Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway.
Transient suppression of B cell function often accompanies acute viral infection. However, the molecular signaling circuitry that enforces this hyporesponsiveness is undefined. In this study, experiments identify up-regulation of the inositol phosphatase PTEN (phosphatase and tensin homolog) as primarily responsible for defects in B lymphocyte migration and antibody responses that accompany acute viral infection. B cells from mice acutely infected with gammaherpesvirus 68 are defective in BCR- and CXCR4-mediated activation of the PI3K pathway, and this, we show, is associated with increased PTEN expression. This viral infection-induced PTEN overexpression appears responsible for the suppression of antibody responses observed in infected mice because PTEN deficiency or expression of a constitutively active PI3K rescued function of B cells in infected mice. Conversely, induced overexpression of PTEN in B cells in uninfected mice led to suppression of antibody responses. Finally, we demonstrate that PTEN up-regulation is a common mechanism by which infection induces suppression of antibody responses. Collectively, these findings identify a novel role for PTEN during infection and identify regulation of the PI3K pathway, a mechanism previously shown to silence autoreactive B cells, as a key physiological target to control antibody responses.
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
Andrew
0000-0002-5663-6812
A
Getahun
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
Scott M
0000-0002-9688-5071
SM
Wemlinger
Department of Biostatistics and Informatics, University of Colorado School of Public Health, Aurora, CO 80045.
Pratyaydipta
P
Rudra
Division of Infectious Disease, University of Colorado School of Medicine, Aurora, CO 80045.
Mario L
ML
Santiago
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
Linda F
LF
van Dyk
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045 john.cambier@ucdenver.edu.|Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
John C
0000-0002-7803-242X
JC
Cambier
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014777:Virus Diseases / Q000276:immunology*
C514936:CXCR4 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011947:Receptors, Antigen, B-Cell; D019718:Receptors, CXCR4; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases