We would like to thank Drs. Syn and Oo for their interest in our recently published article in HEPATOLOGY.1 Our data show an inverse correlation with the accumulation of lipid and the relative proportions and function of hepatic natural killer T (NKT) cells.1 The model used for our studies was intentionally simple, absent of significant inflammation or tissue injury, and human samples were selected to mimic this pathology. Together, it was clear that hepatosteatosis could promote interleukin 12 (IL12) production and the subsequent loss of NKT cells, a process which could be related to T helper 1 (Th1) cytokine production but not lipid accumulation.
NKT cell recruitment and survival within the liver has been described and likely involves a number of factors, including IL15 and chemokines.2 Our studies stopped short of examining chemokine production, although IL15 expression was not significantly altered by lipid accumulation or by the absence of IL12, suggesting that it was not an important factor for NKT cell function in this model (data not shown). It may be that IL12 production disrupts IL15 receptor expression or signaling or it may influence the production of key chemokines responsible for NKT cell recruitment. Studies are underway to better understand this relationship.
The association between NKT cells and hepatic fibrogenesis has only recently been appreciated.3 Following 20 weeks of choline-deficient diet (CDD) feeding, limited fibrosis as evidenced by Sirius red staining and collagen gene expression is observed. However, very recent studies in our laboratory have shown the development of significant fibrosis following 40-60 weeks of feeding (unpublished data). Interestingly, as fibrosis appears, there is a loss of IL12 expression and a shift in the Th cytokine profile toward a predominantly Th2 type cytokine response (i.e., IL4 and IL13). In the absence of IL12, fibrogenesis is enhanced, implicating IL12 in the suppression of fibrosis possibly through the depletion of hepatic NKT cells and inhibition of their production of key profibrogenic Th2-type cytokines. Studies are underway to better understand this potentially important relationship.
Inasmuch as hepatosteatosis affects NKT cells, it may also modulate natural killer (NK) cell numbers and/or function. As is pointed out, NK cell numbers are differentially influenced by loss of Kupffer cells in our studies and has been previously described.4 The relationship between NK cells, Kupffer cells, and hepatosteatosis is not well understood although it is possible that NK cells may contribute to the elevated interferon gamma production in our model. Preliminary studies in beige mice which lack NK cells show little, if any, modulation of fibrogenesis following 40 weeks of CDD feeding. Future studies will be necessary to better understand the connection between NK cells, Th1 cytokine production, and NKT cell responses within the steatotic liver.
From our data, it is clear that NKT cells are lost early during hepatosteatosis in an IL12-dependent and Kupffer cell–dependent manner. After more extended periods of hepatosteatosis, a shift in cytokine profile within the liver may support the recruitment or reconstitution of NKT cells in an environment where they may serve to promote fibrosis development. Future studies will be required to better establish this relationship and to better understand the regulation of key NKT cell regulating cytokine production, specifically IL12 and IL15.