Cytometric and functional analyses of NK and NKT cell deficiencies in NOD mice

Defects in NK and NKT cell activities have been implicated in the etiology of type 1 (autoimmune) diabetes in NOD mice on the basis of experiments per formed using surrogate phenotypes for the identification of these lymphocyt e subsets. Here, we have generated a congenic line of NOD mice (NOD.b-Nkrp1 (b)) which express the allelic NK1.1 marker, enabling the direct study of N K and NKT cells in NOD mice. Major deficiencies in both populations were id entified when NOD.b-Nkrp1(b) mice were compared with C57BL/6 and BALB.B6-Cm v1(r) mice by flow cytometry. The decrease in numbers of peripheral NK cell s was associated with an increase in their numbers in the bone marrow, sugg esting that a defect in NK cell export may be involved. In contrast, the mo st severe deficiency of NKT cells found was in the thymus, indicating that defects in thymic production were probably responsible. The deficiencies in NK cell activity in NOD mice could only partly be accounted for by the red uced numbers of NK cells, and fewer NKT cells from NOD mice produced IL-4 f ollowing stimulation, suggesting that NK and NKT cells from NOD mice shared functional deficiencies in addition to their numerical deficiencies. Despi te the relative lack of IL-4 production by NOD NKT cells, adoptive transfer of alpha beta TCR(+)NK1.1(+) syngeneic NKT cells into 3-week-old NOD recip ients successfully prevented the onset of spontaneous diabetes. As both NK and NKT cells play roles in regulating immune responses, we postulate that the synergistic defects reported here contribute to the susceptibility of N OD mice to autoimmune disease.