Genetic regulation of NKT cells
NKT cells are unusual innate-like ab T cells that recognize glycolipids and glycosphingolipids presented by CD1d. We and others have demonstrated that NKT cell number and function is highly influenced by the host genetic background. We found that a genetic locus on chromosome 1 regulates both the number of NKT cells in the periphery as well as NKT cell cytokine production after stimulation with the agonist, alpha-galactosylceramide. We also found that this locus regulates in vivo macrophage TNF-alpha production in response to lipopolysaccharide. We are currently investigating the implications of this regulation in infectious disease models.
We also made the recent observation that wild-derived inbred strains of mice such as Cast/EiJ, PWD/PhJ, PWK/PhJ and SPRET/EiJ, exhibit a notable deficiency in 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.
These observations, together with the recent demonstration that CAST/EiJ mice possess unusually high numbers of MAIT cells, which comprise another innate-like T cell subset, suggest that there could be a significant amount of flexibility in the evolutionary pathways that determine which innate-like T cell subsets predominate in different species and subspecies.
Benoit, P., Sigounas, Y.Y., Thompson, J.L., van Rooijen, N., Poynter, M.E., Wargo, M.J., and J.E. Boyson. 2015. The role of CD1d-restricted NKT cells in the clearance of Pseudomonas aeruginosa from the lung is dependent on host genetic background. Infect Immun 83(6):2557-25565.
Borg, Z.D., P. Benoit, G.W.J. Lilley, I.A. Aktan, A.Chant, V.L. DeVault, M. Rincon, and J.E. Boyson. 2014. Polymorphisms in the CD1d promoter that regulate CD1d gene expression are associated with impaired NKT cell development.
Journal of Immunology 192(1):189-199.
Aktan, I.A., A. Chant, Z.D. Borg, D.E. Damby, P.C. Leenstra, G.W.J. Lilley, J. Petty, B.T. Suratt, C. Teuscher, E.K. Wakeland, M.E. Poynter, and J.E. Boyson. 2010. Slam haplotypes modulate the response to LPS in vivo through control of NKT cell number and function.
The Journal of Immunology 185:144 -156. PMCID: PMC3055558.
Rymarchyk, S.L., H. Lowenstein, J. Mayette, S.R. Foster, D. Damby, I.W. Howe, I. Aktan, R.E. Meyer, M.E. Poynter, and J.E. Boyson. 2008. Widespread natural variation in NKT cell number and function.
Immunology 125:331-343. PMCID: PMC2669137.