Natural killer (NK) cells express receptors that are specific for MHC class I molecules. These receptors play a crucial role in regulating the lytic and cytokine expression capabilities of NK cells. In humans, three distinct families of genes have been defined that encode for receptors of HLA class I molecules. The first family identified consists of type I transmembrane molecules belonging to the immunoglobulin (Ig) superfamily and are called killer cell Ig-like receptors (KIR). A second group of receptors belonging to the Ig superfamily, named ILT (for immunoglobulin like transcripts), has more recently been described. ILTs are expressed mainly on B, T and myeloid cells, but some members of this group are also expressed on NK cells. They are also referred to as LIRs (for leukocyte Ig-like receptor) and MIRs (for macrophage Ig-like receptor). The ligands for the KIR and some of the ILT receptors include classical (class Ia) HLA class I molecules, as well as the nonclassical (class Ib) HLA-G molecule. The third family of HLA class I receptors are C-type lectin family members and are composed of heterodimers of CD94 covalently associated with a member of the NKG2 family of molecules. The ligand for most members is the nonclassical class I molecule HLA-E. NKG2D, a member of the NKG2 family, is expressed as a homodimer, along with the adaptor molecule DAP10. The ligands of NKG2D include the human class I like molecules MICA and MICB, and the recently described ULBPs. Each of these three families of receptors has individual members that can recognize identical or similar ligands yet signal for activation or inhibition of cellular functions. This dichotomy correlates with particular structural features present in the transmembrane and intracytoplasmic portions of these molecules. In this review we will discuss the molecular structure, specificity, cellular expression patterns, and function of these HLA class I receptors, as well as the chromosomal location and genetic organization.

No abstract

No abstract

The synthesis of HLA-G is increased in monocytes and certain T lymphocytes from HIV-1-infected individuals.

SUMMARYCD69 is a differentiation antigen expressed shortly after activation on T lymphocytes and other cells of haematopoietic origin, including natural killer (NK ) cells. The function of CD69 on T lymphocytes acting as a costimulatory molecule in proliferation and lymphokine secretion is well established. NK cells express CD69 after activation by different stimuli such as phorbol 12-myristate 13-acetate (PMA), interleukin (IL)-2, IL-12, interferon-a (IFN-a) or anti-CD16 monoclonal antibodies (mAbs). However, although it has been shown that CD69 triggers NK-cell-mediated cytolytic activity, its effect on other NK-cell functions has not been studied. Furthermore, the possible interaction of CD69 triggering with other C-lectin type inhibitory receptors is not known. Thus, the objective of this work is to determine whether CD69-mediated NK cytotoxicity can be regulated by CD94 inhibitory receptor and the role of CD69 on other NK-cell functions different of cytotoxicity. The results show that CD69-mediated NK cytotoxicity can be abrogated by CD94 stimulation in NK cells expressing the CD94 inhibitory form of the receptor, indicating that CD94 regulates the cytotoxic events initiated by a wide variety of NK activatory receptors. We also show that anti-CD69 mAbs, not only triggered NK cytotoxicity, but also induce NK-cell proliferation, CD25 and intracellular adhesion molecule-1 (ICAM-1) expression, TNF-a production and Ca2+ mobilization in preactivated NK cells. These results suggest that CD69 plays a crucial role in NK-cell function contributing to sustain NK-cell activation, as it has been previously demonstrated in T cells.

No abstract

IntroductionAn adequate immune response is the result of a fine balance between a multitude of activating and inhibitory signals, and disruption of this delicate balance can lead to autoimmunity or immunodeficiency. Activation signals can be negatively regulated by cell surface receptors bearing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic tail. 1 Examples of ITIM-containing receptors expressed on B cells include Fc␥RIIB, CD22, CD72, paired Ig-like receptor (PIR)-B, CD85j, Fc receptorlike (FCRL)4, and CD305. [2][3][4][5] The coligation of the B-cell receptor (BCR) and ITIM-containing receptors results in the attenuation of BCR-mediated signals. 3,5,6 Depending on the developmental stage or activation status, B cells express different sets of inhibitory receptors on their cell surface. 5,7,8 For example, CD305 is highly expressed on naive human B cells, and its expression is low in memory B cells, 5 whereas FCRL4 is mostly expressed on a subset of memory cells and is almost absent on naive B cells. 7 The expression of certain ITIM-containing receptors, such as FCRL4 and CD85j, is increased in specific B-cell subsets that are substantially expanded in certain disease settings, such as in HIV-infected viremic patients with high viral loads 9 and in persons exposed to Plasmodium falciparum. 10 It is acknowledged that the deregulation of the expression of these receptors contributes to the B-cell dysfunctions observed in HIV and malarial chronic infections. 11 CD300a belongs to the CD300 family of activating/inhibitory receptors whose genes are clustered in human chromosome 17. 12 CD300a is a type I transmembrane receptor with an IgV-like extracellular domain and a cytoplasmic tail that has 3 classic ITIM motifs 12,13 and is expressed on cells of both lymphoid and myeloid lineages. 12 Its ligation is capable of inhibiting natural killer cell-mediated cytotoxicity, 13,14 Fc␥RIIa-mediated reactive oxygen species production and Ca 2ϩ flux in neutrophils, 15 Fc⑀RI-mediated activation of mast cells, 16 and eosinophil responses to eotaxin, granulocyte-macrophage colony-stimulating factor, and IL-5. 17 In a murine model of asthma, treatment of mice with a bispecific antibody linking CD300a to CCR3 reversed remodeling and airway inflammation. 18 In another in vivo study, a bispecific antibody fragment linking CD300a to IgE was able to abrogate allergic reactions. 19 Finally, a recent study showed that a bispecific antibody that links kit with CD300a abrogates the allergic reaction induced by stem cell factor in a model of anaphylaxis. 20 All these studies highlight the potential of specifically targeting CD300a for therapeutic purposes.In this study, we demonstrate that CD300a is differentially expressed on human B-cell subsets and can function as a negative regulator of BCR-mediated signaling. Furthermore, we show that the expression of this receptor is deregulated in HIV-infected patients, suggesting a potential role for CD300a in HIV-associated disease progression. The online version of thi...

Following the Fifth International Conference on non-classical HLA-G antigens (HLA-G), held in Paris in July 2009, we selected some topics which focus on emerging aspects in the setting of HLA-G functions. In particular, HLA-G molecules could play a role in: (1) various inflammatory disorders, such as multiple sclerosis, intracerebral hemorrhage, gastrointestinal, skin and rheumatic diseases, and asthma, where they may act as immunoregulatory factors; (2) the mechanisms to escape immune surveillance utilized by several viruses, such as human cytomegalovirus, herpes simplex virus type 1, rabies virus, hepatitis C virus, influenza virus type A and human immunodeficiency virus 1 (HIV-1); and (3) cytokine/chemokine network and stem cell transplantation, since they seem to modulate cell migration by the downregulation of chemokine receptor expression and mesenchymal stem cell activity blocking of effector cell functions and the generation of regulatory T cells. However, the immunomodulatory circuits mediated by HLA-G proteins still remain to be clarified.