A new look at T cell receptor signaling to nuclear factor-κB

doi:10.1016/j.it.2013.02.002

Trends in Immunology

Volume 34, Issue 6, June 2013, Pages 269-281

https://doi.org/10.1016/j.it.2013.02.002 Get rights and content

Antigen stimulation of T cell receptor (TCR) signaling to nuclear factor (NF)-κB is required for T cell proliferation and differentiation of effector cells. The TCR-to-NF-κB pathway is generally viewed as a linear sequence of events in which TCR engagement triggers a cytoplasmic cascade of protein–protein interactions and post-translational modifications, ultimately culminating in the nuclear translocation of NF-κB. However, recent findings suggest a more complex picture in which distinct signalosomes, previously unrecognized proteins, and newly identified regulatory mechanisms play key roles in signal transmission. In this review, we evaluate recent data and suggest areas of future emphasis in the study of this important pathway.

Highlights

► TCR activation of NF-κB involves a complex web of interconnected signal transducers. ► Many negative regulatory mechanisms cooperatively modulate the TCR-to-NF-κB pathway. ► Both a plasma membrane and a cytosolic signalosome participate in TCR signaling to NF-κB.

Section snippets

The current consensus model of TCR signaling to NF-κB

In the past decade, much progress has been made in defining molecular mechanisms by which the TCR (see Glossary) activates the NF-κB transcription factor. Most of the key mediators in this cascade are now defined, and many key signal transmission mechanisms have been elucidated 1, 2, 3, 4 (Figure 1, Figure 2). The general consensus understanding is that engagement of the TCR by major histocompatibility complex (MHC) plus antigen initiates downstream CD3 immunotyrosine activation motif (ITAM)

New developments in the TCR-to-NF-κB pathway

Deletion of the genes encoding PKCθ and CBM complex proteins results in impaired TCR-induced NF-κB activation. Recent work has also identified several additional molecules that regulate this pathway (Figure 1).

Cell surface TCR microclusters and the IS

The concept of the IS developed in the late 1990s when imaging revealed micrometer-sized clusters, composed of surface receptors and signaling proteins, at the T cell–APC intercellular contact site 68, 69. Initially, the IS was proposed as the site at which intracellular signaling from the TCR is initiated and sustained. Later studies showed that initiation of TCR signaling and tyrosine kinase activation can be detected within seconds following stimulation and before IS formation, in peripheral

Negative regulation of TCR signaling to NF-κB

TCR activation of NF-κB is critical for T cell proliferation and differentiation. However, unrestricted and persistent NF-κB activation can lead to development of autoimmune diseases and neoplasms [83], cellular senescence [84], or apoptosis [85]. In order to strike a balance between productive T cell activation and deleterious consequences of excessive NF-κB activation, TCR signaling has to be precisely regulated. After T cell activation, negative regulation starts at the level of cell surface

Concluding remarks

Recent findings have significantly altered our views of TCR signaling to NF-κB. Certain mediators, such as PKCθ and CARMA1, are phosphorylated by multiple kinases, dispelling early models that postulated a simple linear cascade by which the TCR transmits activating signals to NF-κB. Studies have also revealed that cytosolic mediators in this pathway do not all coalesce in a single TCR-proximal signalosome at the IS. Rather, cytosolic signalosomes far removed from the TCR are also integral to

Acknowledgments

The authors thank A. Snow, C. Gray, K. McCorkell, M. May, and C-Z. Giam for critical reading of the manuscript. Supported by grants from the US National Institutes of Health (AI057481 to B.C.S.), the Center for Neuroscience and Regenerative Medicine (CNRM) (to B.C.S.), and pre-doctoral fellowships (to S.P.) from the American Heart Association (10PRE3150039) and the Henry M. Jackson Foundation. The views expressed are those of the authors and do not necessarily reflect those of the Uniformed

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Published by Elsevier Ltd.

Trends in Immunology

ReviewA new look at T cell receptor signaling to nuclear factor-κB

Highlights

Section snippets

The current consensus model of TCR signaling to NF-κB

New developments in the TCR-to-NF-κB pathway

Cell surface TCR microclusters and the IS

Negative regulation of TCR signaling to NF-κB

Concluding remarks

Acknowledgments

Immunity

Trends Immunol.

Immunity

Immunity

Mol. Immunol.

Mol. Immunol.

J. Biol. Chem.

Mol. Cell

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Immunity

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Dev. Cell

Mol. Cell

Curr. Biol.

J. Biol. Chem.

Cell. Signal.

J. Biol. Chem.

Immunity

Cell

Cell

Immunity

Immunity

Semin. Cell Dev. Biol.

Exp. Cell Res.

Immunity

J. Biol. Chem.

Immunity

Mol. Immunol.

FEBS Lett.

J. Biol. Chem.

Mol. Cell

Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1

Cold Spring Harb. Perspect. Biol.

Regulation and function of NF-kappaB transcription factors in the immune system

Annu. Rev. Immunol.

T cell activation

Annu. Rev. Immunol.

The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-kappaB and activate T cells

Nat. Immunol.

PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation

Science

An active kinase domain is required for retention of PKCtheta at the T cell immunological synapse

Mol. Biol. Cell

Complex and dynamic redistribution of NF-kappaB signaling intermediates in response to T cell receptor stimulation

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

CD28 plays a critical role in the segregation of PKC theta within the immunologic synapse

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

The kinase GLK controls autoimmunity and NF-kappaB signaling by activating the kinase PKC-theta in T cells

Nat. Immunol.

Oncogenic CARD11 mutations induce hyperactive signaling by disrupting autoinhibition by the PKC-responsive inhibitory domain

Biochemistry

A quantitative signaling screen identifies CARD11 mutations in the CARD and LATCH domains that induce Bcl10 ubiquitination and human lymphoma cell survival

Mol. Cell. Biol.

Serine 649 phosphorylation within the protein kinase C-regulated domain down-regulates CARMA1 activity in lymphocytes

J. Immunol.

Activation or suppression of NFkappaB by HPK1 determines sensitivity to activation-induced cell death

EMBO J.

Phosphorylation of CARMA1 by HPK1 is critical for NF- B activation in T cells

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

Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses

Nat. Immunol.

A novel pathway down-modulating T cell activation involves HPK-1-dependent recruitment of 14-3-3 proteins on SLP-76

J. Exp. Med.

Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival

Nature

Ca2+/calmodulin-dependent protein kinase II is a modulator of CARMA1-mediated NF-kappaB activation

Mol. Cell. Biol.

Regulation of NF-kappaB activation in T cells via association of the adapter proteins ADAP and CARMA1

Science

Review
A new look at T cell receptor signaling to nuclear factor-κB

Ca²⁺/calmodulin-dependent protein kinase II is a modulator of CARMA1-mediated NF-kappaB activation