CD46: expanding beyond complement regulation

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TRENDS in Immunology

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CD46: expanding beyond complement regulation Rebecca C. Riley-Vargas, Darcy B. Gill, Claudia Kemper, M. Kathryn Liszewski and John P. Atkinson Washington University School of Medicine, Department of Medicine, Division of Rheumatology, 660 South Euclid Avenue, St. Louis, MO 63110, USA

During the 1980s CD46 was discovered in a search for C3b binding proteins of human peripheral blood cells. Its role as an inactivator of C3b and C4b deposited on selftissue is highlighted by the observation that partial deficiency of CD46 is a predisposing factor to hemolytic uremic syndrome. This discovery has an impact on the treatment options for these patients. Other new findings have expanded the role of CD46 in immunity and disease. For example, signaling through CD46 on human T lymphocytes drives them to become regulatory cells, indicating a novel link between the complement system and cellular immunity. Also, CD46 interacts with at least seven human pathogens and participates in reproduction/fertilization, further suggesting that dissecting its multi-faceted activities will have important clinical implications. CD46 (membrane cofactor protein; MCP) was identified in 1985 as a C3b and C4b binding protein of human peripheral blood mononuclear cells (reviewed in Ref. [1]). Subsequent purification of the protein allowed for the demonstration of its complement regulatory activity, and, following N-terminal sequencing, its cloning [1]. The primary structure and genomic analysis established that it belongs to the regulators of complement activation (RCA) gene cluster at 1q32 [1]. Now known to be nearly ubiquitously expressed, CD46 protects host cells from complement attack by serving as a cofactor for the plasma serine protease factor I, which proteolytically inactivates C3b and C4b bound to host cells [1]. In addition to being a complement inhibitor, CD46 participates in reproduction/ fertilization [2], interacts with at least seven human pathogens [3–10], and, upon crosslinking, induces CD4C T cells to become T regulatory cells [11]. CD46 deficiency has been recently linked to hemolytic uremic syndrome (HUS), highlighting its role in regulating complement activation on injured tissue [12–14]. Expression pattern CD46 is expressed on most cells as four isoforms that are derived via alternative splicing of a single w46 kb gene (Figure 1a) [15]. The isoforms differ in the quantity of juxtamembranous O-glycosylation and by expression of a 16 or 23 amino acid cytoplasmic tail (CYT-1 or CYT-2, Corresponding author: John P. Atkinson ([email protected]). Available online 24 July 2004

respectively), each bearing distinct signaling motifs. The relative ratio of isoforms is inherited in an autosomal co-dominant fashion, with three phenotypes in the population [15,16]: 65% express predominantly the heavily O-glycosylated 65 kDa form, 6% express predominantly the less O-glycosylated 55 kDa form and 29% express both forms in approximately equal ratios. With a few exceptions, this expression pattern is identical on all cell types in a given individual. In brain and male germ cells, the less O-glycosylated isoform bearing CYT-2 is expressed, whereas in the kidneys the more heavily glycosylated isoform with CYT-2 is predominantly expressed [17]. CD46 is not present on human red blood cells [18] but is found on erythrocytes of most other primates [19]. The reasons behind these tissue specific variations in expression remain to be identified. Other rare splice variants have been described (reviewed in Refs [15,20]). Isoforms bearing a third region rich in O-linked sugars are present on tumor cells [21,22]. Function Complement regulation CD46 is an intrinsic cofactor for the factor-I-mediated cleavage of C3b and C4b [1] (Figure 1b). Intrinsic refers to the fact that CD46 efficiently aids in cleaving C3b or C4b that is deposited on the same cell as CD46 itself [23]. The cleavage of C3b produces the fragment C3bi, which is unable to support further complement activation. The cleavage of C4b by factor I and CD46 produces the fragments C4c and C4d. C4c is liberated into the extracellular milieu whereas C4d, incapable of continuing the complement cascade, remains attached to the target. CD46 is most effective in controlling the amplification loop of the alternative pathway [1,24,25]. Currently, this regulator is thought to scan the cell membrane to prohibit deposited C3b from initiating the alternative pathway feedback loop. Signaling Both cytoplasmic tails of CD46 contain signaling motifs (Figure 1a), and crosslinking CD46 leads to cell activation events (Tables 1 and 2). The cytoplasmic tail 2 (CYT-2) undergoes tyrosine phosphorylation by the src kinase lck in the human T cell line Jurkat [26]. Crosslinking of CD46 on primary human CD4C T lymphocytes induces Vav and Rac activation [27] as well as phosphorylation of the

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(a)

1 1

2

2 3

CCPs

3

4 STP region

O O O O

O O O O

B C

4 O

O

C

Membrane Cytoplasm

or

or

BC1 or BC2

C1 or C2

CYT-1:

CYT-2:

CK-2; PKC

Src kinase

TYLTDETHREVKFTSL

(b)

KADGGAEYATYQTKSTTPAEQRG

Factor I

Factor I

C3f

MCP C3b

CK-2

Factor I C3b

C3b

Factor I

C3bi

Factor I Factor I

C4b

C4b

C4c C4d

C4b

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Figure 1. (a) Diagram of CD46 structure. CD46 is a type I transmembrane glycoprotein that is expressed on most tissues as four major isoforms derived by alternative splicing of a single gene. The N-terminus of each isoform consists of four complement control protein repeats (CCPs), and CCPs 1, 2 and 4 each bear one N-linked complex sugar. The CCPs are followed by a serine, threonine and proline-rich (STP) region that is heavily O-glycosylated. The STP region, a site of alternative splicing, arises from three separate exons, designated A, B and C. The four major isoforms of CD46 utilize the C region, whereas the B region is alternatively spliced, giving rise to either a BC or C STP region. Isoforms containing the A exon of the STP region have been reported, but are rarely observed in normal human tissue. The STP region is followed by a 12 amino acid region of unknown function, a transmembrane domain and a cytoplasmic anchor. The carboxyl terminus of CD46 is also differentially spliced, giving rise to two distinct cytoplasmic tails, designated CYT-1 and CYT-2. CYT-1 is 16 amino acids long and contains a casein kinase II phosphorylation site and a protein kinase C phosphorylation site. CYT-2 is 23 amino acids long and contains a src kinase site as well as a casein kinase II site. (b) CD46 is a cofactor for the serine protease factor I to cleave C3b and C4b. Deposited C3b is cleaved to yield membrane-bound C3bi and soluble C3f. Deposited C4b is cleaved to yield membrane-bound C4d and soluble C4c. The cell-bound cleavage fragments are incapable of continuing the complement activation cascade.

mitogen-activated protein kinase Erk [27] and the adaptor proteins p120CLB and LAT [28]. The biological consequences of CD46 signaling in human primary CD4C T cells include the T-cell receptor (TCR)-dependent induction of proliferation (greater than CD3/CD28 stimulation) [11,28] and the development of a T regulatory cell 1 (Tr1) phenotype [11]. This observation is supported by a study from Marie et al. that analyzed the effect of CD4C T cells on T cell-mediated immune responses in mice transgenic for human CD46. This group generated mice that expressed human CD46 with either cytoplasmic tail 1 www.sciencedirect.com

(CD46–1) or tail 2 (CD46–2) and found that CD3-activated CD4C T cells from CD46–1 animals proliferate strongly, produce interleukin (IL)-10 and inhibit contact hypersensitivity reaction (CHS). By contrast, CD3-activated T cells from CD46–2 mice showed weak proliferative capacity, produced low amounts of IL-10 and increased CHS [29]. Thus, this system also generated CD46-induced T cells with an immunoregulatory capacity. Taken together, these findings establish a role for CD46 in regulating human T cells and suggest a novel link between the complement system and cellular immunity.

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Table 1. Signaling events induced in human T cells by crosslinking CD46 Cell type

Stimulation

Major observation

Ref.

Jurkat cells

Monoclonal antibodies (mAbs)

[26]

Human peripheral blood lymphocytes

mAbs mAbs to CD46 and CD3

Purified human CD4C T cells

mAbs to CD46 and CD3

Tyrosine phosphorylation of CD46 (lck dependent) P120cbl phosphorylation Erk1/2 activation Vav phosphorylation Rac activation (but not Rho or Cdc42) LAT phosphorylation Proliferation Actin relocalization Development of T regulatory phenotype

CD46-mediated signaling events in human macrophages are not as clear, as there are conflicting data. Ligation of CD46 on human primary monocytes with monoclonal antibodies (mAbs), C3b dimers or measles virus (MV) hemagglutinin (a CD46 ligand) downregulates IL-12 p70 and p40, providing a putative mechanism for MV-induced immunosuppression [30]. However, early CD46-induced intracellular events in human macrophages include the recruitment of the protein-tyrosine phosphatase SHP-1 to the cytoplasmic domain(s) but also the subsequent production of nitric oxide and IL-12 p40 [31]. The reasons (or molecular mechanisms) underlying these contradictory findings are yet to be determined. A potential explanation could be that one group utilized primary, non-manipulated human monocytes [30], whereas the other group used granulocyte colony-stimulating factor-matured macrophages [31]. Thus, the developmental stage of the monocyte/macrophage/dendritic cell might determine the biological consequences (outcome) of CD46-mediated signaling events. Also, engagement of CD46 in mouse monocytic cell lines transgenic for human CD46 induces phosphorylation of the intracellular domains by several kinases [32] and nitric oxide production [33]. In addition, Ghali et al. have shown that crosslinking of CD46 on human U251 astrocytoma cells induces production of the proinflammatory cytokine IL-6 [34]. CD46-mediated signaling events in the brain are of particular interest because of its tissue specific isoform expression pattern [17]. CD46 also associates with

[28] [27]

[28] [11,28] [27] [11]

b1-integrins [35,36], tetraspans [35,36] and DLG4 [37]. There is much to be learned about the consequences of, as well as the intracellular pathways for, CD46-mediated signaling events.

Pathogen interactions CD46 is a receptor for a growing list of human pathogens (Table 2). Its nearly ubiquitous surface expression, regulatory activity for the complement system and cell signaling capabilities probably contribute to CD46 being a target for multiple pathogens. The CD46–MV interaction is the most thoroughly studied. Peptide mapping, antibody blocking, substitution mutagenesis and crystallography [the crystal structure of complement control protein repeats (CCPs) 1 and 2 is available [38]] have provided information on the regions of CD46 that are reported to interact with the MV hemagglutinin. These studies have revealed a large, glycan free, multi-contact binding site spanning CCPs 1 and 2 (reviewed in Ref. [39]). Notably, the functional sites of CD46 (those required for C3b and C4b binding and cofactor activity) overlap, at least in part, with the regions that interact with MV hemagglutinin [40]. Interestingly, other CD46-using pathogens appear to use alternative sites on CD46. Although fine mapping of these sites has not been performed, domains necessary to these interactions have been identified. Pilus-mediated adhesion of Neisseria gonorrhoeae and interactions with the streptococcal M protein both require regions in

Table 2. Summary of pathogen interactions Pathogen

Ligand

Binding site on membrane cofactor protein

Ref.

Signaling observations after binding

Ref.

Measles virus

Hemagglutinin

CCPs 1-2

[39]

CD46 association with moesin Interleukin (IL)-12 downregulation Tyr-X-X-Leu motif in CYT-1 is essential for CD46 downregulation after injection Recruitment of SHP-1 to the cytoplasmic domain of CD46 and induction of IL-12p40 Alterations in internalization pathways Ca2C flux Phosphorylation of CYT-2 CD46 downregulation Suppression of IL-12 CD46 downregulation Unknown Unknown

[72] [30,73] [74]

Neisseria (gonorrhoeae and meningitidis)

Type IV pilus

CCPs 3 and 4

[41]

Herpesvirus 6 (human)

Complex of glycoproteins H, L and Q M protein Fiber knob

CCPs 2 and 3

[43–45]

CCPs 3 and 4 Unknown

[42] [9,10]

Streptococcus pyogenes Adenoviruses (Group B and D) www.sciencedirect.com

[31]

[47] [48] [48,49] [52] [75] [8]

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CCPs 3 and 4, whereas human herpesvirus 6 requires CCPs 2 and 3 [41–45]. Engagement of CD46 by pathogens has implications beyond cellular adhesion. MV binding to CD46 leads to a decrease in IL-12 production in human macrophages [30], an increase in nitric oxide production in mouse macrophages [46] and alterations in the internalization pathways of CD46 in nonlymphoid cell lines [47]. Neisseria interactions with CD46 produce a calcium flux [48] and tyrosine phosphorylation of CYT-2 [48,49]. CD46 on human cells is downregulated following attachment of MV [50,51], N. gonorrhoeae [52], herpesvirus 6 [8] and rinderpest [53]. MV-induced CD46 downregulation results in increased complement sensitivity of the infected cell [54]. The large number of microbes using CD46 as a receptor, and their diverse disease manifestations, points to the evolution of different strategies by which pathogens exploit their interactions with CD46. MV and Neisseria are human specific pathogens, which do not normally infect mice. CD46 transgenic mice, however, are susceptible to both infections; this has permitted the establishment of new animal models for these diseases. Transgenic mice are permissive to MV replication and exhibit sequelae, such as immunosuppression and central nervous system manifestations similar to those observed in MV-infected humans (reviewed in Ref. [55]). In the case of Neisseria meningitidis, infection of CD46 transgenic mice resulted in bacteremia and more efficient bacterial traversal of the blood–brain barrier, as evidenced by the presence of meningococci in the cerebrospinal fluid, meninges and choroid plexus [56]. In addition, CD46 transgenic mice injected with an adenoviral vector containing the viral ligand for CD46 exhibited a wider distribution of viral DNA than nontransgenic mice [10]. These results indicate that the presence of CD46 enhances susceptibility to infections by the organisms that use it as a receptor. However, the suggestion that CD46 is the sole cellular receptor for MV, Neisseria and Streptococcus pyogenes is associated with some controversy. For example, an inverse correlation has been shown between attachment of N. gonorrhoeae and CD46 expression by various cell lines [57]. Similarly, CD46 expression did not correlate with adhesion of S. pyogenes to L cells [58]. In the case of MV adhesion, there is agreement that, although most MV vaccine strains use CD46 as a receptor, wild type strains appear to preferentially use SLAM (CDw150) (reviewed in Ref. [59]). These studies have challenged the identification of CD46 as the ‘primary’ receptor for the Neisseria pilus, Streptococcal M protein and MV hemagglutinin. However, in contrast to the high affinity interactions with CD46 that are observed with vaccine strains of MV, there might be a second site on the MV hemagglutinin, conserved among wild type and vaccine strains, which mediates a constitutive, low affinity interaction with CD46 [60]. Such interactions, although not sufficient to be solely responsible for adhesion of the pathogen to the host cell, might be sufficient to trigger CD46 dependent cellular responses that are crucial to microbial pathogenesis and/or host defense. The issues are unresolved but, as pointed out in www.sciencedirect.com

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the MV studies, probably reflect more than one receptor being involved in these pathogen interactions. In summary, CD46 contributes to the pathogenic strategies of seven human-specific pathogens. However, the precise role(s) of CD46 in these infections remains enigmatic. Further studies of the contribution of CD46 to microbial adhesion, as well as to the downstream repercussions of CD46 engagement by pathogens, should increase our understanding of the pathogenesis of these infections and uncover novel information about ‘normal’ functions of CD46. Reproduction The expression of CD46 by human spermatozoa is restricted to the inner acrosomal membrane (IAM) (reviewed in Ref. [2]) (Figure 2). This membrane is exposed following binding of spermatozoa to the zona pellucida of the egg. Spermatozoa express the isoform of CD46 with less O-glycosylation and CYT-2 [20]. Moreover, the N-linked sugars are subject to a trimming event [20]. Specifically, the three complex N-linked sugars are pared, resulting in an w8 kDa decrease in mass. This maturation process has been described for three other spermatozoa proteins (summarized in [20]) but its biologic significance is unexplained. Variations in CD46 expression on spermatozoa have been associated with infertility [61,62] and CD46 is a target for anti-sperm antibodies [63]. Rabbit and mouse antibodies against CD46 inhibit both binding and penetration of human sperm to zona-free hamster eggs and to human zona (reviewed in Ref. [2]). The role that CD46 plays in fertilization is unclear. CD46 might be acting solely as a complement regulator in this location. Acrosin, a protease capable of cleaving C3, is released in association with the acrosome reaction [64] so there is a rationale for an inhibitor of C3 in this location. However, other data indicate that CD46 is involved in more than complement regulation. In experiments designed to block fertilization using mAbs to CD46, mAbs to CCP 1 were more effective in inhibiting sperm– egg binding than mAbs to CCPs 3 and 4 [65]. The latter block complement regulatory activity. Consequently, we investigated CD46 in New World monkeys because these primates employ alternative splicing to express CD46 lacking CCP 1 [66]. This manipulation of CD46 structure is proposed to prevent MV infection because many MV strains require CCP 1 for the viral hemagglutinin to bind [66–68]. However, CCP 1 is not required for complement regulatory activity [40]. Surprisingly, and in contrast to other tissues, the New World monkeys retain CCP 1 expression in the testis [69]. This result suggests that this domain participates in an activity unrelated to complement inhibition, but crucial to fertilization. Another indication that CD46 plays an important role in fertilization is its expression pattern in rodents. In mice, rats and guinea pigs, CD46 expression is restricted to spermatozoa (reviewed in Ref. [2]). Crry, a closely related protein to CD46 that is not expressed in humans, performs the complement regulatory function of CD46 in other tissues of rodents (reviewed in Ref. [2]). Thus, the presence of CD46 specifically on the IAM of spermatozoa, despite the expression of another molecule capable of the

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(a) 1o binding Zona pellucida Acrosome reaction

Perivitelline space

Plasma membrane 2o binding Cortical granules

Fusion

(b)

Plasmamembrane

Fusion

Outer acrosomal membrane

Acrosome with contents

MCP exposed

Inner acrosomal membrane

MCP

Inner acrosomal membrane

Nucleus Ca2+ 1o Zona pellucida binding Capacitated

2o Zona pellucida binding Acrosome-reaction Acrosome-reacted

Figure 2. (a) Representation of fertilization. Capacitated human spermatozoa bind to the zona pellucida of the egg (primary binding), inducing the acrosome reaction. The enzymes released from the acrosome allow the spermatozoa to transverse the zona, where secondary binding occurs. This interaction is transient and cyclic. Fusion occurs between the equatorial segment of the spermatozoa and the plasma membrane of the egg. Fusion results in the release of cortical granules that alter the zona and prohibit polyspermy. (b) Representation of the acrosome reaction of human sperm. The acrosome reaction of capacitated sperm occurs after the binding to the zona pellucida or can be induced in vitro by the Ca2C ionophore. Upon these events, the outer acrosomal membrane fuses with the plasma membrane, releasing the contents of the acrosome. CD46 is now exposed on the inner acrosomal membrane. Part (b) reproduced with permission from Ref. [20].

same regulatory function in other tissues, further indicates that CD46 plays an ‘additional’ role in fertilization. In 2003, Inoue et al. described a mouse possessing a targeted deletion of CD46 [70]. There was no difference in C3 deposition between wild type spermatozoa and CD46K/K spermatozoa. However, the classical pathway was used to initiate complement deposition, and CD46 is most effective in regulating C3 deposition by the alternative pathway [1,24,25]. Unexpectedly, CD46K/K mice had an increased number of pups per litter compared with wild type mice. The authors attributed this finding to an accelerated rate of the acrosome reaction in CD46K/K mice, allowing for a greater number of spermatozoa to bind oocytes. There is no obvious explanation, however, for www.sciencedirect.com

the mechanism by which CD46 is connected to an accelerated acrosome reaction. CD46 deficiency Mutations in CD46 were recently linked to HUS [12,13], an illness characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. Most often, ‘typical’ HUS presents after a diarrheal illness due to infection with Escherichia coli O157. ‘Atypical’ HUS occurs without a preceding diarrheal illness in sporadic and familial cases. Richards et al. [12] sequenced CD46 coding exons in 30 atypical HUS families and found CD46 specific mutations in three (Table 3). In Family 1 (Belgium), three male

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Table 3. Families with a CD46 mutation and hemolytic uremic syndrome Family

Sex

Age

Mutation

1 Dominant

M M M M M F M F M

27 31 35 8 15 9 15 1.3 9

Heterozygous DD237/DS238

2 Dominant 3 Recessive 4 Dominant

Heterozygous S206P Homozygous S206P Heterozygous 2 bp del (843-844)

siblings developed the illness between 27–35 years of age. Each developed end stage kidney disease and, interestingly, had no relapses following renal transplantation. These brothers had a heterozygous deletion of two amino acids (D237/S238) in CCP 4. Families 2 and 3 (unrelated) had an identical substitution of a proline for a serine at position 206 (S206P). The two siblings of Family 2 (German) were heterozygous. In Family 3, the Turkish parents were first-degree relatives, and both a son and daughter were homozygous for the mutation. These afflicted individuals with the S206P mutation recovered renal function. Biochemical analyses were performed [12] using the patients’ peripheral blood mononuclear cells (PBMC) as well as transfected Chinese hamster ovary cells expressing the mutant CD46 proteins (Table 4). For Family 1, the mutated protein was synthesized but retained intracellularly in a precursor form, consistent with the half-normal levels of the wild type protein on their blood cells. For Families 2 and 3, the protein was expressed normally, but it had 5–10% of the wild type capacity to bind and inactivate C3b. Its C4b binding and cofactor activity for C4b inactivation were normal. Noris et al. screened 25 patients with atypical HUS and found a two base-pair heterozygous deletion in two siblings [13] (Table 3). This altered three amino acids at position 233–235 and led to a premature stop codon. Expression levels of wild type CD46 on affected cells were w50% of normal. These findings, coupled with earlier studies linking factor H mutations to atypical HUS [71], indicate that complement regulatory protein deficiency predisposes to HUS. Complement dysregulation accounts for about onethird of sporadic and familial cases, and it is likely that other complement proteins will be implicated. The discovery of CD46 mutations associated with HUS has clinical consequences. Approximately two-thirds of Table 4. Effect of the different mutations on CD46 expression and functiona

a

Mutant

Quantity of mutant on cell surface

Defect

S206P DD237/DS238

Normal !5%

Two base-pair del (843-844)

!5%

!10% normal C3b binding Endoplasmic reticulum retention Premature stop codon

These data are taken from Refs [12] and [13].

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CD46 +/+

CD46 +/- or -/-

Endothelial cell Lumen CD46 C3bi

Thrombus C3b

Damage Basement

membrane TRENDS in Immunology

Figure 3. Diagram of complement-mediated damage in hemolytic uremic syndrome. In the presence of fully functional CD46, C3b deposited at sites of cellular damage is cleaved to C3bi, thereby limiting complement activation. With a deficiency of CD46 (complete or a 50% reduction), deposited C3b is not efficiently cleaved and excessive complement activation leads to a procoagulant state [12–14].

atypical HUS patients develop renal failure and therefore become candidates for renal transplantation. Of interest, the three patients transplanted with CD46 deficiency did not have recurrent disease, probably explained by the fact that donor kidneys expressed normal amounts of CD46 (Figure 3, Tables 3 and 4). By contrast, renal transplantation in patients with deficiency of the plasma protein factor H would not be ‘cured’ of their predisposition to HUS [71]. Summary CD46 was initially identified because of its C3b binding and complement regulatory activity. Highlighting the importance of CD46 in this role was a recent discovery of CD46 deficiency predisposing to HUS [12,13] and the more general recognition of the crucial function of complement regulators in preventing excessive cellular destruction at sites of injury. A second advance has been the identification of the signaling capabilities of CD46. Crosslinking CD46 on human peripheral blood naı¨ve T cells and the TCR (CD3) induce T regulatory cells whose role in autoimmunity and maintaining tolerance is currently being elucidated [11]. Human PBMC secrete IL-12 following CD46 crosslinking by MV hemagglutinin, providing an explanation for the transient decrease in T cell-mediated immune responses during this infection [30]. Further elucidation of CD46’s signaling capability will probably lead to an explanation for why CD46 has been subverted as a receptor for seven human pathogens. Lastly, there are multiple lines of evidence suggesting a role for CD46, beyond complement regulation, in reproduction and fertilization [2,64]. Questions for future research † What is the signaling cascade triggered by crosslinking CD46?

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† Why is CD46 such a magnet for pathogens? † Why is CD46 expressed on the inner acrosomal membrane of spermatozoa? † What are the clinical parameters in HUS that suggest a complement regulatory protein deficiency? † Why are endothelial cells of the kidney so sensitive to a deficiency of complement regulators?

Acknowledgements We are grateful to Madonna Bogacki for assistance with the manuscript.

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61 Kitamura, M. et al. (1997) Possible association of infertility with sperm-specific abnormality of CD46. J. Reprod. Immunol. 33, 83–88 62 Nomura, M. et al. (2001) Genomic analysis of idiopathic infertile patients with sperm-specific depletion of CD46. Exp. Clin. Immunogenet. 18, 42–50 63 Jiang, H. and Pillai, S. (1998) Complement regulatory proteins on the sperm surface: relevance to sperm motility. Am. J. Reprod. Immunol. 39, 243–248 64 Anderson, D.J. et al. (1993) The role of complement component C3b and its receptors in sperm-oocyte interaction. Proc. Natl. Acad. Sci. U. S. A. 90, 10051–10055 65 Taylor, C.T. et al. (1994) Inhibition of human spermatozoon-oocyte interaction in vitro by monoclonal antibodies to CD46 (membrane cofactor protein). Hum. Reprod. 9, 907–911 66 Hsu, E.C. et al. (1997) Artificial mutations and natural variations in the CD46 molecules from human and monkey cells define regions important for measles virus binding. J. Virol. 71, 6144–6154 67 Hsu, E.C. et al. (1998) A single amino acid change in the hemagglutinin protein of measles virus determines its ability to bind CD46 and reveals another receptor on marmoset B cells. J. Virol. 72, 2905–2916 68 Manchester, M. et al. (2000) Clinical isolates of measles virus use CD46 as a cellular receptor. J. Virol. 74, 3967–3974 69 Riley, R.C. et al. (2002) Inhibiting measles virus infection but promoting reproduction: an explanation for splicing and tissuespecific expression of CD46. J. Immunol. 169, 5405–5409 70 Inoue, N. et al. (2003) Disruption of mouse CD46 causes an accelerated spontaneous acrosome reaction in sperm. Mol. Cell. Biol. 23, 2614–2622 71 Richards, A. et al. (2001) Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition. Am. J. Hum. Genet. 68, 485–490 72 Schneider-Schaulies, J. et al. (1995) Differential downregulation of CD46 by measles virus strains. J. Virol. 69, 7257–7259 73 Fugier-Vivier, I. et al. (1997) Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells. J. Exp. Med. 186, 813–823 74 Yant, S. et al. (1997) Identification of a cytoplasmic Tyr-X-X-Leu motif essential for down regulation of the human cell receptor CD46 in persistent measles virus infection. J. Virol. 71, 766–770 75 Smith, A. et al. (2003) Selective suppression of IL-12 production by human herpesvirus 6. Blood 102, 2877–2884

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