IFN‐γ production in human NK cells through the engagement of CD8 by soluble or surface HLA class I molecules

Abstract

The engagement of CD8 on NK cell surface by either surface or soluble HLA class I (sHLA-I) molecules induces synthesis and secretion of IFN-+ . HLA-I-mediated effects were inhibited by the covering of CD8 with specific anti-CD8 monoclonal antibodies, indicating a direct interaction of HLA-I and CD8. That CD8 ligation induces IFN-+ production was further supported by the finding that cross-linking of CD8 led to release of IFN-+ at similar levels to those obtained with HLA-I. The sHLA-I-induced IFN-+ production via CD8 was strongly down-regulated by the engagement of the inhibitory isoforms of either CD94/NKG2 complex by sHLA-I-non-(A,B,C,G) (putative sHLA-E) or CD158b by sHLA-I-Cw3 allele. Ligation of CD8 did not elicit, different from other activating NK cell surface molecules such as CD16 or CD69, triggering of NK cell-mediated cytolysis. Cyclosporin A, but not concanamycin A, an H + -ATPase vacuolar inhibitor which affects perforin and granzyme release, strongly reduced the sHLA-I-mediated CD8-dependent IFN-+ production but did not affect cytolytic activity of NK cells, suggesting that different biochemical pathways are involved. Altogether, these findings indicate that CD8 engagement by sHLA-I activates a cyclosporin A-dependent pathway leading to production and secretion of IFN-+ which may play a role in the regulation of innate immune responses in humans.

Stabilization of IFN-γ mRNA by MAPK p38 in IL-12– and IL-18–stimulated human NK cells

“…Six percent to 22% of PBLs were CD56 ϩ CD3 Ϫ (NK cells), whereas 2.5% to 10% were CD56 ϩ CD3 ϩ (NKT cells). As expected, CD56 ϩ cells did not express CD4, however, 30% to 50% expressed the CD8 marker as previously reported 37 (data not shown). After treatment with IL-12 and IL-18 for 4 hours, 45% of CD56 ϩ cells expressed IFN-␥, whereas a similar proportion (40%) showed up-regulation of CD69, a cell surface marker of activated lymphocytes.…”

CD4 Expression on Activated NK Cells: Ligation of CD4 Induces Cytokine Expression and Cell Migration

“…The CD8 molecule is expressed on the surface of many NK cells and on all CTL. The CD8 molecule forms a complex with CD3 and the TCR on T cells and is involved in MHC I binding; however, the function of this molecule on NK cells is not well characterized (30,31). The other major type of T lymphocyte, the helper T cell, expresses CD4 on the surface that interacts with CD3 and the TCR.…”

HLA Class I Molecules Regulate IFN-γ Production Induced in NK Cells by Target Cells, Viral Products, or Immature Dendritic Cells through the Inhibitory Receptor ILT2/CD85j

“…Although it is generally assumed that SHP-1-coupled iNKRs can regulate or even prevent effector functions in NK cells comprising cytotoxicity and cytokine secretion, this last issue has not been formally addressed. Moreover, accumulating evidence supports a differential regulation of cytotoxicity and cytokine production in human and mice NK cells (27)(28)(29)(30)(31)(32)(33)(34). Some published data involve several KIRs as modulators of IFN-␥ production in NK and T cells (27,35,36), and a few publications suggest that CD94/NKG2A might also modulate the production of this cytokine in NK cells (24,(37)(38)(39).…”