Jason Cyster's laboratory studies how cells and antigens come together to generate immune responses. Cyster's group focuses on deciphering the molecular cues that guide immune cell movements and interactions within lymphoid organs, and the signals that promote cell egress from these organs. In complementary studies they address the basis for B lymphocyte selection during antibody affinity maturation in germinal centers and the requirements for barrier immunity in lymphoid organs and at epithelial surfaces.
Structure-Function Analysis of Lymphocyte Egress-Regulating CD69-S1PR1 Complex
Lymphocyte egress from lymphoid organs is essential for immune surveillance and for effector cells to travel to sites of infection or autoimmune inflammation. The G protein-coupled sphingosine-1-phosphate receptor-1 (S1PR1) plays a critical role transmitting an egress-promoting signal in response to lymph and plasma S1P. In the early phases of an immune response, innate stimuli cause a "shutdown" in lymphocyte egress from responding lymphoid organs, a change in flux that increases local cell numbers and facilitates responses. Shutdown occurs as a result of type I interferon upregulating CD69, a type II transmembrane protein that physically associates with S1PR1 and inhibits its egress-promoting function. In past work we have used mutagenesis, domain swapping, and cell transduction approaches to identify regions of CD69 and S1PR1 involved in the interaction.
This project has three goals. The first is to further define the molecular requirements for the CD69-S1PR1 interaction. As well as inhibiting S1PR1’s promigratory signaling, CD69 promotes internalization of the receptor. The second is to use cell biological approaches to discern requirements for receptor internalization. The third is to determine whether analogous interactions occur between other G protein-couple receptors and type II transmembrane proteins as part of a more general mechanism for regulation of this large class of signaling receptors. The project would be performed in the context of ongoing in vivo studies in the lab that aim to elucidate additional requirements for cell emigration from tissue and to fully define egress-regulatory mechanisms. FTY720, a drug that inhibits S1PR1 and lymphocyte egress, was approved in 2010 as a treatment for the autoimmune disease multiple sclerosis. Further defining the physiological mechanisms of egress regulation may suggest new approaches for treating immunological diseases.