/ CD28 induces downstream MAPK-dependent signaling to promote T-cell proliferation and production of cytokines includ- ing IL-2 (11). CD28-dependent costimulation signaling occurs by stimulation of Pi3k, Pkc and induces transcription activity of Nfkb, Rel, and c-Jun, promoting cell proliferation and cytokine production (11)(12)(13). Most of the gene products that were down-regulated in CD4 T cells were involved in cell proliferation and differentiation pathways and can be phosphorylated by TCR stimulation (14), including Vav3, Nfkb, Rel, and c-Jun.…”

Section: Discussionmentioning

confidence: 99%

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

Görgün¹,

Ramsay

Holderried³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

113

102

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Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-cell function in the chronic lymphocytic leukemia (CLL) E -TCL1 transgenic mouse model. With development of leukemia, E -TCL1 transgenic mice developed functional T-cell defects and alteration of gene and protein expression closely resembling changes seen in CLL human patients. Furthermore, infusion of CLL cells into young E -TCL1 mice induced defects comparable to those seen in mice with developed leukemia, demonstrating a causal relationship between leukemia and the T-cell defects. Altered pathways involved genes regulating actin remodeling, and T cells exhibited dysfunctional immunological synapse formation and T-cell signaling, which was reversed by the immunomodulatory drug lenalidomide. These results further demonstrate the utility of this animal model of CLL and define a versatile model to investigate both the molecular mechanisms of cancer-induced immune suppression and immunotherapeutic repair strategies.C ancer cells induce changes in the tumor microenvironment.The mechanisms whereby this occurs are poorly understood, but include direct cancer cell-T cell interactions, production of immune-suppressive factors by cancer cells, and induction of regulatory T-cell subsets (1, 2). Understanding the elusive mechanisms of tumor-driven immune evasion will aid the refinement of existing cancer immunotherapy strategies and identify novel treatments. To date, preclinical animal models that closely model human cancer and, in particular, include examination of the immune-suppressive mechanisms used by cancer cells have been under-characterized. The identification and use of such models should allow better predictions of successful human responses to immunotherapy.Chronic lymphocytic leukemia (CLL) is an ideal model cancer to study immune T cells that have been exposed to circulating tumor B cells and is associated with immune dysfunction. CLL is the most common adult leukemia in North America and Europe and is currently incurable. Immunotherapeutic strategies are believed to represent a promising treatment modality for this disease if immune suppression can be controlled (3). Extensive research has been carried out using CLL human patient cells, including the characterization of altered gene and proteinexpression profiles (4) and suppressed functional responses in patient T cells compared to healthy-donor T cells (1, 5).We sought to determine whether development of leukemia in the well-established E -TCL1 transgenic murine model of CLL (6) would induce changes in nonmalignant T cells. To examine this, we examined changes in gene-expression profile, protein expression, and function in T cells from E -TCL1 transgenic mice as they developed CLL. We demonstrate that development of CLL in these transgenic mi...

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Regulation of Lck activity by CD4 and CD28 in the immunological synapse

Cited by 200 publications

References 45 publications

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

CD4 Dimers Constitute the Functional Component Required for T Cell Activation

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

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Regulation of Lck activity by CD4 and CD28 in the immunological synapse

Cited by 200 publications

References 45 publications

Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

CD4 Dimers Constitute the Functional Component Required for T Cell Activation

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

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Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism