Absence of Coronin 1B in Donor T Cells Diminishes Acute Gvhd By Impairing T Cell Accumulation in Secondary Lymphoid Tissue

Allogeneic stem cell transplant is a standard treatment for patients with high-risk and relapsed myeloid and lymphoid malignancies. However, donor T cells from the stem cell graft mediate graft-versus-host disease (GVHD), which is a common cause of morbidity and mortality for transplant recipients. Our group and others have shown that migration of donor T cells into secondary lymphoid tissue (SLT) and subsequent migration to target organs is critical to the pathogenesis of acute GVHD. The Coronin family of proteins consists of actin-binding proteins, which regulate filament formation by interacting with the Arp2/3 complex. Coronin 1B, a ubiquitously expressed member of the Coronin family, is required for lamellipodial protrusion and effective cell migration. Previous work has not evaluated a role for this protein in the function of T lymphocytes or during acute GVHD. To evaluate the effect of Coronin 1B in acute GVHD pathogenesis, we transplanted B6 T cell depleted bone marrow cells with wild type or Coronin 1B -/- T cells to lethally irradiated B6D2 and BALB/c recipient mice and evaluated clinical score of GVHD and overall survival. B6D2 recipients of Coronin 1B-/- T cells demonstrated 100% survival (Figure 1A. p -/- T cells. Additionally, Coronin 1B -/- T cells were capable of eliminating P815 tumor cells, indicating that loss of Coronin 1B does not inhibit graft-versus-tumor activity. By day 12 post- transplant, all mice receiving bone marrow alone developed tumor compared to none of the mice receiving Coronin 1B -/- T Cells. However, protection was not complete as 40% of Coronin 1B -/- T cell recipients developed tumor by day 23. To determine the effect of Coronin 1B on T cell migration during GVHD, B6D2 recipients were given GFP-expressing wild type or Coronin 1B -/- T cells along with T cell depleted bone marrow. Lymphoid tissue and target organs were harvested and analyzed by flow cytometry or GFP ELISA. We observed decreased accumulation of Coronin 1B -/- CD4 + (Figure 1B. p t -test) and CD8 + T cells in the inguinal lymph node, mesenteric lymph node, and the spleen 4 days after transplant with no difference in accumulation in lymphoid tissue on days 7 and 14 after transplant. Additionally, we found decreased accumulation of Coronin 1B -/- donor T cells in the lung, colon and spleen 14 days after transplant (Figure 1C. p t -test). We also quantified the amount of cytokine in target organs by ELISA, and observed a decrease in IFN-γ and TNF-α in the colon 14 days after transplant. Our data demonstrate that Coronin 1B -/- T cells elicit reduced GVHD compared to wild type T cells. This was correlated with decreased accumulation of Coronin 1B -/- T cells in SLT early after transplant. These data indicate that targeting the migration of T cells to SLT is a viable approach to prevent acute GVHD. Disclosures No relevant conflicts of interest to declare.