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NF-B activation pathways induced by T cell costimulation

M. LIENHARD SCHMITZ^*,1, SUSANNE BACHER^* and OLIVER DIENZ

^* University of Bern, Department of Chemistry and Biochemistry, CH-3012 Bern, Switzerland; and
Immunobiology Program, Department of Medicine, University of Vermont, Burlington, Vermont, USA

¹Correspondence: University of Bern, Department of Chemistry and Biochemistry, Freiestr. 3, CH-3012 Bern, Switzerland. E-mail: Lienhard.Schmitz{at}ibc.unibe.ch

	ABSTRACT

TOP ABSTRACT INTRODUCTION EARLY SIGNALING EVENTS SMAC PROTEINS PKC{theta} PROTEIN KINASES ACTIVATION OF THE IKK... REFERENCES

 
Analysis of knockout mice and of T cells deficient for individual signaling proteins allowed the identification of novel members of the costimulation-induced NF-B activation pathway while biochemical approaches started to unveil their functional mechanisms. These results show that NF-B activation depends on an early wave of tyrosine phosphorylation that allows the inducible formation of multiprotein complexes containing several proteins required for NF-B activation: adaptor proteins including Src homology 2 domain-containing leukocyte phosphoprotein 76 (SLP-76) and proteins with enzymatic activity, such as phospholipase C (PLC) and the exchange factor Vav1. While Vav1 contributes to Rac-dependent reorganization of the actin cytoskeleton, activated PLC1 generates the protein kinase C (PKC) activator diacylglycerol. In T cells, the novel PKC isoform PKC is indispensable for NF-B activation and its enzymatic activity depends on recruitment to the immunological synapse. Downstream from PKC, the caspase recruitment domain (CARD) proteins CARD11/CARMA1 and Bcl10 relay T cell receptor-derived signals to the IB kinase (IKK) complex. Many members of the NF-B activation cascade, including the IKKs, are either constitutively or inducibly translocated to the lipid raft fraction, showing a highly organized spatial distribution of these NF-B activating proteins.—Schmitz, M. L., Bacher, S., Dienz, O. NF-B activation pathways induced by T cell costimulation.

Key Words: IKK • Vav • PKC

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EARLY SIGNALING EVENTS SMAC PROTEINS PKC{theta} PROTEIN KINASES ACTIVATION OF THE IKK... REFERENCES

 
TRANSCRIPTION FACTORS belonging to the NF-B/Rel family are important for the maturation and survival of T lymphocytes and the induced expression of gene products mediating innate and adaptive immunity. Although the NF-B activation pathways induced by IL-1 and TNF are relatively well characterized, the components of the NF-B activation cascade triggered by T cell costimulation are just emerging. T lymphocytes become fully activated by an antigen-presenting cell (APC) through triggering of their T cell receptor (TCR) complex and a costimulatory receptor such as CD28. T cell activation depends on simultaneous delivery of signals from both receptors, as repeated stimulation of the TCR alone leads to anergy and activation-induced cell death (1) . In the physiological context, CD28 serves to lower the threshold for TCR-mediated signaling, as illustrated in Fig. 1 .

View larger version (38K): [in this window] [in a new window]   Figure 1. The concept of costimulation for T cell activation.

At a biochemical level, the principle of costimulation is mirrored by the activation of NF-B (2) . NF-B target genes mediate innate and adaptive immune responses and contribute to the control of cell proliferation and apoptosis. The contribution of NF-B to innate immunity is mediated through induction of genes encoding cytokines, chemokines, enzymes, and antimicrobial peptides, making this transcription factor indispensable for building the first line of defense against invading pathogens (3) . A variety of functions contribute to the role of NF-B in adaptive immunity, including its antiapoptotic effects and the induced expression of MHC proteins, costimulatory molecules such as B7.1, and cytokines including IL-2, IL-12, and IFN (4) .

The NF-B transcription factor system consists of various DNA binding dimers that are retained in the cytoplasm upon association with an inhibitory IB protein. For a detailed description, consult some recent, excellent reviews (5 , 6) . Activation of NF-B by a wide array of stimuli—including cytokines such as IL-1 and TNF, byproducts of bacterial and viral infections, radiation, or T cell costimulation—leads to the onset of signaling cascades that ultimately converge at the level of the IKK complex. This complex is composed of the two catalytic subunits IKK and IKKß and the regulatory IKK (NEMO, IKKAP) protein. The IKK complex inducibly phosphorylates IB proteins, including IB, IBß, and IB. Phosphorylated IB is recognized by ß-TrCP, thus allowing subsequent polyubiquitination and proteasome-mediated destruction of IB (7) . Genetic evidence obtained from mouse models and from NF-B defects identified in humans demonstrates the importance of NF-B for an effective mounting of the immune response (8) . Therefore, hyperactivation of otherwise beneficial immune responses as seen in diseases such as asthma, arthritis, or autoimmunity may be combated by interference with NF-B activity. This review focuses on signal transducing proteins relevant for NF-B activation elicited by T cell costimulation, as schematically shown in Fig. 2 .

View larger version (46K): [in this window] [in a new window]   Figure 2. Schematic summary of the TCR/CD28-induced NF-B activation pathways in T cells.

	EARLY SIGNALING EVENTS

TOP ABSTRACT INTRODUCTION EARLY SIGNALING EVENTS SMAC PROTEINS PKC{theta} PROTEIN KINASES ACTIVATION OF THE IKK... REFERENCES

 
Interaction between a T lymphocyte and an APC results in a temporal and spatial reorganization of multiple cellular elements at the contact site between both cells, a specialized region referred to as the immunological synapse (9) . A large active multicomponent complex, termed supramolecular activation complex (SMAC), is formed at the immunological synapse (10 , 11) . This contact area is highly enriched in cholesterol- and sphingolipid-rich membrane microdomains, the lipid rafts. These are used as platforms for the assembly of the signaling complex and contain a number of constitutive or recruitable proteins (12) . Whereas the Src kinases LCK and FYN are constitutive residents of lipid rafts, ZAP-70 and members of the TEC (tyrosine kinase expressed in hepatocellular carcinoma) kinase family become inducibly transported to this membrane subdomain after stimulation. The early wave of protein tyrosine kinase (PTK) activation leads to the phosphorylation of a plethora of substrate proteins, contributing to the activation of intrinsic enzyme activities and allowing the dynamic disruption or formation of multiprotein signaling complexes (13) . Therefore, tyrosine phosphorylation couples TCR-derived signals to multiple downstream signaling pathways including activation of PLC1, stimulation of mitogen-activated protein kinase (MAPK) pathways, and activation of Vav1. The inhibitory effect of the broad spectrum PTK inhibitor herbimycin A for TCR/CD28-induced NF-B activation points to a role of early PTK activation (14) , and it will be interesting to look at the effects of further PTK inhibitors such as genestein and tryphostins. Jurkat leukemia T cells lacking the PTK ZAP-70 fail to activate NF-B in response to engagement of TCR and CD28 (15) . Further studies must also show whether other PTKs such as LCK and ITK (IL-2-inducible T cell kinase) are important members of the NF-B signaling cascade.

	SMAC PROTEINS

TOP ABSTRACT INTRODUCTION EARLY SIGNALING EVENTS SMAC PROTEINS PKC{theta} PROTEIN KINASES ACTIVATION OF THE IKK... REFERENCES

 
One of the first phosphorylated proteins at the immunological synapse is SLP-76. This adaptor protein lacks any intrinsic enzymatic activity but is important for recruitment and correct assembly of the SMAC at the cell membrane. Jurkat T cells lacking SLP-76 expression are disabled to induce IKK activation and NF-B activity after TCR/CD28 costimulation (15) . One interaction partner of SLP-76 is the lymphocyte-specific signaling protein Vav1. Similar to SLP-76, T cell costimulation induces tyrosine phosphorylation and SMAC translocation of Vav1 (16) . In vitro experiments show that Vav1, once activated by phosphatidylinositol-3,4,5-triphosphate (PIP3) binding and LCK phosphorylation, acts as a GDP/GTP exchange factor (GEF) for small GTPases of the RAC/RHO family (17 , 18) . Vav1 is a signal integrator for TCR- and CD28-derived events and controls several early events in T cell activation, including Ca²⁺ homeostasis and cytoskeletal reorganization (19 , 20) . The importance of Vav1 for the activation of NF-B was revealed by analysis of Vav1^-/- mice, which fail to induce NF-B activity after T cell costimulation (21) . Since addition of the ionophore ionomycin cannot rescue the defect in IB degradation in Vav1^-/- T cells, Vav1-mediated NF-B activation seems to be independent from calcium signals (21) . Accordingly, overexpression of Vav1 in T cells results in the activation of NF-B via induction of IKK activity and NF-B DNA binding (22) . The NF-B activating function of Vav1 relies on its GEF activity, as expression of a Vav1 mutant lacking GEF activity fails to reconstitute NF-B activation in a Vav1 null Jurkat cell line (23) .

Another SMAC protein that recently revealed its identity as a member of the NF-B activation cascade is PLC1, which converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol (1 , 4 , 5) -triphosphate (IP3) and diacylglycerol (DAG). While IP3 mobilizes Ca²⁺ from intracellular stores, DAG mediates activation of protein kinase C (PKC) family members (24) . Prenatal mortality of PLC1^–/– mice precludes analysis of this enzyme in a mouse model, but Jurkat cells deficient in PLC1 expression fail to induce NF-B activation in response to TCR/CD28 stimulation. Replenishment of PLC1 expression restores costimulation-induced IKK activity as well as NF-B DNA binding and trans-activation (16) , thus identifying PLC1 as an essential member of the TCR/CD28-triggered NF-B activation pathway.

A mechanistic link between Vav1 and PLC1 was recently established by analysis of double-positive thymocytes from Vav1^-/- mice, which fail to phosphorylate and activate PLC1 in response to T cell costimulation. This defect can be attributed to missing activation of the PTKs ITK and TEC and to a defective assembly of a signaling complex containing PLC1 and SLP-76 (25) . Accordingly, the activating tyrosine phosphorylation of PLC1 is absent in SLP-76-negative Jurkat in response to T cell costimulation. Thus, Vav1 and SLP-76 are essential for TCR/CD28-induced PLC1 activation in the NF-B signaling cascade.

Another adaptor protein important for TCR-mediated NF-B activation is SHC (SH2-containing sequence). It is a ZAP-70 substrate and inducibly associates with Grb2 after TCR stimulation (26) . Expression of a mutated form of SHC blocks TCR-induced signal transduction, while targeting of SHC to lipid rafts results in enhanced TCR signaling (27) . Jurkat T cells lacking SHC are unable to activate a NF-B-dependent reporter gene and show no induced IL-2 transcription (28) . Whereas the absence of SHC remains without effect on the induced nuclear translocation of p65, nuclear import of c-Rel is impaired. This finding provides an interesting opportunity to study differential gene expression between these two trans-activating members of the NF-B transcription factor family. However, the precise mechanisms leading to the selective failure of c-Rel recruitment to the nucleus remain to be established.

	PKC

TOP ABSTRACT INTRODUCTION EARLY SIGNALING EVENTS SMAC PROTEINS PKC{theta} PROTEIN KINASES ACTIVATION OF THE IKK... REFERENCES

 
This Ca²⁺-independent serine/threonine kinase is selectively expressed in T cells and skeletal muscle and has been revealed in several studies as an essential member of the NF-B activation cascade in T cells. Mature T lymphocytes from PKC^-/- mice fail to induce IB degradation after T cell costimulation, but NF-B activation induced by IL-1 or TNF remains unaffected (29) . In unstimulated T cells, Vav1 is found in association with PKC, whereas T cell costimulation leads to the transient dissociation of the Vav1/PKC complex (22) . Expression of a constitutively active form of PKC, but not of any other PKC isoform, potently activates NF-B in T cells (22 , 30 , 31) . PKC exerts its activating effects on NF-B upon triggering of IKK activity, but it also stimulates the trans-activating function of NF-B by physical and functional cooperation with Akt1 (protein kinase B) (32) . The activating function of PKC for NF-B strictly relies on its kinase activity, but direct phosphorylation substrates on the road to NF-B activation remain incompletely defined. After T cell stimulation, only PKC, none of the other various PKC isoforms, is selectively transported to lipid rafts contained within the immunological synapse (33 , 34 , 35) . This inducible raft translocation of PKC is required for its NF-B activating function (34) . Lipid raft recruitment is a regulated process that depends on LCK, phosphatidylinositol 3-kinase (PI3-K), 3-phosphoinositide-dependent kinase-1 (PDK1) (36) , and SLP-76 (16) .

The relative importance of PLC1 and Vav1 for lipid raft recruitment of PKC does not yield a coherent picture. Selective inhibition of PLC1 enzymatic activity or expression of a dominant-negative PLC1 mutant does not preclude PKC raft recruitment (36) . On the other hand, Jurkat cells lacking PLC1 fail to translocate PKC to the lipid raft fraction (16) , suggesting that the importance of PLC1 for PKC raft recruitment can be attributed to its function as an adaptor protein rather than to its enzymatic function. Although PKC transport to lipid rafts cannot be seen in T cells from Vav1^-/- mice (37) , a Vav1-deficient human Jurkat cell line generated by somatic gene targeting shows normal raft translocation (23) . These differences may reflect species specificity or, alternatively, suggest that the recruitment pathways depend on the developmental stage of the T cell. Accordingly, PKC is required only for NF-B activation in mature T lymphocytes but not in thymocytes (29) .

	PROTEIN KINASES

TOP ABSTRACT INTRODUCTION EARLY SIGNALING EVENTS SMAC PROTEINS PKC{theta} PROTEIN KINASES ACTIVATION OF THE IKK... REFERENCES

 
A variety of different protein kinases have been implicated in the TCR-induced NF-B activation pathway. One of these is calmodulin-dependent kinase II (CaMKII). Overexpression of a constitutively active form of this Ca²⁺-dependent kinase leads to NF-B activation in T cells. A CaMKII inhibitor prevents degradation of IB induced by TCR- or the phorbol ester PMA (38) . In contrast, activation of NF-B by TNF is not affected in the presence of this inhibitor, pointing to a pathway-specific role of CaMKII. In addition, IB degradation by the pleiotropic PKC activator PMA does not occur in the presence of a CaMKII inhibitor, suggesting CaMKII acts downstream from PKC.

In T cells, two MAPKKKs have been shown to be important for T cell costimulation-induced NF-B activity: mixed lineage kinase-3 (MLK3) and the proto-oncogene COT/Tpl-2. Expression of the wild-type form of MLK3 induces nuclear immigration and DNA binding of NF-B, whereas MLK3-induced transcriptional activity of NF-B is relatively weak (39) . MLK3 directly binds and phosphorylates both IKKs. A kinase-deficient version of MLK3 impairs only NF-B-dependent transcription induced by T cell costimulation, but not NF-B activity elicited by TNF or IL-1. Accordingly, endogenous MLK3 is phosphorylated only after T cell costimulation but not by treatment with TNF or IL-1. In support of a signal-specific role for MLK3 in T cells, the Tax protein encoded by the human T lymphotropic virus type 1 up-regulates MLK3 levels and activates NF-B (40) . The TCR/CD28-mediated MLK3 activation pathway is mediated by Rho family GTPases RAC and CDC42 (39 , 41) .

The second MAP3K involved in TCR/CD28-induced activation of NF-B is COT. Overexpression of COT triggers transcription from a NF-B-dependent reporter gene and stimulates endogenous IKK activity (42) . A dominant-negative form of COT prevents only TCR/CD28- but not TNF-mediated activation of NF-B. COT physically assembles with NIK and IKK in vivo, but the pathway triggered by COT is distinct from that activated by MLK3 since COT leads to the activation of NIK. COT can be activated by AKT, which binds to COT and phosphorylates serine 400 near the carboxyl terminus of COT. Mutation of this serine in COT creates a dominant-negative form of COT that selectively prevents TCR/CD28-induced NF-B activation while not affecting TNF-derived signals (43) . Besides its stimulatory effect on COT, the AKT kinase also enhances NF-B-dependent trans-activation triggered by PKC (32) . It will be interesting to see whether mice lacking COT (44) or MLK3 have any defects in NF-B activation triggered by T cell costimulation. A role for NIK was revealed by analysis of T cells from aly mice, a strain with mutant NIK. TCR stimulation resulted in an impaired NF-B DNA binding in mature and immature T cells, while responses to costimulatory signals were not significantly changed (45) .

Evidence for the involvement of RICK/RIP2/CARDIAK was obtained from an analysis of mice lacking this serine/threonine kinase. T cells from Rip2^-/- animals show strongly impaired phosphorylation of IB and NF-B DNA binding after TCR engagement (46) . Since RIP2 is important for signals transmitted via Toll-like receptors 2 and 4, this kinase operates in several pathways. T cells also contain IKK, another member of the IKK family. IKK (termed IKKi) displays 30% sequence identity to IKK/ß. IKK activity can be induced upon TCR stimulation but not by IL-1 or TNF (47) , suggesting that this kinase may be important in the process of TCR-derived NF-B activation. IKK phosphorylates serine 36 of IB, but it remains to be seen whether IB is the main physiologically important substrate for this kinase. IKK is closely related to the IKK homologous kinase TBK1/NAK. Knockout experiments show that TBK1/NAK is dispensable for induced phosphorylation of IB; rather, it contributes to NF-B-mediated trans-activation. Therefore, it will be interesting to study the effect of targeted disruption of IKK for NF-B trans-activation in T lymphocytes.

	ACTIVATION OF THE IKK COMPLEX

TOP ABSTRACT INTRODUCTION EARLY SIGNALING EVENTS SMAC PROTEINS PKC{theta} PROTEIN KINASES ACTIVATION OF THE IKK... REFERENCES

 
It was recently shown that costimulation causes the inducible recruitment of IKK/NEMO to the TCR chain, causing inducible translocation of the IKK complex to the immunological synapse (48) . Targeting of IKK/NEMO to the membrane is sufficient to induce constitutive NF-B activation (48) , showing that the immunological synapse is the site of IKK activation. IKK activation is mediated by phosphorylation of two conserved serines located within their activation loops, but it is not clear whether this phosphorylation is mediated by upstream kinases (such as PKC) or by auto- and transphosphorylation of the IKKs themselves (49 , 50) . The oligomerization of the IKK complex may be mediated by caspase recruitment domain (CARD) -containing proteins. One of these CARD proteins is Bcl10, which was identified from a genetic breakpoint in mucosa-associated lymphoid tissue (MALT) lymphoma (51) . NF-B activation induced by transient overexpression of wild-type Bcl10 in cell lines is dependent on its amino-terminal CARD (52) . T lymphocytes from Bcl10^–/– mice show no activation of NF-B in response to T cell costimulation (53) , thereby revealing Bcl10 as an essential component of this signaling pathway. Treatment of the knockout cells with PMA and ionomycin fails to induce NF-B activation. Since these agents bypass the early signaling steps and directly elevate Ca²⁺ fluxes and PKC activity, this finding indicates that Bcl10 is located at the level of or downstream from PKC. Accordingly, early tyrosine phosphorylation, mobilization of Ca²⁺, and activation of JNK/AP-1 are normal in Bcl10^–/–cells (53) . How can Bcl10 activate NF-B in the absence of any intrinsic enzymatic activity? A possible clue comes from the finding that its viral homologue vCLAP/E10 from equine herpes virus persistently activates NF-B through direct binding and oligomerization of IKK (54) . Since forced oligomerization of IKK strongly activates NF-B (55) , it is tempting to speculate that Bcl10-assisted multimerization of IKKs accounts for the NF-B activating function of Bcl10. Accordingly, Bcl10-mediated NF-B activation requires the arrangement of Bcl10 in cytoplasmic filaments (56) . Thus, the organized assembly of proteins in ordered structures linked to the cytoskeleton is important for this NF-B activation pathway.

Bcl10 is found in association with several other proteins, including MALT1. Similar to Bcl10, the gene encoding MALT1 is affected by a chromosomal translocation involved in the same type of MALT lymphoma. MALT1 is composed of a death domain, two immunoglobulin-like domains, and a carboxyl-terminal caspase-like domain and cooperates with Bcl10 for the induction of NF-B (57) . Bcl10 also binds to the membrane-associated guanylate kinase (MAGUK) proteins CARD10 (58) , CARD14 (59) , and CARD11/CARMA1 (59 , 60) . The importance of CARMA1 for the activation of NF-B was revealed in several studies. Elimination of CARMA1 expression by either somatic mutagenesis or expression of small interfering RNAs prevents NF-B activation triggered by TCR/CD28 cross-linking (61 , 62) . Accordingly, a CARMA1 mutant incapable of binding to Bcl10 acts as a dominant-negative mutant and prevents TCR/CD28-stimulated NF-B activation and IL-2 production (63) . It seems that CARMA1 serves to link PKC-derived signals to Bcl10, as overexpression of a constitutively active form of PKC fails to induce NF-B in CARMA1-deficient Jurkat T cells but not in control cells retransfected to express CARMA1 (61) . A dominant-negative CARMA1 mutant also interferes with PMA/ionomycin-induced NF-B activation, showing that this MAGUK family member acts downstream from PKC. On the other hand, there is increasing evidence that CARMA1 functions upstream from Bcl10. Overexpression of CARMA1 stimulates the phosphorylation of Bcl10 (60) , but neither the exact phosphorylation sites nor the kinases involved are known to date. CARMA1 is constitutively associated with lipid rafts, whereas cytoplasmic Bcl10 translocates into lipid rafts only upon TCR engagement (63) . Overexpression of CARMA1 recruits Bcl10 to the cytoplasmic membrane (61) ; association of both proteins is observed only in stimulated T cells (63) , suggesting that CARMA1 assists in lipid raft recruitment of Bcl10. The use of genetic models in combination with new tools in biochemistry (e.g., tandem affinity purification technology, which allows the identification of inducible protein/protein interactions), molecular biology (e.g., knockdown by RNA interference), and cell biology (visualization of protein migration in living cells using fusions to the green fluorescent protein) will open new doors to the identification of further NF-B regulators in T lymphocytes. Since the global inhibition of this transcription factor might result in serious side effects, this information will be valuable for the development of T cell-specific immunosuppressive NF-B inhibitors.

	FOOTNOTES

 
doi: 10.1096/fj.02-1100rev

Received for publication March 27, 2003. Accepted for publication August 5, 2003.

	REFERENCES

TOP ABSTRACT INTRODUCTION EARLY SIGNALING EVENTS SMAC PROTEINS PKC{theta} PROTEIN KINASES ACTIVATION OF THE IKK... REFERENCES

 

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