Flt3 ligand expressed on the surface of T-cells contributes to effector function

Abstract

Abstract Flt3 ligand (FL) is a growth factor that contributes to the homeostasis of the dendritic cell (DC) compartment. FL provides signals for differentiation, development, and survival by binding to the Flt3 receptor tyrosine kinase. Flt3 expression is maintained on DCs through their terminal differentiation. Endogenously, FL is produced by stromal cells and select immune cells, including T-cells and some DC subsets. FL may be expressed as a membrane-bound form (mFL), with no intracellular signaling domain, and may undergo cell-autonomous shedding to generate soluble FL. This is believed to contribute to a localized source of FL for those DC subsets, however T-cells do not express Flt3 and have no FL requirement. As such, it remains unclear why T-cells express mFL on their surface. Interestingly, FL-driven DCs are more steady state-like, secreting less pro-inflammatory cytokines, and can suppress graft-versus-host disease (GvHD). We hypothesized that mFL on T-cells may regulate effector responses through binding to Flt3 on DCs. To test this, we compared GvHD in a murine bone marrow transplant model using WT compared to FL−/− donor cells. Engraftment, T-cell reconstitution, and activation were monitored weekly. We also performed mixed leukocyte reactions (MLR) to measure T-cell proliferation in WT versus FL−/− T-cells. Infusion of FL−/− donor cells resulted in significantly worse GvHD and higher expression of T-cell activation markers CD25 and CD69 in vivo. The absence of mFL also resulted in significantly enhanced alloreactive T-cell proliferation in vitro. These studies indicate that mFL expressed on the surface of T-cells can alter their effector function, which may be a result of the engagement of mFL with Flt3 receptor expressed on DCs.