Ceacam1 Regulates Experimental Graft-Versus-Host-Disease

Carcinoembryonic antigen associated cell adhesion molecule 1 (Ceacam1) is a type I transmembrane glycoprotein that regulates numerous processes including bacterial colonization of the gastrointestinal lumen and leukocyte function. Ceacam1 is expressed on gut epithelium and activated T cells, particularly in the intestines. We found that T cells from Ceacam1-/- mice had elevated phosphorylation of STAT3. Upon stimulation with anti-CD3+CD28, IL-2, IL-4, IL-6, or IL-12 in vitro, Ceacam1-/- T cells showed hyperphosphorylation of corresponding canonical STAT proteins, indicating that Ceacam1 can regulate the sensitivity of T cells to cytokines and TCR stimulation. Ceacam1-/- T cells also had defective anergy induction as measured by IL-2 secretion. This was associated with decreased cleaved caspase 3 (but not decreased apoptosis) and hypophosphorylation of STAT1 upon IFNγ treatment. We assessed Ceacam1 regulation of T cells in vivo during GVHD. Ceacam1-/- T cells caused increased mortality and large intestinal GVHD, had more profound activation (CD25, CD62L) and expression of integrin α4β7 and demonstrated selective infiltration of the intestines. By contrast, Ceacam1-overexpressing T cells caused significantly less GVHD mortality and damage to all target organs, which correlated with decreased proliferation and organ infiltration. We also studied Ceacam1 in recipients of allogeneic bone marrow transplantation (allo-BMT), and found that compared to wildtype (WT) recipients, Ceacam1-/- recipients with GVHD showed accelerated mortality and increased damage to the large intestines and thymus. Donor alloactivated CD4 T cells in Ceacam1-/- allo-BMT recipients had increased activation (CD25), and trafficked preferentially to the mesenteric lymph nodes, small and large bowel, but had decreased accumulation in the liver and peripheral lymph nodes (PLN). Finally, Ceacam1-/- mice were more sensitive to radiation injury as demonstrated by accelerated kinetics of mortality and decreased numbers of surviving or regenerating small intestinal crypts. We conclude that Ceacam1 is an important regulator of alloreactivity during GVHD through its effects on T cell (allo)activation, proliferation, trafficking, cytokine sensitivity, and anergy. Moreover, Ceacam1 expression on gut epithelium regulates sensitivity to radiation injury, T cell alloreactivity, and intestinal GVHD.