Clonal deviation is a mechanism by which immature thymocytes expressing a self-reactive T cell antigen receptor (TCR) are rescued from clonal deletion by adopting an alternative differentiation pathway resistant to apoptosis. Here, we confirm and generalize previous indications that genetic alleles in NOD mice condition ineffective clonal deviation toward the CD8alphaalpha lineage, a peculiar population of TCRalphabeta lymphocytes that electively colonizes the intraepithelial lymphocyte pool in the gut. Thymic selection of CD8alphaalpha cells was very age-dependent, occurring almost exclusively in the postnatal period. Fewer CD8alphaalpha cells were found in the thymus and intraepithelial lymphocytes of BDC2.5 TCR transgenic mice on the NOD than on the C57BL/6 (B6) background; this paucity extended to standard NOD mice, albeit to a lesser extent. CD8alphaalpha cells resided in the BDC2.5 pancreatic infiltrate, and they were more abundant on the B6 than the NOD background, correlating with aggressivity of the lesion. A (B6(g7) x NOD)F(2) intercross in agonist-challenged BDC2.5 fetal thymic organ cultures demonstrated the existence of a major quantitative trait locus on chromosome 3, coincident with an interval associated with resistance to clonal deletion. A replicate linkage confirmed these positions and showed that the same region also controls clonal deviation toward the CD4(+)FoxP3(+) regulatory T cell lineage. That clonal deviation toward the CD8alphaalpha and regulatory T cell pathways share genetic control further highlights the similarities between these two "rescue lineages," consistent with an immunoregulatory role for CD8alphaalpha cells.