Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice.
BACKGROUND
The B-cell receptor transmembrane activator and calcium modulator ligand interactor (TACI) is important for T-independent antibody responses. One in 200 blood donors are heterozygous for the TACI A181E mutation.


OBJECTIVE
We sought to investigate the effect on B-cell function of TACI A181E heterozygosity in reportedly healthy subjects and of the corresponding TACI A144E mutation in mice.


METHODS
Nuclear factor κB (NF-κB) activation was measured by using the luciferase assay in 293T cells cotransfected with wild-type and mutant TACI. TACI-driven proliferation, isotype switching, and antibody responses were measured in B cells from heterozygous TACI A144E knock-in mice. Mouse mortality was monitored after intranasal pneumococcal challenge.


RESULTS
Levels of natural antibodies to the pneumococcal polysaccharide component phosphocholine were significantly lower in A181E-heterozygous than TACI-sufficient Swedish blood donors never immunized with pneumococcal antigens. Although overexpressed hTACI A181E and mTACI A144E acted as dominant-negative mutations in transfectants, homozygosity for A144E in mice resulted in absent TACI expression in B cells, indicating that the mutant protein is unstable when naturally expressed. A144E heterozygous mice, such as TACI+/-mice, expressed half the normal level of TACI on their B cells and exhibited similar defects in a proliferation-inducing ligand-driven B-cell activation, antibody responses to TNP-Ficoll, production of natural antibodies to phosphocholine, and survival after intranasal pneumococcal challenge.


CONCLUSIONS
These results suggest that TACI A181E heterozygosity results in TACI haploinsufficiency with increased susceptibility to pneumococcal infection. This has important implications for asymptomatic TACI A181E carriers.
Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
Haifa H
HH
Jabara
Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
John J
JJ
Lee
Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
Erin
E
Janssen
Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
Sumana
S
Ullas
Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
Kyriaki
K
Liadaki
Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
Lilit
L
Garibyan
Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
Halli
H
Benson
Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
Tatyana
T
Sannikova
Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minn.
Richard
R
Bram
Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
Lennart
L
Hammarstrom
Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md.
Anthony C
AC
Cruz
Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md.
Richard
R
Siegel
Division of Transfusion Medicine, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
John
J
Manis
Division of Infectious Diseases, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass.
Richard
R
Malley
Division of Immunology, Boston Children's Hospital, Boston Children's Hospital, and Harvard Medical School, Boston, Mass. Electronic address: raif.geha@childrens.harvard.edu.
Raif S
RS
Geha
D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000235:genetics* / Q000276:immunology; D016133:Polymerase Chain Reaction; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics* / Q000276:immunology
D053303:Transmembrane Activator and CAML Interactor Protein
B cells; Transmembrane activator and calcium modulator ligand interactor; common variable immunodeficiency; natural antibodies; pneumococcal susceptibility