Li Ruobing, Perez Nicolas, Karumuthil-Melethil Subha, Vasu Chenthamarakshan
Department of Surgery, University of Illinois at Chicago, Chicago, IL 60612, USA.
Diabetes. 2007 Sep;56(9):2251-9. doi: 10.2337/db07-0502. Epub 2007 Jun 27.
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.
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 beta-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.
The bone marrow T-cells from both hyperglycemic and young euglycemic mice demonstrated profoundly higher proliferation and cytokine production in response to stimulation with beta-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.
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.
胰腺微环境被认为是1型糖尿病中自身反应性T细胞的主要所在部位。在非肥胖糖尿病（NOD）小鼠的脾脏中也检测到了致糖尿病T细胞。然而，尚不清楚在患有自身免疫性疾病的宿主中，骨髓是否也含有针对自身抗原的T细胞。在本研究中，我们调查了NOD小鼠的骨髓中是否存在自身反应性致糖尿病T细胞。
纯化雌性NOD小鼠的骨髓和脾脏T细胞，并检测它们在受到胰腺β细胞免疫显性肽刺激时的细胞因子分泌和增殖情况。将纯化的骨髓T细胞的致糖尿病特性和归巢特性与NOD-Scid和野生型小鼠脾脏T细胞的进行比较。
与脾脏T细胞相比，来自高血糖和年轻血糖正常小鼠的骨髓T细胞在受到β细胞抗原刺激时，表现出显著更高的增殖和细胞因子产生。在NOD-Scid小鼠中，骨髓T细胞显示出快速扩增并大量浸润到胰岛中，且比脾脏T细胞更早诱发高血糖。骨髓T细胞的过继转移导致它们主要迁移到骨髓和胰腺淋巴结。
我们的研究表明，雌性NOD小鼠的骨髓中存在大量致糖尿病T细胞，并且这些自身反应性T细胞在疾病临床发作之前很久就能被检测到。
