CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation.
We used a genome-wide screen in mutagenized mice to identify genes which inactivation protects against lethal neuroinflammation during experimental cerebral malaria (ECM). We identified an ECM-protective mutation in coiled-coil domain containing protein 88b (Ccdc88b), a poorly annotated gene that is found expressed specifically in spleen, bone marrow, lymph nodes, and thymus. The CCDC88B protein is abundantly expressed in immune cells, including both CD4(+) and CD8(+) T lymphocytes, and in myeloid cells, and loss of CCDC88B protein expression has pleiotropic effects on T lymphocyte functions, including impaired maturation in vivo, significantly reduced activation, reduced cell division as well as impaired cytokine production (IFN-γ and TNF) in response to T cell receptor engagement, or to nonspecific stimuli in vitro, and during the course of P. berghei infection in vivo. This identifies CCDC88B as a novel and important regulator of T cell function. The human CCDC88B gene maps to the 11q13 locus that is associated with susceptibility to several inflammatory and auto-immune disorders. Our findings strongly suggest that CCDC88B is the morbid gene underlying the pleiotropic effect of the 11q13 locus on inflammation.
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
James M
JM
Kennedy
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Nassima
N
Fodil
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Sabrina
S
Torre
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Silayuv E
SE
Bongfen
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Jean-Frédéric
JF
Olivier
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Vicki
V
Leung
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
David
D
Langlais
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Charles
C
Meunier
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Joanne
J
Berghout
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Pinky
P
Langat
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Jeremy
J
Schwartzentruber
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Jacek
J
Majewski
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Mark
M
Lathrop
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada.
Silvia M
SM
Vidal
Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada Department of Biochemistry, Department of Human Genetics, McGill and Genome Quebec Innovation Center, Complex Traits Group, McGill University, Montreal, Quebec H3A 0G4, Canada philippe.gros@mcgill.ca.
Philippe
P
Gros
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D060467:Disease Resistance / Q000276:immunology; D005038:Ethylnitrosourea; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006413:Hematopoietic System / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D016779:Malaria, Cerebral / Q000235:genetics / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010962:Plasmodium berghei; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*
D002352:Carrier Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C000595938:coiled-coil domain containing 88B protein, mouse; D005038:Ethylnitrosourea