|Coordinate||57,223,465 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||CD40 ligand|
|Synonym(s)||gp39, Cd40L, Tnfsf5, Ly-62, CD154, IMD3, HIGM1, T-BAM|
|Chromosomal Location||57,212,143-57,224,042 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is expressed on the surface of T cells. It regulates B cell function by engaging CD40 on the B cell surface. A defect in this gene results in an inability to undergo immunoglobulin class switch and is associated with hyper-IgM syndrome. [provided by RefSeq, Jul 2008]
PHENOTYPE: Nullizygous mutations affect T-dependent humoral responses, germinal center formation, isotype switching and T cell differentiation, and may alter osteoclastogenesis, thrombogenesis, and susceptibility to autoimmune diabetes and prion infection. ENU mutants fail to show an IgG response to rSFV. [provided by MGI curators]
|Amino Acid Change||Serine changed to Proline|
|Institutional Source||Beutler Lab|
S221P in Ensembl: ENSMUSP00000033466 (fasta)
|Gene Model||not available|
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.998 (Sensitivity: 0.27; Specificity: 0.99)
|Phenotypic Category||X-linked Recessive|
|Alleles Listed at MGI|
|Mode of Inheritance||X-linked Recessive|
|Last Updated||2018-05-17 1:53 PM by Anne Murray|
|Record Created||2010-06-08 4:39 PM by Carrie N. Arnold|
The walla phenotype was identified by forward genetic screening of ENU-mutagenized G3 mice: a total of three male siblings exhibited null T-dependent IgG responses to rSFV-encoded antigen (T-dependent Humoral Response Screen) but normal T-independent IgM responses and serum IgA levels (T-independent B Cell Response Screen) (see figure). The frequencies and surface phenotypes of peripheral blood T cells and B cells were normal.
|Nature of Mutation|
Because multiple male walla mice displayed a selective defect in the class-switched response and no obvious defect in lymphocyte development was observed, the X-linked gene encoding CD40 ligand (CD40L) was sequenced. A T to C transition was detected at position 673 of the Cd40lg transcript, in exon 5 of 5 total exons.
The mutated nucleotide is indicated in red, and results in substitution of serine with proline at position 221 of the CD40L protein.
CD40 and CD40L constitute a receptor-ligand pair that provides costimulatory, activating signals to antigen presenting cells (APCs) such as B cells, macrophages, and dendritic cells (DCs). The CD40 receptor, expressed on B cells and other APCs, is engaged by CD40L that is present primarily on activated T cells. A soluble form of CD40L, generated by proteolytic processing of the full length transmembrane protein, is also active (1;2). The protein sequences of human and mouse CD40L are 78% identical.
The CD40-binding site consists of a shallow groove between two adjacent CD40L monomers, formed by hydrophobic and hydrophilic residues from both monomers (11;12). These residues are mostly from the AA” and DE loops, with contributions from the CD and GH loops, and strands C, D, G, and H. Site-directed mutagenesis confirms the requirement for amino acids K143, Y145, Y146 (all in AA” loop), R203 (DE loop), and Q220 (strand F) for binding to CD40 (10;11). Interestingly, almost no sequence conservation exists between CD40L and LTα or TNFα in these regions. Comparison of the structure of the uncomplexed CD40L trimer with that of the CD40L trimer in complex with mouse monoclonal antibody 5c8 (which inhibits the CD40L-CD40 interaction) reveals that complex formation does not induce significant conformational changes in CD40L (10).
The walla mutation (S→P) at position 221 resides in strand F of the extracellular domain of CD40L.
CD40L is expressed by T lymphocytes, predominantly by activated CD4+ T cells (7;9), as well as by some CD8+ T cells, activated B cells (18) and platelets (19). Under inflammatory conditions, CD40L is induced on monocytes/macrophages (20), natural killer cells (21), mast cells, eosinophils, and basophils. It is localized at the plasma membrane (6;22) and may be cleaved and released extracellularly (1;2).
During infection, initial contact with antigen activates tissue-resident dendritic cells (DCs) that acquire antigen before homing to the T cell zones of draining secondary lymphoid organs (Figure 4). There, they activate CD4+ T helper (Th) cells by presenting antigen within the context of MHC class II, resulting in selection and preferential expansion of antigen-specific Th cell clones. Activated Th cells are induced to transiently express CD40L (23;24), permitting them to engage CD40 expressed on DCs. CD40 signaling is essential for the maturation and survival of DCs, resulting in enhanced survival, secretion of cytokines such as interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12, and TNFα, and upregulation of costimulatory molecules including ICAM-1 (25), LFA-3, CD80, and CD86. Conversely, crosslinking CD40L on Th cells contributes to the generation of helper function (26), for example by enhancing cytokine production (27). Once activated, Th cells migrate to the border between the B cell follicles and the T cell zone where they encounter antigen-activated B cells (28).
A mature B cell can be activated by antigenic epitopes that are recognized by its cell surface immunoglobulin (Ig) (29). In contrast to T-independent B cell activation in which antigens directly crosslink membrane Ig molecules, T-dependent B cell activation requires ‘cognate help’ from Th cells, which allows B cells to mount responses against proteins and other antigens that cannot crosslink receptors. B cells bind antigen through their membrane Ig, leading to antigen endocytosis, proteolytic processing, and presentation at the cell surface within class II MHC molecules; the peptide-MHC II complex forms the ligand for the antigen-specific T cell receptors (TCRs) of Th cells. Antigen-activated B cells migrate toward T-B cell borders to encounter activated, cognate Th cells expressing CD40L (28). CD40 is constitutively expressed on B cells.
B cell induction of an effective humoral response requires the physical interaction, via the immunological synapse, of a B cell with a T cell through the MHC-peptide-TCR complex (30;31). In addition, cytokines as well as secondary cell contact-dependent stimuli, known as costimulatory signals, are required to stimulate sustained B cell growth and differentiation. Through in vitro experiments in which activating monoclonal antibodies against CD40 have been shown to induce B cell proliferation (32-34), cell-cell adhesion (35), differentiation (36;37), and tyrosine phosphorylation (38;39), it was demonstrated that B cells receive a critical costimulatory signal from T cells through CD40. A CD40-Ig fusion protein could block the ability of plasma membrane fractions from activated Th cells to stimulate B cell proliferation and isotype switching (22). Subsequently, the CD40-Ig fusion protein was used to isolate, identify, and clone the ligand for CD40 from activated Th cells (6;22).
The B cell response to T-dependent antigen involves induction of a variety of cell surface molecules, including CD134L (40), Fas (41), CD80 and CD86 (42), within hours of activation. This costimulatory molecule induction requires engagement of CD40 on B cells (43-45). Cell cycle entry follows, with early proliferating B cells located in T cell zones differentiating into short-lived plasma cells (plasmablasts) that secrete germline-encoded IgM and then IgG, but do not undergo somatic hypermutation. Activated B cells that expand within B cell zones seed secondary follicles, rapidly proliferate, and interact with Th cells in the germinal center (GC) reaction where isotype switching and somatic hypermutation occur. Selected GC B cells further differentiate into long-lived plasma cells or memory B cells with high affinity B cell receptors of the switched isotypes. During the selection for high affinity memory B cells, CD40L has been shown to differentially induce either clonal expansion or deletion of B cells in vivo depending on the antigen-specificity of the B cell Ig (46). The concerted action of CD40L and Fas ligand on activated T cells promotes clonal proliferation of B cells stimulated by foreign antigen, whereas CD40L and Fas ligand trigger deletion when B cell receptors have been desensitized by chronic stimulation with self-antigens or have not been bound by antigen.
Lack of CD40L:CD40 signaling completely abolishes T-dependent humoral immunity. Thus, blockade of CD40:CD40L interactions between Th cells and cognate B cells using an anti-CD40L blocking antibody abolished the plasmablast response (47). Study of mice deficient in either CD40 or CD40L demonstrated that CD40L:CD40 interactions are also required for GC formation, progression, and maintenance, as well as antibody isotype switching and affinity maturation, with these processes essential for the generation of memory B cells and long-lived plasma cells (48-51). IgM responses to some T-dependent antigens were found to be impaired in CD40L-deficient mice, suggesting that CD40L:CD40 signaling is not only required for secondary Ig responses but also for primary IgM responses. Interestingly, while no GC response was observed in mice lacking CD40L:CD40 signaling, excessive CD40 stimulation during a primary immune response, either using agonistic CD40 antibodies or elevated T cell help, resulted in ablation of GC formation and premature termination of the humoral immune response, blocked the generation of B cell memory and long-lived bone marrow plasma cells, and diverted all B cells to the plasmablast lineage (52). Thus, a normal GC response requires CD40 signaling to fall within a defined range.
Once B cells are committed to the GC lineage, the GC reaction is sustained by signals, including IL-21 and CD40L, from T follicular helper cells (TFH) (53). TFH cells themselves also depend on CD40L and IL-21 for their generation and function (53;54). Blockade of CD40L with antibodies 6-10 days after priming with a T-dependent antigen abrogated established GCs but had no effect on serum Ig production, suggesting that CD40L:CD40 interactions are required for the initiation but not maintenance of B cell differentiation leading to Ig production (55). However, long-lived bone marrow plasma cells decreased their average affinity for antigen subsequent to blockade of CD40L (56), presumably because of disrupted interactions between cognate GC Th cells and B cells during affinity maturation in the GC.
Humans with mutations in CD40L develop a severe form of X-linked immunodeficiency, hyper IgM syndrome 1 (HIGM1, OMIM #308230), characterized by normal to elevated levels of IgM and low levels of IgA, IgG, and IgE, the absence of germinal centers, and the inability to mount a T-dependent humoral response [(57-61), reviewed in (62)]. These phenotypes arise from deficient CD40L:CD40 interaction that is required for T-dependent B cell activation, as described above. As a result, HIGM1 patients suffer from recurrent bacterial infections that typically begin between the first and second years of life. These infections include a high incidence of upper and lower respiratory tract infections, otitis media, and pneumonia (63). Patients are also susceptible to developing autoimmunity, neutropenia, and lymphoproliferative diseases, and to opportunistic infections such as cryptosporidium, Pnuemocystis carinii, mycobacteria, and cytomegalovirus (CMV). T cells from a majority of HIGM1 patients exhibit reduced or absent CD40L protein expression and defective Th function despite normal CD40L mRNA levels (64). A high proportion of mutations occur in the extracellular domain (65), resulting in a range of defective binding ability for several CD40L antibodies (64). Both CD40L- and CD40-deficient mice (48-51) and some 50% of HIGM1 patients (63) display normal levels of circulating IgM, suggesting that an increased IgM level is a secondary phenotype and not a genetically determined feature of the disease.
CD40 in cell-mediated immunity
Cell-mediated immunity is carried out by macrophages, granulocytes, natural killer cells, and cytotoxic T lymphocytes stimulated by activated Th cells to destroy intracellular microorganisms. Both humans (63;66) and mice (67-69) deficient in CD40 signaling display increased susceptibility to intracellular infections and the development of lymphomas and gastrointestinal cancers, pointing to a role for CD40L:CD40 signaling in cell-mediated immunity.
CD40L and CD40 play an important role in the priming and expansion of antigen-specific Th cells. Adoptively transferred antigen-specific CD4+ T cells lacking CD40L failed to expand upon antigen challenge of the recipients (70). In vitro, Th cells from immunized CD40L-deficient mice proliferated poorly and produced no IL-4 and IFNγ when challenged with priming antigen, although they proliferated normally in response to polyclonal activators. These findings demonstrate that expression of CD40L on T cells is required for priming of CD4+ T cells. The requirement for CD40 signaling in T cell priming was also shown in experiments of allograft transplantation in mice. T cells transferred from wild type mice, but not from CD40L-deficient mice, elicited graft-versus-host disease (GVHD) leading to death of recipient mice within 21 days [discussed in (71)]. Persistence of allografts of skin, kidney, pancreatic islets, heart, and lung could be enhanced by co-infusion of donor-specific alloantigen (splenocytes) and anti-CD40L antibody (72-75). In these experiments, antibody blockade of CD40L impaired the upregulation of costimulatory molecules by host DCs, thus preventing them from effectively activating T cells. Alloantigen-presenting, non-matured DCs induced abortive activation and anergy of the host alloreactive T cell pool. CD40 signaling is not only required for the upregulation of costimulatory molecules and cytokine production by DCs, but also for increasing the expression and stability of the MHC:alloantigen complex (76). Signals from CD40 also promote the survival of DCs by upregulating the anti-apoptotic factor Bcl-XL in an NF-κB-dependent manner (see section on CD40 signaling below) (77).
A fundamental role for CD40L:CD40 signaling in monocyte activation by T cells has also been demonstrated. Monocytes upregulate CD40 expression in response to treatment with IFNγ, GM-CSF, or IL-3 (78;79). Engagement of CD40 on macrophages using recombinant CD40L or CD40L-expressing cells resulted in activation of effector function, including production of the proinflammatory cytokines IL-12, IL-6, and TNF-α (78;79). However, CD40L-deficient activated Th cells failed to induce IL-12 or nitric oxide production by macrophages (80-82).
Since CD40, like all TNFR family proteins, lacks intrinsic enzymatic activity, it propagates signaling by recruiting adapter proteins to its cytoplasmic domain. Most CD40 signaling depends on proteins of the TNF receptor-associated factor (TRAF) adapter family that interact directly or indirectly with CD40. TRAF proteins contain a TRAF domain at their C-termini that mediates direct interactions with CD40. At their N-termini, TRAFs (except TRAF1) have a RING finger domain with E3 ubiquitin ligase activity that is critical for signal transduction (83). CD40 contains two distinct domains in its 62-amino acid cytoplasmic tail, cyt-N (membrane-proximal) and cyt-C (membrane-distal), that bind to different members of the TRAF family and can activate NF-κB independently (84-86), although both binding sites are required for optimal NF-κB activation (87). TRAF1, TRAF2, TRAF3, and TRAF5 bind to the minimal consensus sequence (P/H)(V/I)QE(T/S) in cyt-C, whereas TRAF6 binds to the sequence (Q/N/R)X(P/A)XEXX(F/W/Y) in cyt-N (87;88). Upon CD40 engagement, TRAF2 and TRAF3 directly bind to the cytoplasmic tail of CD40; TRAF1 and TRAF5 are recruited to CD40 through associations with CD40-bound TRAFs (88;89).
The canonical and non-canonical NF-κB signaling pathways are activated downstream of TRAFs upon CD40L:CD40 engagement, and are major pathways for transducing the effects of CD40 activation (Figure 5). NF-κB proteins are dimeric transcription factors consisting of RelA (p65), RelB, NF-κB1 (p105, processed to p50), NF-κB2 (p100, processed to p52), and c-Rel [reviewed in (90)]. In most cell types, NF-κB dimers are held in the cytoplasm by IκB inhibitory proteins, including IκBα, IκBβ, IκBγ, and the unprocessed p100 and p105 precursors. Activation of NF-κB through the classical pathway depends on degradation of IκB, thus releasing NF-κB to enter the nucleus to coordinate expression of multiple inflammatory and innate immune genes. Briefly, in response to a variety of inflammatory signals, IκBs are phosphorylated on conserved serine residues by the IκB kinase (IKK) complex, composed of IKK-1 (or IKK-α), IKK-2 (or IKK-β) and IKK-γ (NEMO, see panr2). This modification induces the K48-linked polyubiquitination of IκB molecules and subsequent recognition by the 26S proteasome as substrates for proteolysis. Recruitment of TRAF2, TRAF3, or TRAF6 to CD40 upon CD40L engagement leads to IKK complex activation (91). In the case of TRAF1, which lacks the RING finger domain critical for NF-κB activation, evidence suggests that its role is to regulate the association of other TRAFs with CD40 (89;92;93).
Stimulation of CD40 also activates the non-canonical NF-κB pathway, which requires IKK-α, but not the IKK complex, and the proteasome-mediated processing of NF-κB2 (p100) (see xander) to p52 (90;94). In unstimulated cells, a complex consisting of cellular inhibitor of apoptosis (cIAP) 1, cIAP2, TRAF2, and TRAF3 associates with NF-κB inducing kinase (NIK) (see lucky) and promotes constitutive NIK degradation (95;96). CD40 engagement results in recruitment and subsequent degradation of TRAF2 and TRAF3, destabilizing the complex with NIK and permitting NIK accumulation (97-99). NIK binds and phosphorylates both IKK-α and p100 (100-102). Phosphorylation of p100 on two C-terminal sites triggers its polyubiquitination and proteasomal degradation to p52. Since p52 is typically associated with RelB, activation of the non-canonical NF-κB pathway results in nuclear translocation of p52-RelB dimers (103).
In support of the essential role of NF-κB signaling downstream of CD40, mice deficient in p50 fail to respond to CD40L stimulation and display impaired class switch recombination and decreased serum IgE (104). B cell-specific knockout of either IKK-β or NEMO results in a lack of B cells in the spleen, suggesting that NF-κB activation by the classical pathway is required for the maintenance of mature B cells (105). In contrast, non-canonical NF-κB activation by IKK-α and NIK are required for normal B cell development, Ig production, isotype switching, and GC formation (106;107). Mutations in NEMO in humans have been associated with a rare form of X-linked hyper IgM syndrome accompanied by ectodermal dysplasia (108;109).
In addition to NF-κB activation, CD40 also mediates its cellular effects by initiating signaling through pathways controlled by p38 MAP kinase, c-Jun, STAT, and Jak3, as well as PI3K and PLC-γ [reviewed in (110)]. Interestingly, whereas CD40-dependent activation of most of these proteins relies on the function of TRAF proteins, Jak3 is activated by binding directly to a proline-rich sequence in the membrane proximal region of the CD40 tail (111). This binding results in phosphorylation, activation, and translocation to the nucleus of STAT3. Jak3 is not required for CD40-mediated B cell proliferation, isotype switching, or upregulation of ICAM-1 or CD80 (112). However, pharmacological inhibition of Jak3 prevented the expression of costimulatory molecules and the production of IL-12 in response to CD40 stimulation of DCs (113).
It has been proposed that differential recruitment of TRAFs to the CD40 cytoplasmic tail, as a result of different stimuli, receptor oligomerization states, or cell type, leads to distinct physiological outcomes. This hypothesis is supported by studies of transgenic mice expressing CD40 receptors with mutations in defined TRAF binding sites. Introduction of CD40 with mutations in either the TRAF2/3 or TRAF6 binding sites into Cd40-/- mice demonstrated that either TRAF2/3 or TRAF6 are sufficient for isotype switching, but both TRAF2/3 and TRAF6 are required for normal GC formation (114;115). In another study, mutation of the TRAF6 binding site in the CD40 cytoplasmic domain resulted in the selective ablation of affinity maturation and generation of long-lived plasma cells after immunization (116). Disruption of both the TRAF6 and TRAF2/3 binding sites was necessary to arrest GC formation in response to immunization. However, CD40-induced B cell proliferation and early Ig production occurred even when all three of these TRAF binding sites were ablated. These intact responses are mediated by TRAF2 binding to a non-canonical site at the C-terminus of CD40 (117;118). This site (SVQE) is sufficient to mediate CD40 signaling leading to NF-κB activation, clonal B cell activation, antibody isotype switching, and affinity maturation. However, GC formation was impaired in transgenic mice expressing only the C-terminal TRAF2 binding motif, indicating that either or both TRAF3 and TRAF5 are necessary for GC formation.
The walla mutation at position 221 of CD40L resides in β strand F of the CD40L extracellular domain. The serine to proline change presumably disrupts the structure of this β strand, and probably the overall structure of the extracellular domain. Binding to CD40 requires Q220, also located in strand F of the CD40L protein (10;11). Together with the phenotype of walla homozygotes, which agrees with that of Cd40-/- and Cd40lg-/- mice, these data suggest that CD40Lwalla is impaired in its ability to engage CD40 and initiate signaling.
|Primers||Primers cannot be located by automatic search.|
Walla genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change.
walla (F): 5’-CAGTTCTACAGTGGGCCAAGAAAGG -3’
walla (R): 5’- ATAGGGAAGACTGCCAGCATCAGC -3’
1) 95°C 2:00
2) 95°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C ∞
Primers for sequencing
walla_seq(F): 5’- CCATGAAAAGCAACTTGGTAATGC -3’
walla_seq(R): 5’- AGCATCAGCCCTGCTGC -3’
The following sequence of 432 nucleotides (from Genbank genomic region NC_000086 for linear genomic sequence of Cd40lg, sense strand) is amplified:
11066 cagtt ctacagtggg ccaagaaagg atattatacc
11101 atgaaaagca acttggtaat gcttgaaaat gggaaacagc tgacggttaa aagagaagga
11161 ctctattatg tctacactca agtcaccttc tgctctaatc gggagccttc gagtcaacgc
11221 ccattcatcg tcggcctctg gctgaagccc agcagtggat ctgagagaat cttactcaag
11281 gcggcaaata cccacagttc ctcccagctt tgcgagcagc agtctgttca cttgggcgga
11341 gtgtttgaat tacaagctgg tgcttctgtg tttgtcaacg tgactgaagc aagccaagtg
11401 atccacagag ttggcttctc atcttttggc ttactcaaac tctgaacagt gcgctgtcct
11461 aggctgcagc agggctgatg ctggcagtct tccctat
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated T is indicated in red.
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|Science Writers||Eva Marie Y. Moresco|
|Illustrators||Diantha La Vine|
|Authors||Carrie N. Arnold, Elaine Pirie, Bruce Beutler|