T cell populations in the pancreatic lymph node naturally and consistently expand and contract in NOD mice as disease progresses

Nonobese diabetic (NOD) mice develop spontaneous autoimmune Type 1 diabetes (T1D) that results from the destruction of insulin secreting β cells by diabetogenic T cells. The activation of autoreactive T cells occurs in the pancreatic lymph nodes (PLN) from where effector T cells migrate to the pancreas. This study was designed to explore whether T cell populations in the NOD PLN expand in a predictable and reproducible way during disease progression. Complementary determining region (CDR) 3 length spectratype analysis of 19 TCR Vβ families was used to identify the relative frequency of T populations in PLN of 4 and 10 week old NOD mice and mice at T1D onset. Significant and highly reproducible changes in specific T cell populations were detected in 14 of Vβ families tested at all stages of disease. However, of these, the CDR3 spectratype of only four Vβ families was significantly more perturbed at T1D onset than in 10 week old mice. Intriguingly, when diabetes was induced in 10 week old mice with cyclophosphamide (CYP) the same four Vβ families, Vβ5.1, Vβ9, Vβ10, and Vβ15, were again significantly more perturbed than in the untreated non-diabetic age matched mice. Taken together the data show that while T cell responses in PLN of NOD mice are heterogeneous, they are ordered and consistent throughout disease development. The finding that within this heterogeneous response four Vβ families are significantly more perturbed in diabetic mice, whether spontaneous or induced, strongly suggests their selection as part of the disease process.

► 80% of 4 week old NOD mice share the altered TCR Vβ repertoire in PLN.
► Few T cell populations in NOD mice contract and expand as disease progresses.
► The TCR repertoire is more diverse at 10 weeks of age than at 4 weeks of age.
► Increased global repertoire diversity is not due to a decrease in total perturbation.
► CYP accelerated changes that occur naturally in the PLN TCR repertoire of NOD mice.