Can an NKT cell change its spots?

The answer to this question seems to be yes ... if the natural killer gene complex (NKC) is involved. A study published in Immunity by Diana Hansen, Louis Schofield and colleagues indicates that CD1d-restricted natural killer T (NKT) cells can contribute to either protection against or susceptibility to malaria depending on the host genetic background.

Plasmodium berghei ANKA mouse malaria is an accepted model of the cytokine-dependent pro-inflammatory cascade that develops in human malaria. However, whereas C57BL6 mice, which have a genetic bias to T helper 1 (T_H1) responses, are susceptible to disease, BALB/c mice, which have a genetic bias to T_H2 responses, are resistant to disease. As high-level cytokine production occurs early in infection, it has been suggested that progress of the mouse disease involves non-conventional lymphocytes of innate immunity.

To investigate the possible role of CD1d-restricted NKT cells, the authors compared Cd1d^−/− and wild-type mice on both backgrounds in terms of percentage death and histological markers of infection. On the BALB/c background, NKT cells seem to be protective, as Cd1d^−/− BALB/c mice are more susceptible than wild-type BALB/c mice to disease. By contrast, NKT cells are moderately disease promoting on the C57BL6 background as Cd1d^−/− C57BL6 mice are partially protected against disease.

Serum levels of interferon-γ (IFN-γ) were increased in susceptible Cd1d^−/− BALB/c mice compared with resistant wild-type mice, whereas levels of IFN-γ were decreased in partially resistant Cd1d^−/− C57BL6 mice compared with susceptible wild-type mice. By looking at the cytokine production of isolated CD4⁺ T cells from infected wild-type and knockout mice, the authors were able to show that in BALB/c mice, the function of NKT cells promotes a switch from high-level IFN-γ production (T_H1 response) to interleukin-4 production (T_H2 response), which is protective. The opposite is true for C57BL6 mice, in which NKT cells promote sustained IFN-γ production.

What are the host genetic factors responsible for the different roles of NKT cells in the different mouse strains? The authors used congenic mice to investigate the role of differences in expression of NKC loci between BALB/c and C57BL6 mice. For example, BALB.B6-Cmv1^r mice, which contain the NKC from susceptible C57BL6 mice on a resistant BALB/c background, are susceptible to disease compared with non-congenic BALB/c mice. The expression of C57BL6 NKC loci leads to increased levels of IFN-γ production.

So, not only is this one of the first reports of a clear role for NKT cells in infection, but it also shows that the exact role of these cells is more flexible than previously imagined. The response of the same type of cell to the same pathogen can vary as a result of host genetic factors such as NKC polymorphisms.