A new neural network architecture is introduced for incremental supervised learning of recognition categories and multidimensional maps in response to arbitrary sequences of analog or binary input vectors. The architecture, called Fuzzy ARTMAP, achieves a synthesis of fuzzy logic and Adaptive Resonance Theory (ART) neural networks by exploiting a close formal similarity between the computations of fuzzy subsethood and ART category choice, resonance, and learning. Fuzzy ARTMAP also realizes a new Minimax Learning Rule that conjointly minimizes predictive error and maximizes code compression, or generalization. This is achieved by a match tracking process that increases the ART vigilance parameter by the minimum amount needed to correct a predictive error. As a result, the system automatically learns a minimal number of recognition categories, or "hidden units", to met accuracy criteria. Category proliferation is prevented by normalizing input vectors at a preprocessing stage. A normalization procedure called complement coding leads to a symmetric theory in which the MIN operator (A) and the MAX operator (v) of fuzzy logic play complementary roles. Complement coding uses on-cells and off-cells to represent the input pattern, and preserves individual feature amplitudes while normalizing the total on-cell/off-cell vector. Learning is stable because all adaptive weights can only decrease in time. Decreasing weights correspond to increasing sizes of category "boxes". Smaller vigilance values lead to larger category boxes. Improved prediction is achieved by training the system several times using different orderings of the input set. This voting strategy can also be used to assign probability estimates to competing predictions given small, noisy, or incomplete training sets. Four classes of simulations illustrate Fuzzy ARTMAP performance as compared to benchmark back propagation and genetic algorithm systems. These simulations include (i) finding points inside vs. outside a circle; (ii) learning to tell two spirals apart; (iii) incremental approximation of a piecewise continuous function; and (iv) a letter recognition database. The Fuzzy ARTMAP system is also compared to Salzberg's NGE system and to Simpson's FMMC system.

Naive lymphocytes continually enter and exit lymphoid organs in a recirculation process that is essential for immune surveillance. During immune responses, the egress process can be shut down transiently. When this occurs locally it increases lymphocyte numbers in the responding lymphoid organ; when it occurs systemically it can lead to immunosuppression as a result of the depletion of recirculating lymphocytes. Several mediators of the innate immune system are known to cause shutdown, including interferon alpha/beta (IFN-alpha/beta) and tumour necrosis factor, but the mechanism has been unclear. Here we show that treatment with the IFN-alpha/beta inducer polyinosine polycytidylic acid (hereafter 'poly(I:C)') inhibited egress by a mechanism that was partly lymphocyte-intrinsic. The transmembrane C-type lectin CD69 was rapidly induced and CD69-/- cells were poorly retained in lymphoid tissues after treatment with poly(I:C) or infection with lymphocytic choriomeningitis virus. Lymphocyte egress requires sphingosine 1-phosphate receptor-1 (S1P1), and IFN-alpha/beta was found to inhibit lymphocyte responsiveness to S1P. By contrast, CD69-/- cells retained S1P1 function after exposure to IFN-alpha/beta. In coexpression experiments, CD69 inhibited S1P1 chemotactic function and led to downmodulation of S1P1. In a reporter assay, S1P1 crosslinking led to co-crosslinking and activation of a CD69-CD3zeta chimaera. CD69 co-immunoprecipitated with S1P1 but not the related receptor, S1P3. These observations indicate that CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream of IFN-alpha/beta, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs.

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Plasmacytoid dendritic cells (pDCs) produce copious type I interferon (IFN) upon sensing nucleic acids through Toll-like receptor (TLR) 7 and TLR9. Uncontrolled pDC activation and IFN production are implicated in lymphopenia and autoimmune diseases; therefore, a mechanism controlling pDC IFN production is essential. Human pDCs specifically express an orphan receptor, immunoglobulin-like transcript 7 (ILT7). Here, we discovered an ILT7 ligand expressed by human cell lines and identified it as bone marrow stromal cell antigen 2 (BST2; CD317). BST2 directly binds to purified ILT7 protein, initiates signaling via the ILT7–FcεRIγ complex, and strongly inhibits production of IFN and proinflammatory cytokines by pDCs. Readily induced by IFN and other proinflammatory cytokines, BST2 may modulate the human pDC’s IFN responses through ILT7 in a negative feedback fashion.

Increasingly, roles are emerging for C-type lectin receptors in immune regulation. One receptor whose function has remained largely enigmatic is human NKR-P1A (CD161), present on NK cells and subsets of T cells. In this study, we demonstrate that the lectin-like transcript-1 (LLT1) is a physiologic ligand for NKR-P1A. LLT1-containing liposomes bind to NKR-P1A+ cells, and binding is inhibited by anti-NKR-P1A mAb. Additionally, LLT1 activates NFAT-GFP reporter cells expressing a CD3ζ-NKR-P1A chimeric receptor; reciprocally, reporter cells with a CD3ζ-LLT1 chimeric receptor are stimulated by NKR-P1A. Moreover, LLT1 on target cells can inhibit NK cytotoxicity via interactions with NKR-P1A.

Immunoglobulin-like transcripts are a family of inhibitory and stimulatory cell surface immune receptors. Transcripts for one member of this family, ILT7, are selectively expressed in human plasmacytoid dendritic cells (pDCs). We demonstrate here that ILT7 protein associates with the signal adapter protein FcɛRIγ to form a receptor complex. Using an anti-ILT7 monoclonal antibody, we show that ILT7 is expressed specifically on human pDCs, but not on myeloid dendritic cells or other peripheral blood leukocytes. Cross-linking of ILT7 resulted in phosphorylation of Src family kinases and Syk kinase and induced a calcium influx in freshly isolated pDCs, which was blocked by Src family and Syk kinases inhibitors, thus indicating the activation of an immunoreceptor-based tyrosine activation motif–mediated signaling pathway. ILT7 cross-linking on CpG or influenza virus-stimulated primary pDCs inhibited the transcription and secretion of type I interferon and other cytokines. Therefore, the ILT7–FcɛRIγ receptor complex negatively regulates the innate immune functions of human pDCs.

Lectin-like transcript-1 (LLT1) (also named osteoclast inhibitory lectin or CLEC2D) is a ligand for the human NKR-P1A (CD161) receptor, present on NK cells and T cells. To further understand the physiological relevance of this interaction, we developed mAbs against LLT1, characterized the expression pattern of LLT1, and explored the functional consequence of LLT1 engagement of the NKR-P1A receptor on NK cells and T cells. LLT1 is expressed on TLR-activated plasmacytoid dendritic, TLR-activated monocyte-derived dendritic cells, and on B cells stimulated through TLR9, surface Ig, or CD40. Interactions between NKR-P1A on NK cells and LLT1 on target cells inhibit NK cell-mediated cytotoxicity and cytokine production and can inhibit TNF-α production by TCR-activated NKR-P1A+ CD8+ T cells. In contrast, NKR-P1A failed to inhibit or augment the TCR-dependent activation of NKR-P1A-bearing CD4+ T cells. Expression of LLT1 on activated dendritic cells and B cells suggests that it might regulate the cross-talk between NK cells and APCs.

Dendritic cells are equipped with lectin receptors to sense the extracellular environment and modulate cellular responses. Human plasmacytoid dendritic cells (pDCs) uniquely express blood dendritic cell antigen 2 (BDCA2) protein, a C-type lectin lacking an identifiable signaling motif. We demonstrate here that BDCA2 forms a complex with the transmembrane adapter FcɛRIγ. Through pathway analysis, we identified a comprehensive signaling machinery in human pDCs, similar to that which operates downstream of the B cell receptor (BCR), which is distinct from the system involved in T cell receptor (TCR) signaling. BDCA2 crosslinking resulted in the activation of the BCR-like cascade, which potently suppressed the ability of pDCs to produce type I interferon and other cytokines in response to Toll-like receptor ligands. Therefore, by associating with FcɛRIγ, BDCA2 activates a novel BCR-like signaling pathway to regulate the immune functions of pDCs.