Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

MALT1(Mucosa-Associated Lymphoid Tissue Translocation Gene 1)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_234


Historical Background

Around the beginnings of the 1990s several cytogenetic studies reported the occurrence of t(11;18)(q21;q21) chromosomal translocations in several cases of low-grade Mucosa-Associated Lymphoid Tissue (MALT) lymphoma. Later, Akagi and colleagues identified a novel gene on chromosome 18 to be involved in the t(11;18)(q21;q21) translocation which they named MALT1 as a candidate gene involved in the pathogenesis of MALT lymphoma (Akagi et al. 1999). Already a few months earlier, Dierlamm and colleagues also reported MALT1 (which they named MLT) as part of the t(11;18)(q21;q21) translocation as well its translocation partner on chromosome 11, the API2 gene, resulting in the expression of a 5-API2-MALT1-3′ fusion transcript (Dierlamm et al. 1999). While the function of the MALT1 gene product was completely unclear at that time, the API2 gene had already been known to encode for a member of the family of inhibitor of apoptosis (IAP) proteins. Breakpoint analyses showed that the API2 gene contributed its three baculovirus IAP repeat (BIR) motifs to the 5′ part of the API2-MALT1 fusion transcript. Since the BIR region was known to be sufficient for the inhibition of caspases and, therefore, for the suppression of apoptosis, it was suggested that the API2-MALT1 fusion might be involved in an inappropriate inhibition of apoptosis and thereby might confer a survival advantage to MALT lymphomas. However, subsequent biochemical and genetic characterization did not support a direct role for API2-MALT1 or MALT1 in apoptosis inhibition but revealed that MALT1 (and the API2-MALT1 fusion) promotes the activation of the  NF-κB signaling pathway.

MALT1 as Part of the CBM Complex

In silico analyses revealed that a C-terminal part of the MALT1 amino acid sequence has similarity to the proteolytic domain of caspases, a family of cysteine proteases centrally involved in the induction of apoptosis. Importantly, the essential catalytic histidine and cysteine diad is conserved in the MALT1 sequence. Uren and colleagues therefore proposed that human MALT1 and its orthologs in, for example, mouse, zebrafish, and Caenorhabditis elegans should be classified as a novel family of caspase-related proteins, the paracaspases (Uren et al. 2000). The caspase-like catalytic domain of MALT1 was called the paracaspase domain which is preceded by an N-terminal death domain (DD) and two immunoglobulin (Ig)-like domains (Fig. 1). MALT1 is known to be constitutively associated with the BCL10 protein: the interaction occurs between the MALT1 Ig-like domains and a sequence stretch (aa 107–119) immediately downstream of the Bcl10 CARD domain. BCL10 is encoded by a gene that had been previously shown to be involved in t(1;14)(p22;q32) chromosomal translocations associated with cases of MALT lymphomas and which upon overexpression induces NF-κB. BCL10 also interacts with the CARD-containing protein  CARMA1 which also is able to activate NF-κB upon overexpression. The NF-κB-activating potential of CARMA1 and BCL10 is dependent on homotypic interaction between the CARD domains of BCL10 and CARMA1 for the formation of oligomeric protein complexes (Fig. 1). The ectopic overexpression of Bcl10 or CARMA1 by itself induces NF-κB, whereas overexpression of MALT1 alone is not sufficient for NF-κB activation. However, MALT1 was shown to enhance Bcl10-mediated activation of NF-κB and it was proposed that BCL10 mediates the oligomerization of MALT1 molecules for the enhanced activation of NF-κB. This hypothesis was supported by the observation that the oligomerization of the MALT1 paracaspase domain or oligomerization of API2-MALT1 via the N-terminal BIR domains resulted in NF-κB activation. Mutation of the active-site cysteine residue of the proteolytic paracaspase domain reduced the capacity of API2-MALT1 for induction of NF-κB, however, not completely. Taken together, MALT1 was identified to be part of a complex with BCL10 and CARMA1 – the so-called CBM (CARMA1-BCL10-MALT1) complex (Thome et al. 2010) – which is involved in NF-κB activation (Fig. 2). How MALT1 is thought to be activated within the CBM complex and how MALT1 participates in the regulation of NF-κB under physiological settings will be described within the subsequent paragraphs.
MALT1(Mucosa-Associated Lymphoid Tissue Translocation Gene 1), Fig. 1

The CBM complex. The CBM complex consists of the three proteins Carma1 (Card11), Bcl10, and Malt1. Bcl10 and Malt1 interact via a sequence immediately downstream of the Bcl10 CARD domain and the Ig-like domains of Malt1. While the Bcl10-Malt1 interaction is assumed to be constitutive, Bcl10-Malt1 is recruited to Carma1 in response to antigen-receptor signaling. Bcl10 and Carma1 associate via CARD-CARD interaction, and the Carma1 coiled-coil domain can bind to the C-terminal part of Malt1 that contains the paracaspase domain. The CBM complex is believed to form the core of a molecular scaffold that upon activation recruits various further signaling components to activate NF-κB and other signaling pathways

MALT1(Mucosa-Associated Lymphoid Tissue Translocation Gene 1), Fig. 2

TCR signaling via the CBM complex to NFkB. The signaling events emanating from the activated T-cell receptor (TCR) complex have been studied in detail. Receptor proximal signaling leads to the activation of various kinases such as Scr and Syk family kinases and to the recruitment of adaptor molecules such as LAT and SLP76. The adaptors assemble and activate a plethora of signaling molecules, among others phospholipase C-gamma (PLCg) and protein kinase C theta (PKC-theta). PKC-theta and other kinases are thought to activate Carma1 by phosphorylation leading to the assembly of the CBM complex for activation of the IKK complex and the NF-κB transcriptional program which affects various biological processes

MALT1 in Antigen-Receptor

Phenotype of MALT1 Knockout Mice

A role for the CBM complex in cells of the immune system could be expected from the expression patterns of its components: in the mouse, Malt1 and Carma1 are predominantly expressed in lymphoid organs whereas Bcl10 is quite ubiquitously expressed in various tissues including the lymphoid compartments. Analysis of Bcl10-deficient mice revealed severe immunodeficiency with strong defects in antigen receptor (AgR)-mediated activation, proliferation, and NF-κB signaling of B and T cells (Ruland et al. 2001), which is comparable to the phenotype of mice deficient in Carma1. The importance of the CBM complex in the immune system is further supported by the phenotype of Malt1-deficient mice (Ruefli-Brasse et al. 2003; Ruland et al. 2003). Malt1-deficient mice proved to be viable and fertile, and are born at the expected Mendelian ratio. Of note, while a fraction of Bcl10-deficient mice die during embryonic development due to a neural tube closure defect, Malt1-deficient mice as well as Carma1-deficient mice are not affected by a developmental defect, indicating that Bcl10 can exert functions independent of Malt1 and Carma1. Malt1-deficient mice are severely immunodeficient with markedly reduced basal immunoglobulin serum levels and a defective antibody response after immunizations. While Bcl10 is essential for the development of all main subtypes of B cells, follicular B2 cells, marginal zone B (MZB) cells and B1 cells (Xue et al. 2003), Malt1-deficiency revealed impairment of MZB and B1 cell development but showed normal follicular B2 cell development. Malt1-deficient mice display normal numbers of peripheral T lymphocytes despite some irregularity during thymocyte development due to a premature maturation of double-negative thymocytes. However, it was demonstrated that Bcl10/Malt1 signaling is dispensable for negative and positive selection of thymocytes (Jost et al. 2007). T cells isolated from Malt1-deficient mice reveal severe impairment of proliferation, IL-2 production, and NF-κB activation in response to stimulation with phorbol-12-myristate-13-acetate (PMA) plus ionomycin or with anti- CD3 plus anti-CD28 antibodies. While ERK1/2 activation, calcium release, and JNK1 activation proves to be normal, the activation of JNK2 is impaired. Ruefli-Brasse and colleagues reported that B lymphocytes isolated from their Malt1 knockout mouse strain also showed severe defects in the proliferative response and in NF-κB activation (Ruefli-Brasse et al. 2003). However, the Malt1-deficient mouse strain of Ruland and colleagues revealed only a moderate effect of Malt1 on B-cell receptor (BCR) signaling, since conventional B2 cells from those mice were still able to activate NF-κB and showed only a partial reduction of proliferation after stimulation (Ruland et al. 2003). More detailed analysis of this Malt1 knockout mouse strain revealed that Malt1-deficiency in B cells does not affect the activation of the NF-κB subunit RelA but selectively impairs the formation of cRel-containing complexes (Ferch et al. 2007). The same study demonstrated that Malt1, therefore, seems to control only certain aspects of BCR-mediated NF-κB signaling such as activation of survival signals but does not control cell proliferation. This is in contrast to the role of Bcl10 which is essential for all aspects of BCR-mediated NF-κB activation (Ruland et al. 2001). Taken together, analysis of Malt1-deficient mice clearly demonstrated its central importance for a regular adaptive immune response and its essential involvement in AgR-mediated NF-κB signaling downstream of Bcl10.

MALT1 as an Adaptor Protein in AgR-Mediated CBM Signaling

During recent years, the mechanisms by which MALT1, as part of the CBM complex, contributes to AgR-mediated NF-κB activation were intensely studied on the molecular level. The early T-cell receptor (TCR)-proximal events had already been studied quite in detail: ligation of the TCR and its costimulatory CD28 receptor at the immunological synapse first results in the recruitment and activation of the Src protein tyrosine kinase Lck. Lck phosphorylates the immunoreceptor tyrosine based activation motives (ITAMs) of  CD3 subunits to which the Syk family protein tyrosine kinase  ZAP-70, and subsequently the adaptors  LAT and  SLP-76 are recruited. Then several additional molecules, such as Grb2, Vav1, and Tec kinases, associate with the activated receptor complex by which multiple signaling events are initiated, including the activation of the MAP kinases, phospholipase C (PLC)-gamma, and phosphatidylinositole-3-kinase (PI3-K). Those events again trigger a cascade of downstream events such as the formation of diacylglycerol(DAG), the release of intracellular calcium, and activation of the serine/threonine protein kinases Akt/PKB and PKC-theta (Fig. 2). Upon activation, PKC-theta translocates into specialized membrane microdomains, the so-called lipid rafts, where it is essential for TCR-mediated NF-κB and AP-1 activation. Importantly, in unstimulated T cells CARMA1 was identified to be constitutively present in lipid rafts, whereas BCL10 was not. However, upon TCR stimulation, BCL10 was shown to be recruited from the cytoplasm to the membrane lipid raft fraction in a CARMA1-dependent manner. Upon activation of the AgR signaling pathways, PKC-theta in T cells or PKC-beta in B cells as well as other kinases such as IKK-beta and CK1-alpha were described to phosphorylate CARMA1 within its linker region. This might result in a conformational change of CARMA1, enabling its CARD-dependent interaction with BCL10 which on the other hand is constitutively associated with MALT1 (Thome et al. 2010). Once recruited to the immunological synapse by CARMA1 and BCL10, MALT1 contributes to the activation of the inhibitor of NF-κB kinase (IKK) complex for NF-κB activation. Up to now, the mechanisms by which MALT1 (in synergy and/or in parallel with BCL10) activates and regulates IKK activity are not completely understood. It seems to be clear, however, that MALT1 acts as an adaptor protein that recruits several binding partners for the induction of downstream signaling events. For example, the association of MALT1 with  TRAF6-containing ubiquitin ligase complexes results in the addition of K63-linked ubiquitin chains to a multitude of proteins, among others TRAF6, Bcl10, and MALT1 but also to the regulatory domain of the IKK complex, NEMO (Fig. 3). The modification with K63-linked ubiquitin chains is essential for the recruitment of the IKK complex and other signaling molecules to the CBM complex at the immunological synapse and subsequent NF-κB activation (Duwel et al. 2010). First evidence for the participation of a TRAF6-dependent ubiquitin ligase complex in CBM-mediated NF-κB activation was obtained from studying a cell-free system (Sun et al. 2004). Sun and colleagues were able to reconstitute BCL10- and MALT1-dependent IKK activation in vitro in the presence of recombinant TRAF6, Ubc13/Uev1A, and TAK1/TAB1/TAB2. This study also suggests that MALT1 oligomers must be formed via its interaction with BCL10. Those MALT1 oligomers supposedly bind to the RING domain-containing ubiquitin ligase TRAF6 which in concert with the ubiquitin-conjugating enzyme complex Ubc13/Uev1A is activated as a ubiquitin ligase. TRAF6 was shown to directly bind and K63-ubiquitylate MALT1. Subsequently, the IKK complex can be recruited to the CBM complex since NEMO binds to K63-polyubiquitylated MALT1 via its ubiquitin-binding domain (UBD). Besides NEMO, also the TAK1/TAB2 kinase complex was shown to be associated with ubiquitylated MALT1 (Oeckinghaus et al. 2007) and might contribute to the activation of the IKK complex by phosphorylating two serine residues within the activation loop of IKK-β. However, the exact role and mode of function of TAK1 in IKK activation is not yet resolved.
MALT1(Mucosa-Associated Lymphoid Tissue Translocation Gene 1), Fig. 3

Malt1 as a scaffold protein in IKK activation. As part of the activated CBM complex, Malt1 serves as a scaffold protein that recruits further signaling components such as the ubiquitin ligase complex consisting of TRAF6 and Ubc13/Uev1A. This results in the K63-type ubiquitination of several molecules, among others Malt1 and TRAF6 themselves but also of Bcl10 and the regulatory IKK subunit NEMO. Those ubiquitination events contribute to the association of NEMO and the IKK complex to the CBM complex with subsequent activation of the IKK complex and NF-κB

Evidence accumulated for a surprising contribution of caspase-8 to TCR signaling including NF-κB activation. In this setting, caspase-8 does not signal for apoptosis but associates with various NF-κB signaling molecules in lipid rafts. Kawadler and colleagues demonstrated that MALT1 associates with procaspase-8 and promotes a partial proteolytical processing and activation of procaspase-8, which was shown to contribute to the activation of NF-κB via cleavage of cFlipL (Kawadler et al. 2008). The interaction between MALT1 and procaspase-8 proved to be dependent on the MALT1 paracaspase domain but independent of paracaspase activity since inactivation of the paracaspase active site did not interfere with procaspase-8 binding and processing.

In conclusion, the role of MALT1 as an adapter protein that recruits several signaling molecules to the CBM complex for the activation of NF-κB is well established.

MALT1 as a Protease in the Regulation of AgR-Mediated NF-κB Signaling

Uren and colleagues recognized that MALT1 belongs to a family of proteins that contain a common domain with sequence homology to the large protease subunit of caspases. Members of this protein family were identified in mammals, fish, nematodes, and amoeba and were collectively named paracaspases (Uren et al. 2000). Like caspases, the paracaspases possess an active-site cysteine together with a catalytic histidine and belong to the CD clan of cysteine-dependent proteases. In contrast to caspases, which specifically cleave behind aspartatic acid residues in the substrates P1 position, paracaspases were predicted to have different substrate specificities. Indeed, upon stimulation of human lymphocytes, MALT1 was shown to cleave BCL10 behind an arginine residue at its very C-terminal end (Rebeaud et al. 2008). The tetrapeptide inhibitor z-VRPR-fmk was able to block MALT1-mediated cleavage of BCL10 and thereby was validated as an inhibitor of MALT1 paracaspase proteolytic activity. Z-VRPR-fmk treatment of stimulated human T cells also reduced NF-κB signaling. However, BCL10 cleavage was not required for NF-κB signaling but instead might be important for integrin-mediated adhesion of activated lymphocytes to the extracellular matrix. Those findings suggest that other MALT1 paracaspase substrates should exist. In fact, Coornaert and colleagues recognized that the zinc-finger protein A20 is also cleaved by MALT1 paracaspase activity in stimulated human T and B cells (Coornaert et al. 2008). The cleavage site was identified behind an arginine residue between the first and second zinc finger of human A20. The MALT1 cleavage site in human A20 is different from that in BCL10 and is not conserved in the murine A20 protein which instead is presumably cleaved by MALT1 at another more C-terminal site. MALT1-dependent cleavage of A20 might indeed represent a mechanism that contributes to the regulation of CBM-mediated NF-κB signaling. A20 is a transcriptional target of NF-κB and, implementing a negative feedback loop, downregulates NF-κB signaling by removing K63-linked ubiquitin chains from various signaling molecules such as TRAF6, NEMO, and MALT1. MALT1-mediated A20 cleavage inactivates A20 as a negative regulator of NF-κB and, therefore, might contribute to a more sustained or amplified NF-κB signal (Fig. 4). This view is supported by the findings of Düwel and colleagues upon reconstitution of Malt1-deficient murine T cells with either wild-type MALT1 or the active-site mutant MALT1 C464A. MALT1 C464A was able to restore early events in NF-κB activation such as IκBα degradation but displayed a reduced long-term response in terms of IL2 production compared to reconstituted wild-type MALT1 (Duwel et al. 2009). Very recently, MALT1 paracaspase was reported to cleave the deubiquitinating enzyme CYLD and thereby positively regulate JNK signaling (Staal et al. 2012) and to cleave RelB leading to RelB degradation with concomitant increase in canonical NF-κB signaling (Hailfinger et al. 2012). It appears likely that there are even more MALT1 paracaspase substrates which contribute to the regulation of CBM complex-mediated NF-κB signaling and beyond.
MALT1(Mucosa-Associated Lymphoid Tissue Translocation Gene 1), Fig. 4

MALT1 as a paracaspase for the regulation of CBM signaling. As a paracaspase Malt1 possesses proteolytic activity which is induced upon CBM activation. It has been reported that Malt1 as a paracaspase cleaves Bcl10, A20, CYLD, and RelB. A20 as a deubiquitinatin enzyme removes polyubiquitin chains from several proteins such as TRAF6, Malt1, and NEMO and, therefore, acts as a negative regulator of NF-κB signaling which transcriptionally upregulates A20 in a negative autoregulatory manner. A20 cleavage by Malt1 paracaspase therefore is believed to enhance CBM-mediated NF-κB signaling. CYLD is also a deubiquitinating enzyme and has been shown to be a negative regulator of Jnk activation. Inactivating cleavage of CYLD by Malt1 paracaspase therefore has been proposed to enhance Jnk signaling. Malt1-mediated cleavage of RelB leads to the degradation of RelB resulting in enhanced canonical NF-κB signaling

MALT1 Functions Beyond AgR Signaling

After AgR ligation, the most immediate sequence of events is the phosphorylation of ITAM motifs within coreceptor transmembrane proteins leading to the recruitment and activation of Syk kinase family members. Activation of ITAMs and Syk kinases is absolutely essential for the activation of most signaling pathways downstream of the AgRs including the formation of the CBM complex for NF-κB activation. Many other immunoreceptors also signal via ITAM or ITAM-like motifs and via activation of Syk kinases (Mocsai et al. 2010). And indeed, Malt1 as part of the CBM complex was found to be centrally involved in the activation of NF-κB upon stimulation of a variety of ITAM-coupled immunoreceptors other than AgRs. As a first example, Klemm and colleagues reported the essential contribution of Bcl10 and Malt1 to FcεRI-mediated NF-κB activation in mast cells, suggesting an important role for the CBM complex in the regulation of allergic inflammatory responses (Klemm et al. 2006; Klemm and Ruland 2006). Of special interest was the finding that Malt1 together with Bcl10 and the Carma1 homolog Card9 mediates NF-κB signaling triggered by innate C-type lectin receptors such as Dectin-1 for the immune response to fungal infections (Gross et al. 2006). This demonstrated for the first time that Bcl10 and Malt1 not only are central for adaptive immunity provided by AgR signaling on T and B lymphocytes but also for innate immunity provided by so-called pattern recognition receptors (PRRs) on dendritic cells (DCs) and macrophages (Hara and Saito 2009). Another example for the involvement of Card9/Bcl10/Malt1 in the response of PRRs to pathogen-associated molecular patterns (PAMPs) is the activation of DCs and macrophages by the mycobacterial cell wall component TDM via recognition of the ITAM-coupled C-type lectin receptor Mincle (Schoenen et al. 2010). Furthermore, also activating NK cell receptors such as NK1.1 and  NKG2D couple to ITAM-containing signaling chains and signal to NF-κB in a Carma1/Bcl10/Malt1-dependent manner (Gross et al. 2008). The CBM complex has been described to also mediate NF-κB activation independently of upstream ITAM-Syk signaling. Tusche and colleagues reported that BAFF-induced alternative NF-κB signaling is dependent on Malt1 in B lymphocytes and that this BAFF pathway is essential for the survival and immune function of MZB but not of follicular B cells (Tusche et al. 2009). In nonimmune cells such as MEFs, Bcl10 and Malt1 were shown to be specifically required for NF-κB signaling upon activation of G protein-coupled receptors (GPCRs) by the phospholipid lysophosphatidic acid, LPA, which might be of relevance for tumorigenesis (Klemm et al. 2007).

MALT1 as a Potential Drug Target in Lymphoma Treatment

As mentioned above, MALT1 had been initially identified as a gene that is involved in the t(11;18)(q21;q21) translocation in cases of MALT lymphoma. This translocation results in the expression of the API2-MALT1 fusion protein that independently of Bcl10 can auto-oligomerize and mediate ubiquitin ligase activity for deregulated NF-κB signaling in the process of lymphomagenesis. API2-MALT1 is known to activate the classical NF-κB pathway but Rosebeck and colleagues recently observed that also the alternative pathway is involved (Rosebeck et al. 2012). According to this report, the paracaspase activity of API2-MALT1 is directly responsible for the cleavage of the NF-κB-inducing kinase (NIK) behind its arginine residue R325, leading to the stabilization of NIK due to its rescue from proteasomal degradation. Cleavage-stabilized NIK was shown to result in enhanced processing of p100 to p52 and activation of the alternative NF-κB transcriptional program in t(11;18)-positive MALT lymphoma samples. Those data suggest that the inhibition of MALT1 paracaspase activity might offer a potential approach for the treatment of t(11;18)-positive MALT lymphoma. In contrast to the t(11;18)(q21;q21) translocation which generates an API2-MALT1 fusion protein, the recurrent translocation t(14;18)(q23;q21) brings MALT1 into proximity of the immunoglobulin heavy-chain (IGH) locus and leads to high-level expression of MALT1 in the affected lymphoma cells. The mechanisms by which aberrant expression of MALT1 contributes to NF-κB-dependent lymphomagenesis are not yet clear; nucleocytoplasmic shuttling of MALT1 and associated BCL10 might play a role. MALT1, BCL10, and CARMA1 were demonstrated to be indispensable for the survival of NF-κB-dependent diffuse large B-cell lymphoma (DLBCL) cell lines of the activated B cell (ABC) type and, therefore, might represent “Achilles’ heels” that might be targeted for therapeutic intervention. Indeed, ABC-type DLBCL cell lines were shown to be selectively sensitive to treatment with the MALT1 paracaspase tetrapeptide inhibitor z-VRPR-fmk (Ferch et al. 2009). Thus, MALT1 as a component of the CBM complex with enzymatic paracaspase activity may be an attractive drug target for the treatment of lymphomas because inhibition of MALT1 paracaspase would not generally block NF-κB signaling but would only affect certain aspects of NF-κB signaling within a few cell types suggesting low side effects of such a therapeutic approach. However, the importance of MALT1 paracaspase activity in the physiological context of an organism is not known, and therefore, the consequences of MALT1 paracaspase inhibition remain to be investigated.


MALT1 was initially identified as a gene that is involved in chromosomal translocations in cases of MALT lymphoma. Soon it was recognized that MALT1 interacts and collaborates with BCL10, which also is translocated in MALT lymphoma, for the induction of NF-κB signaling. In response to the activation of adaptive and innate immune receptors MALT1 and BCL10 are recruited by CARD-containing proteins such as CARMA1 and CARD9 to form so-called CBM complexes. CBM complexes mediate the activation of the IKK complex and subsequent NF-κB signaling. Within the CBM complex, MALT1 functions as an adaptor protein that recruits further signaling molecules but also regulates CBM signaling via its paracaspase protease activity. Regular CBM-mediated NF-κB signaling is essential for intact adaptive and innate immune functions. In contrast, aberrant CBM-mediated NF-κB signaling can contribute to and even might be essential for the development and/or maintenance of lymphomas. MALT1 as a component of the CBM complex with enzymatic paracaspase activity is an attractive drug target and first in vitro data indicate that inhibition of MALT1 paracaspase might indeed impair survival of specific subtypes of lymphoma cells. The physiological functions of MALT1 paracaspase activity, however, remain to be elucidated.



We thank Frank Oliver Gorka for thoughtfully reading and discussing the manuscript.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Laboratory for Signaling in the Immune SystemHelmholtz Zentrum München – German Research Center for Environmental HealthNeuherbergGermany
  2. 2.Third Medical Department, Institute for Molecular ImmunologyTechnical University of Munich, Klinikum rechts der IsarMunichGermany