Neutralizing IL-2 Early after HCT Specifically Prevents Expansion of Donor GM-CSF-Producing CD4⁺ T Cells That Initiate Acute Gut Gvhd

Acute graft versus host disease (GVHD) in gut has a critical impact on the outcome after allogenic hematopoietic cell transplantation (allo-HCT). It was recently reported that BATF-dependent GM-CSF-producing donor CD4⁺ T cells play a critical role in initiating acute gut GVHD (Ullrich et al: JCI 2018; Zeng: JCI; 2018). We recently reported that IL-2 from donor CD4⁺ T cells made infiltrating T cells resistant to host-tissue PD-L1-mediated tolerance (Ni & Song et al: JCI 2017). In the current studies, we tested whether in vivo neutralization of IL-2 early after allo-HCT regulates the expansion of GM-CSF-producing CD4⁺ T cells and the development of acute gut GVHD, and if so, whether host-tissue PD-L1 is required for this effect. We transplanted spleen (5x10⁶) and BM cells (2.5x10⁶) from C57BL/6 (H-2^b) donors into irradiated wild-type (WT) or PD-L1^-/- BALB/c (H-2^d) recipients bearing BCL1 leukemia/lymphoma cells and into recipients without BCL1 cells. Recipients were treated with anti-IL-2 mAb IP (500 µg/mouse) on days 0, 2, 4 and 6, and controls were treated with isotype-matched IgG. We observed the following results. 1) Administration of anti-IL-2 fully prevented acute gut GVHD while preserving GVL activity in WT recipients. 2) Administration of anti-IL-2 did not prevent acute gut GVHD in PD-L1^-/- recipients, indicating that GVHD prevention depends on expression of PD-L1 in recipient tissues. 3) Prevention of GVHD in WT recipients was associated with a marked reduction in the number of donor-derived GM-CSF-producing CD4⁺ T cells infiltrating gut tissue, together with decreased Paneth cell damage and bacterial translocation to the liver. These results indicate that neutralizing IL-2 early after allo-HCT specifically prevents expansion of acute gut GVHD-initiating GM-CSF-producing CD4⁺ T cells and prevents acute gut GVHD in a host-tissue PD-L1-dependent manner. These results also indicate that a short-term administration of anti-IL-2 following allo-HCT prevents induction of acute gut GVHD while preserving GVL effects. Current experiments are testing the molecular mechanisms whereby neutralizing IL-2 decreases the numbers of GM-CSF-producing CD4⁺ T cells in gut tissues via tissue expression of PD-L1. (Grant support: NIH 1R01CA228465-01 to Zeng).