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

Bone Marrow Is a Preferential Homing Site for Autoreactive T-Cells in Type 1 Diabetes Ruobing Li , Nicolas Perez , Subha Karumuthil-Melethil and Chenthamarakshan Vasu Department of Surgery, University of Illinois at Chicago, Chicago, Illinois Address correspondence and reprint requests to Chenthamarakshan Vasu, Department of Surgery, University of Illinois at Chicago, 909 S. Wolcott, COMRB 7113, M/C790, Chicago, IL 60612. E-mail: chenta{at}uic.edu 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. APC, antigen-presenting cell CFSE, carboxyfluorescein succinimidyl ester FACS, fluorescence-activated cell sorting IFN-γ, γ interferon IL, interleukin MHC, major histocompatibility complex SLO, secondary lymphoid organ TCR, T-cell receptor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 27 June 2007. DOI: 10.2337/db07-0502. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0