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To date, not much has been known regarding the role of CD80 and CD86 molecules in signaling of B cells. The CD28/CTLA4 ligands, CD80 (B7-1) and CD86 (B7-2), are expressed on the surface of freshly isolated splenic B cells, and their expression is up-regulated by lipopolysaccharides. In the present study, we have investigated whether signaling via CD80/CD86 could alter the proliferation and immunoglobulin synthesis of B cells. Splenic B cells were stimulated with lipopolysaccharides in the presence of anti-B7-1 (16-10A1) and anti-B7-2 (GL1) monoclonal antibodies (mAbs). Exciting features observed during the study were that cross-linking of CD86 with GL1 enhanced the proliferation and production of IgG1 and IgG2a isotypes. In contrast, anti-B7-1 (16-10A1) mAb could efficiently block the proliferation and production of IgG1 and IgG2a. Furthermore, GL1 mAb could also induce the secretion of IgG isotypes from B cell lymphomas. Importantly, 16-10A1 could retard the growth of lymphomas and favored the up-regulation of pro-apoptotic molecules caspase-3, caspase-8, Fas, FasL, Bak, and Bax and down-regulation of antiapoptotic molecule Bcl-x(L). In contrast, GL1 augmented the level of anti-apoptotic molecules Bcl-w and Bcl-x(L) and decreased the levels of pro-apoptotic molecule caspase-8, thereby providing a novel insight into the mechanism whereby triggering through CD80 and CD86 could deliver regulatory signals. Thus, this study is the first demonstration of a distinct signaling event induced by CD80 and CD86 molecules in B cell lymphoma. Finally, the significance of the finding is that CD80 provided negative signal for the proliferation and IgG secretion of normal B cells and B cell lymphomas. In contrast, CD86 encouraged the activity of B cells.Evidence from a variety of studies has suggested that the B cell contact with T helper cells is important for its optimal activation and responsiveness to cytokines during Ig secretion (1-3). Contact between B and T cells can be mediated by antigen presentation, as well as antigen-independent cell interaction by molecules known as adhesion (LFA-1, LFA-3, ICAM-1, etc.) and costimulatory molecules (CD80, CD86, CD40, etc.) (3-7). Signals from T cells induce two opposite fates in B cells: clonal expansion of B cells that bind specifically to foreign antigens and clonal deletion of equivalent B cells that bind self-antigen. The role of costimulatory molecules is very well established in the activation of T cells (3), but nothing has been determined definitively about how these molecules operate in the activation and differentiation of B cells (8 -10).The best defined co-stimulators to date are two structurally related proteins, . Both of these play a major role in providing costimulation to T cells, leading to their proliferation, cytokine production, and development of effector functions. CD80 and CD86 could also serve as counter-receptors that transduce distinct signal to the antigen-presenting cells upon engagement by CD28 or CTLA-4. The intracellular domains of CD80 and CD86 are ...

Mycobacterium tuberculosis–macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis–macrophage lipids can interact with host peroxisome proliferator-activated receptor γ and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor γ and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation.

SummaryWe have outlined the carefully orchestrated process of CD4 + T-cell differentiation from naïve to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T-cell interaction with antigen-presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4 + T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multi-faceted roles of CD4 + effector and memory T cells in protective responses to influenza infection and support the concept that efficient priming of CD4 + T cells that react to shared influenza proteins could contribute greatly to vaccine strategies for influenza. Overview and historyOver the past decade, others and we have concluded that naïve precursor T cells must undergo many steps of division and differentiation before they acquire the effector functions necessary for their many regulatory activities (1). One of these activities is 'help' for B cells, which promotes B-cell isotype switching, somatic mutation, and differentiation in germinal centers to plasma cells and memory cells (2-4). Another key regulatory activity carried out by CD4 + T cells involves help for naïve CD8 + T cells to promote their optimum differentiation into cytotoxic effectors and memory cells and to support their maintenance (5-7). In addition, there are a host of other regulatory effects of CD4 + effectors on macrophages as well as other antigenpresenting cells (APCs). These CD4 + T-cell functions are mediated by surface coreceptors on the effector cells, including CD40L, CD28, cytotoxic T-lymphocyte antigen-4, etc., that interact with receptors on B cells, dendritic cells, macrophages, or other APCs, and by potent cytokines secreted by the CD4 + effectors upon recognition of antigen on APCs.CD4 + T-cell effectors represent a collection of distinct subsets characterized in part by their abilities to produce different patterns of cytokines. The two best characterized subsets are designated T-helper 1 (Th1), producing interferon-γ (IFN-γ), and Th2, producing interleukin-4 (IL-4), IL-5, and IL-13 as 'signature' cytokines. Recently, evidence has accumulated for a third . Most probably the APCs that stimulate the naïve CD4 + T cells are also the initial source of cytokines that imprint these subsets in situ (11). It is also increasingly accepted that the polarizing cytokines secreted by the APCs are dictated by the context of the antigen, be it from a pathogen or...

The gut microbiota significantly regulates the development and function of the innate and adaptive immune system. The attribute of immunological memory has long been linked only with adaptive immunity. Recent evidence indicates that memory is also present in the innate immune cells such as monocytes/macrophages and natural killer cells. These cells exhibit pattern recognition receptors (PRRs) that recognize microbe- or pathogen-associated molecular patterns (MAMPs or PAMPs) expressed by the microbes. Interaction between PRRs and MAMPs is quite crucial since it triggers the sequence of signaling events and epigenetic rewiring that not only play a cardinal role in modulating the activation and function of the innate cells but also impart a sense of memory response. We discuss here how gut microbiota can influence the generation of innate memory and functional reprogramming of bone marrow progenitors that helps in protection against infections. This article will broaden our current perspective of association between the gut microbiome and innate memory. In the future, this knowledge may pave avenues for development and designing of novel immunotherapies and vaccination strategies.