CDB20:0002681 CLEC2D — KLRB1

ABSTRACT: The NKR-P1 family of C-type lectin-like receptors are expressed on natural killer (NK) cells and NKT cells. We report the cloning and characterization of a cognate ligand for the inhibitory mouse NK receptors (NKR)-P1B and NKR-P1D (CD161b/d). The NKR-P1B/D ligand is osteoclast inhibitory lectin (Ocil), also known as Clr-b, a member of a previously cloned group of C-type lectin-related (Clr) proteins linked to the NKR-P1 receptors in the mouse NK gene complex (NKC). Expression of Ocil/Clr-b on mouse tumor cell lines inhibits NK cell-mediated killing. Inhibition is blocked with a new mAb (4A6) specific for Ocil/Clr-b. By using 4A6 mAb, we demonstrate that Ocil/Clr-b is displayed at high levels on nearly all hematopoietic cells, with the exception of erythrocytes, in a pattern that is similar to that of class I MHC molecules. Remarkably, Ocil/Clr-b is frequently down-regulated on mouse tumor cell lines, indicating a role for this receptor-ligand system in a new form of "missing self-recognition" of tumor cells.

ABSTRACT: Human NK cells and subsets of T cells or NKT cells express the orphan C-type lectin receptor CD161 (NKR-P1A) of unknown function. In contrast to rodents that possess several NKR-P1 genes coding for either activating or inhibitory receptors, the nature of signals delivered by the single human NKR-P1A receptor is still to be clarified. In this article, we show that the lectin-like transcript 1 (LLT1) molecule is a ligand for the CD161 receptor. Engagement of CD161 on NK cells with LLT1 expressed on target cells inhibited NK cell-mediated cytotoxicity and IFN-gamma secretion. Conversely, LLT1/CD161 interaction in the presence of a TCR signal enhanced IFN-gamma production by T cells. These findings identify a novel ligand/receptor pair that differentially regulate NK and T cell functions.

ABSTRACT: NK1.1 alloantigen expression can be used to define NK cells in certain mouse strains, such as B6 (NKR-P1C) and SJL (NKR-P1B). However, BALB/c NK cells do not react with the anti-NK1.1 mAb, PK136. To investigate the NK1.1(-) phenotype of BALB/c NK cells, we have undertaken NK1.1 epitope mapping and genomic analysis of the BALB/c Nkrp1 region. Bacterial artificial chromosome library analysis reveals that, unlike the Ly49 region, the Nkrp1-Ocil/Clr region displays limited genetic divergence between B6 and BALB/c mice. In fact, significant divergence is confined to the Nkrp1b and Nkrp1c genes. Strikingly, the B6 Nkrp1d gene appears to represent a divergent allele of the Nkrp1b gene in BALB/c mice and other strains. Importantly, BALB/c NK cells express abundant and functional Nkrp1 transcripts, and the BALB/c NKR-P1B receptor functionally binds Ocil/Clr-b ligand. However, the BALB/c NKR-P1B/C sequences differ from those of the known NK1.1 alloantigens, and epitope mapping demonstrates that directed mutation of a single amino acid in the NKR-P1B(BALB) protein confers NK1.1 reactivity. Thus, PK136 mAb recognizes, in part, a distal C-terminal epitope present in NKR-P1B(Sw/SJL) and NKR-P1C(B6), but absent in NKR-P1A/D/F(B6) and NKR-P1B/C(BALB). Allelic divergence of the Nkrp1b/c gene products and limited divergence of the BALB/c Nkrp1-Ocil/Clr region explain a longstanding confusion regarding the strain-specific NK1.1 alloantigen reactivity of mouse NK cells.

ABSTRACT: Co-stimulatory and inhibitory receptors expressed by immune cells in the tumor microenvironment modulate the immune response and cancer progression. Their expression and regulation are still not fully characterized and a better understanding of these mechanisms is needed to improve current immunotherapies. Our previous work has identified a novel ligand/receptor pair, LLT1/CD161, that modulates immune responses. Here, we extensively characterize its expression in non-small cell lung cancer (NSCLC). We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment. CD161-expressing immune cells are found at the vicinity of these structures, with a global enrichment of NSCLC tumors in CD161+ CD4+ and CD8+ T cells as compared to normal distant lung and peripheral blood. CD161+ CD4+ T cells are more activated and produce Th1-cytokines at a higher frequency than their matched CD161-negative counterparts. Interestingly, CD161+ CD4+ T cells highly express OX40 co-stimulatory receptor, less frequently 4-1BB, and display an activated but not completely exhausted PD-1-positive Tim-3-negative phenotype. Finally, a meta-analysis revealed a positive association of CLEC2D (coding for LLT1) and KLRB1 (coding for CD161) gene expression with favorable outcome in NSCLC, independently of the size of T and B cell infiltrates. These data are consistent with a positive impact of LLT1/CD161 on NSCLC patient survival, and make CD161-expressing CD4+ T cells ideal candidates for efficient anti-tumor recall responses.