Inhibition of natural killer (NK) cells is mediated by MHC class I receptors including the killer cell Ig-like receptor (KIR). We demonstrate that HLA-C binding peptides can function as altered peptide ligands for KIR and antagonize the inhibition mediated by KIR2DL2/ KIR2DL3. Antagonistic peptides promote clustering of KIR at the interface of effector and target cells, but do not result in inhibition of NK cells. Our data show that, as for T cells, small changes in the peptide content of MHC class I can regulate NK cell activity.killer cell immunoglobulin-like receptors | MHC class I

IntroductionB cell-activating factor belonging to the TNF family (BAFF) has emerged as an important regulator of B-cell homeostasis and survival: it acts alone or in combination with B-cell receptor (BCR), IL-4, or CD40 ligands. 1-4 BAFF binds 3 different TNF receptors: BCMA (B-cell maturation), 5,6 TACI (transmembrane activator and CAML interactor), 7 and BAFF-R/BR3 (BLys receptor 3). 8 A highly similar homolog (called "a proliferation-inducing ligand" or APRIL) 1 also binds TACI and BCMA but not BAFF-R. 9 BCMA, TACI, and BAFF-R are mostly found on B lymphocytes, [10][11][12] whereas BAFF-R is also present on a subset of T cells. 11,13 Accordingly, BAFF produced by antigen-presenting cells provides T-cell costimulation. 13 The BAFF/BAFF-R pair is essential for survival of immature T2, B2, and marginal zone (MZ) B cells, [14][15][16] but not for that of B1 cells, 17,18 whereas TACI exerts a negative control over 20 BCMA has no obvious effect on mature B-cell survival, but is important for long-term plasma cell biology 10,12 and antigen presentation. 21 BAFF-or BAFF-R-deficient mice form only rudimentary germinal centers (GCs) and produce low levels of IgG in response to T-dependent (TD) antigens. 22,23 In contrast, TACI-deficient mice display an impaired response to type II T cell-independent antigens, suggesting that TACI is required for B1 cell survival. 24 BAFF-R and TACI provide signals for isotype switching toward IgG and IgE, but the switch to IgA is mainly controlled by TACI. 17,25 Many BAFF transgenic mice show signs of autoimmunelike diseases, 2,26 whereas aged APRIL-transgenic mice display a progressive expansion of B1 cells infiltrating the peritoneum and lymphoid organs. 27 These various observations support a major role for the TACI/APRIL and BAFF-R/BAFF pairs in B1 and B2 cell physiology, respectively.Like CD40L, BAFF mainly promotes NF-B and MAPK activation. 28,29 Triggering BAFF-R results in activation of NF-B2 and NF-B1 pathways, whereas triggering BCMA and TACI only activate the NF-B1 pathway. 7,9,28,30,31 Different sets of MAPK and transcription factors are activated downstream from BCMA, TACI, and BAFF-R. 29,32,33 In particular, it has been shown that p38MAPK but not ERK is stimulated early after BAFF-R triggering. 34 Lymphocyte recirculation, which is essential for maintaining an effective immune system, is tightly regulated by the expression of adhesion molecules, chemoattractant receptors, and environmental cytokines. 35,36 Trafficking of human naive and memory B cells is mainly orchestrated by CXCR4/CXCL12, CXCR5/CXCL13, and CCR7/CCL21 (or CCL19) pairs. 37,38 The efficiency of the humoral response depends on the chemotactic response of mature B cells that is modulated by BCR-and IL-4-receptor triggering and CD40/CD40L interactions. 37,[39][40][41][42] In particular, BCR triggering enhances the chemotactic response of naive B cells to CCL21 but decreases that to CXCL13. In contrast, CD40L enhances the migration of memory B cells to CXCL13 without modifying that of CXCL12, CCL21, or CCL19. ...

The immunological roles of B-cells are being revealed as increasingly complex by functions that are largely beyond their commitment to differentiate into plasma cells and produce antibodies, the key molecular protagonists of innate immunity, and also by their compartmentalisation, a more recently acknowledged property of this immune cell category. For decades, B-cells have been recognised by their expression of an immunoglobulin that serves the function of an antigen receptor, which mediates intracellular signalling assisted by companion molecules. As such, B-cells were considered simple in their functioning compared to the other major type of immune cell, the T-lymphocytes, which comprise conventional T-lymphocyte subsets with seminal roles in homeostasis and pathology, and non-conventional T-lymphocyte subsets for which increasing knowledge is accumulating. Since the discovery that the B-cell family included two distinct categories — the non-conventional, or extrafollicular, B1 cells, that have mainly been characterised in the mouse; and the conventional, or lymph node type, B2 cells — plus the detailed description of the main B-cell regulator, FcγRIIb, and the function of CD40+ antigen presenting cells as committed/memory B-cells, progress in B-cell physiology has been slower than in other areas of immunology. Cellular and molecular tools have enabled the revival of innate immunity by allowing almost all aspects of cellular immunology to be re-visited. As such, B-cells were found to express “Pathogen Recognition Receptors” such as TLRs, and use them in concert with B-cell signalling during innate and adaptive immunity. An era of B-cell phenotypic and functional analysis thus began that encompassed the study of B-cell microanatomy principally in the lymph nodes, spleen and mucosae. The novel discovery of the differential localisation of B-cells with distinct phenotypes and functions revealed the compartmentalisation of B-cells. This review thus aims to describe novel findings regarding the B-cell compartments found in the mouse as a model organism, and in human physiology and pathology. It must be emphasised that some differences are noticeable between the mouse and human systems, thus increasing the complexity of B-cell compartmentalisation. Special attention will be given to the (lymph node and spleen) marginal zones, which represent major crossroads for B-cell types and functions and a challenge for understanding better the role of B-cell specificities in innate and adaptive immunology.