Genetic regulation of NKT cells and its effect on the host immune response
We and others have demonstrated that NKT cell number and function is highly variable among different host genetic backgrounds. One consequence of this variability in number and function is that the role of NKT cells in promoting an effective host immune response to pathogens may be highly dependent on the host genetic background. Indeed, we found that while CD1d and NKT cells play a critical role in the host immune response to the opportunistic lung pathogen Pseudomonas aeruginosa in BALB/c mice, CD1d and NKT cells were quite dispensable in C57BL/6 mice. This suggests the possibility that genetic determinants of NKT cell development/function may be important regulators of the host immune response to this lung pathogen.
As part of an effort to define genetic determinants of NKT cell development/function, we made the observation that certain strains of mice such as CAST/EiJ, PWD/PhJ, and SPRET/EiJ possess few detectable NKT cells. Using B6.PWD consomic strains, we mapped one locus responsible for the low NKT cell numbers to chromosome 3 which contains the CD1d genes. We found that the low numbers of NKT cells in two of these strains (PWD and PWK) was associated with decreased CD1d expression on thymocytes, suggesting that impaired CD1d expression in the thymus led to impaired NKT cell development in these strains.
Finally, using a series of overlapping B6.129 subcongenic lines, we recently identified a previously unknown regulator of NKT cell development/function that maps centromeric to the Slam family of genes. Fine-mapping of this region suggested Fcgr3 as a possible candidate gene.