The majority of T cell clones derived from islets of NOD mice react with insulin, and 97% of these clones react with an immunodominant peptide termed B2 (amino acids 9 to 23 of the insulin B chain). These clones are CD4 positive and restricted by I-Ag7 and are able to transfer diabetes into young NOD mice and destroy transplanted human islets. Administration of insulin, insulin B chain, insulin B2 peptide, or genetic introduction of insulin into NOD mice all prevent diabetes. With the potential importance of insulin reactivity we have begun the sequencing of the T cell receptors of anti-insulin T cell clones. To date, sequencing is complete on four clones derived from three different mice. Four different Vβ (2,6,12,14) and four Jβ elements with different NDN junctions have been found. Three different Vα chains were utilized (3, 10, and two 13). In contrast to the above heterogeneity, the first two sequenced clones utilized the same Jα (45) with a KLTFGKGT octamer. The next two clones contained Jα 9 and Jα 34, which are the only other two Jαs (out of a reported 49) sharing the KLTFGKGT octamer. As reported in the literature, this Jα octamer was utilized by 0/4 non-insulin reactive diabetogenic CD4 NOD clones and 1/5 islet reactive CD4 clones with unknown specificity. Thus far, we have also sequenced two islet-derived GAD reactive clones and both utilize Jα chains (6, 40) lacking the octamer. This data suggests that the Jα octamer KLTFGKGT may relate to B2 peptide specificity and islet targeting. Both the Jα octamer and the insulin B2 peptide are preserved in the human genome, suggesting that a similar process may occur in type I diabetes.