NKT lymphocyte ontogeny and function are impaired in low antibody-producerBiozzi mice: gene mapping in the interval-specific congenic strains raisedfor immunomodulatory genes

NKT cells are CD4(+) or CD4(-)CD8(-) CD1d-restricted lymphocytes, character ized by the property to rapidly produce IL-4 and IFN-gamma in response to T CR ligation. This IL-4 burst is lacking in autoimmunity-prone SJL and NOD s trains of mice, which suggests an immunoregulatory role for NKT cells. The NKT cell status was thus investigated in the genetically selected high (H) and low (L) antibody-producer mice. The results show that (i) the frequency of cells expressing the NKT cell markers is 3- to 4-fold lower in thymus a nd spleen from L than H mice, (ii) L mice spleen cells did not produce IL-4 following injection of anti-TCR alpha beta antibody, and (iii) L mice thym us and spleen cells failed to produce IL-4 after in vitro stimulation by an ti-TCR alpha beta antibody or alpha -galactosylceramide, a newly described NKT cell ligand. These parameters were investigated in six interval-specifi c congenic strains raised for the quantitative trait loci which contain the immunomodulatory genes responsible for the high/low antibody production ph enotypes. IL-4 production recovery occurred only in the congenic strain in which the H origin chromosome 4 segment was introgressed on the L backgroun d. This finding was not due to increased NKT cell frequency but appeared de pendent of antigen-presenting cells in co-culture experiments. This result strongly suggests the presence of gene(s) modulating NKT function on chromo some 4, close to several genes predisposing to autoimmunity.