DNAM-1 Expression Marks an Alternative Program of NK Cell Maturation

Although the mechanisms governing the innate recognition of pathogen-associated molecular patterns have been well defined, how allogeneic cellular stimuli evoke innate responses remains less so. In this article, we report that upon i.v. transfer (to avoid major iatrogenic interference), allogeneic but not syngeneic leukocytes could induce a rapid (after 1 d) accumulation of host monocyte–derived dendritic cells (moDCs) without any increase in conventional DCs. This occurred in various donor–host strain combinations, did not require MHC mismatch, and could be induced by various donor cell types including B cells, T cells, or NK cells. Using RAG−/−γc−/− and scid γc−/−mice with different MHC, we found that the presence of either donor or host lymphoid cells was required. Alloinduced moDC accumulation was significantly reduced when splenocytes from mice deficient in NK cells by genetic ablation were used as donors. A major component of this moDC accumulation appears to be recruitment. Our findings provide new insights into how the innate and adaptive immune system may interact during allogeneic encounters and thus transplant rejection.

Section: Discussionmentioning

confidence: 99%

Innate Allorecognition Results in Rapid Accumulation of Monocyte-Derived Dendritic Cells

Chow

Delconte

Huntington

et al. 2016

“…Moreover, a recent study demonstrated that DNAM-1Ls are rapidly induced during murine CMV infection in vivo, and the engagement of DNAM-1 is essential for the optimal NK cell-mediated host defense against the virus (11). Of note, because DNAM-1 is also expressed by many other leukocyte subsets and is an important activator of their effector functions, it may affect a wide range of immunological responses (8,12,13,77).…”

Section: Discussionmentioning

confidence: 99%

Distinct Roles for Human Cytomegalovirus Immediate Early Proteins IE1 and IE2 in the Transcriptional Regulation of MICA and PVR/CD155 Expression

Pignoloni

Fionda

Dell’Oste

et al. 2016

Elimination of virus-infected cells by cytotoxic lymphocytes is triggered by activating receptors, among which NKG2D and DNAM-1/CD226 play an important role. Their ligands, that is, MHC class I–related chain (MIC) A/B and UL16-binding proteins (ULBP)1–6 (NKG2D ligand), Nectin-2/CD112, and poliovirus receptor (PVR)/CD155 (DNAM-1 ligand), are often induced on virus-infected cells, although some viruses, including human CMV (HCMV), can block their expression. In this study, we report that infection of different cell types with laboratory or low-passage HCMV strains upregulated MICA, ULBP3, and PVR, with NKG2D and DNAM-1 playing a role in NK cell–mediated lysis of infected cells. Inhibition of viral DNA replication with phosphonoformic acid did not prevent ligand upregulation, thus indicating that early phases of HCMV infection are involved in ligand increase. Indeed, the major immediate early (IE) proteins IE1 and IE2 stimulated the expression of MICA and PVR, but not ULBP3. IE2 directly activated MICA promoter via its binding to an IE2-responsive element that we identified within the promoter and that is conserved among different alleles of MICA. Both IE proteins were instead required for PVR upregulation via a mechanism independent of IE DNA binding activity. Finally, inhibiting IE protein expression during HCMV infection confirmed their involvement in ligand increase. We also investigated the contribution of the DNA damage response, a pathway activated by HCMV and implicated in ligand regulation. However, silencing of ataxia telangiectasia mutated, ataxia telangiectasia and Rad3–related protein, and DNA-dependent protein kinase did not influence ligand expression. Overall, these data reveal that MICA and PVR are directly regulated by HCMV IE proteins, and this may be crucial for the onset of an early host antiviral response.

“…ltNK cells produced relatively low levels of IFN-g, similar to CD56 dim NK cells, and required prior stimulation to exert cytotoxicity. Together with the low expression of DNAM-1 (46,47), this suggests that ltNK cells may be a hypofunctional NK cell population. It is possible that these cells have an immunomodulatory function within the lymphoid tissues to bridge innate and adaptive immunity, rather than exerting one of the classical NK cell functions.…”

Section: Cd49amentioning

confidence: 99%

“…DNAM-1 is involved in adhesion and immune synapse formation and was shown to play an important role in the control of cytotoxicity (44)(45)(46)(47). A bimodal expression pattern for DNAM-1 on human NK cells was only reported in bone marrow of myelodysplastic syndrome patients and in liver (41,48).…”

Section: Cd49amentioning

confidence: 99%

Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population

Lugthart

Melsen

Vervat

et al. 2016

120

Knowledge of human NK cells is based primarily on conventional CD56bright and CD56dim NK cells from blood. However, most cellular immune interactions occur in lymphoid organs. Based on the coexpression of CD69 and CXCR6, we identified a third major NK cell subset in lymphoid tissues. This population represents 30–60% of NK cells in marrow, spleen, and lymph node but is absent from blood. CD69+CXCR6+ lymphoid tissue NK cells have an intermediate expression of CD56 and high expression of NKp46 and ICAM-1. In contrast to circulating NK cells, they have a bimodal expression of the activating receptor DNAX accessory molecule 1. CD69+CXCR6+ NK cells do not express the early markers c-kit and IL-7Rα, nor killer cell Ig-like receptors or other late-differentiation markers. After cytokine stimulation, CD69+CXCR6+ NK cells produce IFN-γ at levels comparable to CD56dim NK cells. They constitutively express perforin but require preactivation to express granzyme B and exert cytotoxicity. After hematopoietic stem cell transplantation, CD69+CXCR6+ lymphoid tissue NK cells do not exhibit the hyperexpansion observed for both conventional NK cell populations. CD69+CXCR6+ NK cells constitute a separate NK cell population with a distinct phenotype and function. The identification of this NK cell population in lymphoid tissues provides tools to further evaluate the cellular interactions and role of NK cells in human immunity.