Anti-CD4/CD8 antibody therapy induces Foxo1 transcriptional activity promoting T cell egress from inflamed tissue during type 1 diabetes

Abstract

Abstract Type 1 diabetes (T1D) is considered to be a T cell driven autoimmune disease, for which clinical treatment of T1D has been unsuccessful creating a need for immunotherapeutics to match world-wide rising incidence of disease. Pancreatic inflammation in non-obese diabetic (NOD) mice is primarily T cell mediated resulting in immune destruction of the insulin producing β cells in the pancreatic islets of Langerhans, which induces a hyperglycemic state that requires daily insulin injections to maintain homeostasis. The use of nondepleting antibodies provides a strategy to modulate the function of T cells while avoiding their systemic depletion. Our lab has previously reported that treatment of recent onset diabetic NOD mice with a short-course of both monoclonal anti-CD4 and anti-CD8 (anti-CD4/CD8) antibodies rapidly and indefinitely reversed established T1D. Remission of T1D by anti-CD4/CD8 treatment is accompanied by the egress of T cells from the pancreatic islets and pancreatic draining lymph node. Microarray analysis of anti-CD4/CD8 treated T cells revealed increased activity of the Forkhead box protein O1 (Foxo1) transcriptional axis that controls expression of the blood homing chemokine receptor sphingosine-1-phosphate receptor 1 (S1Pr1). In contrast, T cell activation related genes that promote tissue residency of T cells were down regulated. T cell receptor (TCR) signaling negatively regulates Foxo1 transcriptional activity by phosphorylation via the AKT signaling pathway. Our studies have revealed that dampened TCR signaling shortly after anti-CD4/CD8 treatment results in enhanced Foxo1 transcriptional activity promoting S1Pr1-mediated T cell egress from inflamed tissues providing long-term protection from T1D.