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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.

LRBA is Essential for Allogeneic Responses in Bone Marrow Transplantation