Bone Marrow Is a Preferential Homing Site for Autoreactive T-Cells in Type 1 Diabetes

Abstract

OBJECTIVE—The pancreatic microenvironment is considered to be the primary location of autoreactive T-cells in type 1 diabetes. Diabetogenic T-cells have also been detected in the spleens of NOD mice. However, it is not known whether bone marrow also contains T-cells specific for self-antigens in hosts with autoimmunity. In this study, we investigated whether autoreactive diabetogenic T-cells are present in the bone marrow of NOD mice. RESEARCH DESIGN AND METHODS—Bone marrow and splenic T-cells of female NOD mice were purified and tested for their cytokine secretion and proliferation in response to stimulation with immunodominant peptides of pancreatic β-cells. The diabetogenic nature and homing properties of purified bone marrow T-cells were compared with those of splenic T-cells in NOD-Scid and wild-type mice. RESULTS—The bone marrow T-cells from both hyperglycemic and young euglycemic mice demonstrated profoundly higher proliferation and cytokine production in response to stimulation with β-cell antigens than T-cells from spleen. Bone marrow T-cells showed rapid expansion and aggressive infiltration into pancreatic islets in NOD-Scid mice and induced hyperglycemia earlier than splenic T-cells. Adoptive transfer of bone marrow T-cells resulted in their trafficking predominantly to bone marrow and pancreatic lymph nodes. CONCLUSIONS—Our study demonstrates that a large number of diabetogenic T-cells are present in the bone marrow of female NOD mice and that these autoreactive T-cells can be detected long before clinical onset of the disease.