Interleukin-15 (IL-15) promotes NK cell survival and cytotoxic function and has been tested as a potential cancer therapy, but clinical trials have shown that this cytokine has toxic side-effects that preclude its widespread use. The authors were therefore interested in identifying alternative methods for promoting IL-15-type effector activity in NK cells. They found that mRNAs for Cish and other members of the SOCS family — which are crucial negative regulators of JAK–STAT signalling — were upregulated in IL-15-stimulated NK cells. To explore how CIS regulates IL-15 signalling in NK cells, the authors generated CIS-deficient mice. These animals were healthy and showed normal development and numbers of NK cells and other immune cell populations. However, when co-cultured CIS-deficient and wild-type NK cells were stimulated with IL-15, the CIS-deficient NK cells showed enhanced proliferation, survival and interferon-γ (IFNγ) production. In addition, CIS-deficient NK cells showed greater cytotoxic activity than wild-type NK cells in various in vitro killing assays.
Comparison of gene-expression profiles in wild-type and CIS-deficient NK cells suggested that CIS is not a major regulator of NK cells in the steady state but instead regulates many genes in IL-15-stimulated NK cells that are associated with their effector immune functions. Closer analysis of the mechanisms involved indicated that CIS regulates IL-15 signalling in NK cells by targeting the JAK–STAT pathway. Compared with wild-type NK cells, CIS-deficient NK cells showed increased phosphorylation of JAK1 and STAT5 in response to IL-15 treatment; CIS was found to directly interact with JAK1 via its SH2 domain, inhibiting the kinase activity of JAK1 and targeting it for proteasomal degradation.
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