Haggag Zein

The immune response to influenza virus infection comprises both innate and adaptive defenses. NK cells play an early role in the destruction of tumors and virally-infected cells. NK cells express a variety of inhibitory receptors, including those of the Ly49 family, which are functional homologs of human killer-cell immunoglobulin-like receptors (KIR). Like human KIR, Ly49 receptors inhibit NK cell-mediated lysis by binding to major histocompatibility complex class I (MHC-I) molecules that are expressed on normal cells. During NK cell maturation, the interaction of NK cell inhibitory Ly49 receptors with their MHC-I ligands results in two types of NK cells: licensed ("functional"), or unlicensed ("hypofunctional"). Despite being completely dysfunctional with regard to rejecting MHC-I-deficient cells, unlicensed NK cells represent up to half of the mature NK cell pool in rodents and humans, suggesting an alternative role for these cells in host defense. Here, we demonstrate that after influenza infection, MHC-I expression on lung epithelial cells is upregulated, and mice bearing unlicensed NK cells (Ly49-deficient NKCKD and MHC-I-deficient B2m-/- mice) survive the infection better than WT mice. Importantly, transgenic expression of an inhibitory self-MHC-I-specific Ly49 receptor in NKCKD mice restores WT influenza susceptibility, confirming a direct role for Ly49. Conversely, F(ab')2-mediated blockade of self-MHC-I-specific Ly49 inhibitory receptors protects WT mice from influenza virus infection. Mechanistically, perforin-deficient NKCKD mice succumb to influenza infection rapidly, indicating that direct cytotoxicity is necessary for unlicensed NK cell-mediated protection. Our findings demonstrate that Ly49:MHC-I interactions play a critical role in influenza virus pathogenesis. We suggest a similar role may be conserved in human KIR, and their blockade may be protective in humans.

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Plasmacytoid dendritic cells (pDC) are the major producers of type I IFN during
the initial immune response to viral infection. Ly49Q, a C-type lectin-like
receptor specific for MHC-I, possesses a cytoplasmic ITIM and is highly expressed
on murine pDC. Using Ly49Q-deficient mice, we show that, regardless of strain
background, this receptor is required for maximum IFN-α production by pDC.
Furthermore, Ly49Q expression on pDC, but not myeloid dendritic cells, is
necessary for optimal IL-12 secretion, MHC-II expression, activation of CD4(+) T
cell proliferation, and nuclear translocation of the master IFN-α regulator IFN
regulatory factor 7 in response to TLR9 agonists. In contrast, the absence of
Ly49Q did not affect plasmacytoid dendritic cell-triggering receptor expressed on
myeloid cells expression or pDC viability. Genetic complementation revealed that
IFN-α production by pDC is dependent on an intact tyrosine residue in the Ly49Q
cytoplasmic ITIM. However, pharmacological inhibitors and phosphatase-deficient
mice indicate that Src homology 2 domain-containing phosphatase 1 (SHP)-1, SHP-2,
and SHIP phosphatase activity is dispensable for this function. Finally, we
observed that Ly49Q itself is downregulated on pDC in response to CpG exposure in
an ITIM-independent manner. In conclusion, Ly49Q enhances TLR9-mediated signaling
events, leading to IFN regulatory factor 7 nuclear translocation and expression
of IFN-I genes in an ITIM-dependent manner that can proceed without the
involvement of SHP-1, SHP-2, and SHIP.

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