Thus, in downregulating HLA-B expression to avoid T cell recognition, the HIV virus makes itself vulnerable to NK recognition and clearance in a manner commensurate with hierarchies of KIR3DL1-dictated NK education. maintaining tolerance to self. Regulating these functions is a diverse spectrum of NK cells, endowed with varied capacities for effector response through a process termed education, governed by receptor interactions with major histocompatibility complex (MHC) proteins (see glossary). Broadly, the education of an NK cell by a particular MHC molecule is defined by its capacity to sense downregulation of that same HLA molecule on an adjacent putative target cell to mount an effector response. As a result, Amodiaquine dihydrochloride dihydrate the NK response to damaged or infected cells, whose appearance to the NK cell is termed as altered self, can vary based on each specific disease and patient. The functional diversity of NK cells found within and between individuals is driven by germline-encoded ligands and their receptors Rabbit polyclonal to ATF6A (Tables 1 and ?and2).2). Notably, a large number of NK inhibitory receptors, Ly49 in mice and KIR in humans, recognize MHC proteins, and together play a major role in governing NK cell education. Interestingly, the Ly49 and KIR receptor families are independently evolved but functionally orthologous. Despite marked genetic and structural differences, inhibitory members of the Ly49 and KIR families perform a remarkably similar immunologic role: programming NK responsiveness via interaction with self-MHC[1,2]. Table 1 The major NK receptor-ligand pairs in humans. or molecules for self MHC class I molecules are educated and exhibit the lowest threshold for activation. NK cells that do not express inhibitory receptors for self-MHC class I molecules are uneducated and require higher activation signals (+) to become reactive, but are insensitive to inhibition (?) by self-MHC class I. Hence, education programs a different reactive threshold to each NK cell; shown are relative requirements for activating signals in representative educated and uneducated NK cells. (B) against an HLA-negative target cell expressing an activating ligand, educated NK cells are activated but as uneducated NK cells exhibit a higher threshold for reactivity, they are hyporesponsive against the same target. (C) Against an HLA-positive target cell, activation is nullified by inhibitory signaling through KIR and the educated NK cell is hyporesponsive. Uneducated NK cells are refractory to inhibition because they lack cognate inhibitory receptors for self class I molecules, but also require a high signal for activation. Without strong stimulation, uneducated NK cells are hyporesponsive to target cells. (D) Accessory activating factors, including pro-inflammatory cytokines (not shown) Amodiaquine dihydrochloride dihydrate or antibodies, which trigger NK cells for ADCC, Amodiaquine dihydrochloride dihydrate support activation of both educated and uneducated Amodiaquine dihydrochloride dihydrate NK cells. Open in a separate window Figure 2 Molecular features of NK cell educationNK cell education increases with a cells sensitivity to inhibition by self class I molecules and can be additive based on the co-expression of multiple receptor types. Shown is a schematic heatmap describing the relative expression and function of NK cells with increasing education from left to right. Potential receptor expression profiles associated with increasing education are presented at the top of the table (black boxes indicates expression). Factors are shown on a yellow (low) to red (high) heatmap and striped cells indicate factors that are not uniformly expressed on a population of cells or consistently changed with increasing activation. Where cells are white, data are not available. *DNAM-1 is required for the expansion of adaptive NK cells, but downregulated after their differentiation. **CD57 is expressed on a fraction of cells; this proportion increases with education. Separate from the and genes, other conserved MHC-binding receptors confer additional diversity in NK education and protection from autoreactivity. These include the C-type lectin inhibitory CD94/NKG2A heterodimer which binds to MHC class I sequences presented by the universally expressed Qa1 and HLA-E in mice and humans respectively; the paired immunoglobulin-like receptors (PIR), the leukocyte immunoglobulin-like receptors (LIR) and the signaling leukocyte activating molecule (SLAM) family receptors, which enable both activating and inhibitory reactivity of NK cells[13C16]. Variably expressed on the surface of individual NK cells, these additional receptors and their interaction.