Fgl2 regulates CD8+ T cell responses and promotes transplant acceptance in a cell-intrinsic manner 3841

Description The mechanisms by which transplant rejection is precipitated are incompletely understood. We found that fibrinogen-like protein 2 (Fgl2), an immunosuppressive cytokine, was elevated in transplant recipients with stable graft function relative to those undergoing rejection or to healthy controls, but the source and function of Fgl2 was unknown. An allogeneic mouse model revealed that donor-reactive, graft-infiltrating CD8+ T cells are a source of Fgl2. To determine the role of CD8+ T cell-derived Fgl2 in regulating alloreactive CD8+ T cell responses, we adoptively transferred WT vs. Fgl2-/- OT-I T cells into Fgl2-/- mice and challenged with an OVA-expressing skin graft. The absence of Fgl2 production by OT-I T cells significantly accelerated allograft rejection (p = 0.043), increased OT-I accumulation (p = 0.019), increased IL-2 production (p = 0.004), and decreased inhibitory receptor expression on day 10 post-transplant. In human PBMCs, TIGIT+ CD8+ cells produced significantly more Fgl2 vs. TIGIT- CD8+ T cells (p < 0.0001). Of note, the addition of calcineurin inhibitor tacrolimus but not costimulation blocker belatacept significantly inhibited Fgl2 production by TIGIT+ CD8+ T cells (p < 0.0001). We conclude that Fgl2 promotes contraction of CD8+ T cell effector responses during transplantation by inducing an exhaustion-like profile and inhibiting IL-2 production. Bolstering production of Fgl2 may be an effective immunotherapy to attenuate CD8+ T cell responses in transplantation.