LRBA is Essential for Allogeneic Responses in Bone Marrow Transplantation.
The PH-BEACH-WD40 (PBW) protein family members play a role in coordinating receptor signaling and intracellular vesicle trafficking. LPS-Responsive-Beige-like Anchor (LRBA) is a PBW protein whose immune function remains elusive. Here we show that LRBA-null mice are viable, but exhibit compromised rejection of allogeneic, xenogeneic and missing self bone-marrow grafts. Further, we demonstrate that LRBA-null Natural Killer (NK) cells exhibit impaired signaling by the key NK activating receptors, NKp46 and NKG2D. However, induction of IFN-γ by cytokines remains intact, indicating LRBA selectively facilitates signals by receptors for ligands expressed on the surface of NK targets. Surprisingly, LRBA limits immunoregulatory cell numbers in tissues where GvHD is primed or initiated, and consistent with this LRBA-null mice also demonstrate resistance to lethal GvHD. These findings demonstrate that LRBA is redundant for host longevity while being essential for both host and donor-mediated immune responses and thus represents a unique and novel molecular target in transplant immunology.
Department of Microbiology &Immunology, SUNY Upstate Medical University, Syracuse, NY, US.
Mi Young
MY
Park
Department of Microbiology &Immunology, SUNY Upstate Medical University, Syracuse, NY, US.
Raki
R
Sudan
Department of Microbiology &Immunology, SUNY Upstate Medical University, Syracuse, NY, US.
Neetu
N
Srivastava
Department of Microbiology &Immunology, SUNY Upstate Medical University, Syracuse, NY, US.
Sudha
S
Neelam
Department of Microbiology &Immunology, SUNY Upstate Medical University, Syracuse, NY, US.
Christie
C
Youngs
Department of Internal Medicine, University of South Florida, Tampa, Florida, US.
Jia-Wang
JW
Wang
Department of Pathology &Cell Biology, University of South Florida, Tampa, Florida, US.|Department of Pediatrics, University of South Florida, Tampa, Florida, US.|H. Lee Moffitt Comprehensive Cancer Center &Research Institute; University of South Florida, Tampa, FL.
Robert W
RW
Engelman
Department of Microbiology &Immunology, SUNY Upstate Medical University, Syracuse, NY, US.|Department of Biochemistry &Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, US.|Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, US.|Chemistry Department, Syracuse University, Syracuse, NY 13210 USA.
William G
WG
Kerr
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D064591:Allografts; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D016026:Bone Marrow Transplantation; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014181:Transplantation Immunology
D048868:Adaptor Proteins, Signal Transducing; D000950:Antigens, Ly; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; C498954:Lrba protein, mouse