Pathogen-associated molecular patterns (PAMPs) have the capacity to couple inflammatory gene expression to changes in macrophage metabolism, both of which influence subsequent inflammatory activities. Similar to their microbial counterparts, several self-encoded damage-associated molecular patterns (DAMPs) induce inflammatory gene expression. However, whether this symmetry in host responses between PAMPs and DAMPs extends to metabolic shifts is unclear. Here, we report that the self-encoded oxidized phospholipid oxPAPC alters the metabolism of macrophages exposed to lipopolysaccharide. While cells activated by lipopolysaccharide rely exclusively on glycolysis, macrophages exposed to oxPAPC also use mitochondrial respiration, feed the Krebs cycle with glutamine, and favor the accumulation of oxaloacetate in the cytoplasm. This metabolite potentiates interleukin-1β production, resulting in hyperinflammation. Similar metabolic adaptions occur in vivo in hypercholesterolemic mice and human subjects. Drugs that interfere with oxPAPC-driven metabolic changes reduce atherosclerotic plaque formation in mice, thereby underscoring the importance of DAMP-mediated activities in pathophysiological conditions.

Cytokines have context-dependent roles that dictate their normal physiological function; however, dysregulation or chronic activation of cytokine pathways can alter tissue balance away from a return to homeostatic quiescence toward disease-associated immunopathology.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Vaccines represent one of the greatest triumphs of modern medicine. Despite the common origins of vaccinology and immunology more than 200 years ago, the two disciplines have evolved along such different trajectories that most of the highly successful vaccines have been made empirically, with little or no immunological insight. Recent advances in innate immunity have offered new insights about the mechanisms of vaccine-induced immunity and have facilitated a more rational approach to vaccine design. Here we will discuss these advances and emerging themes on the immunology of vaccination.

Natural killer (NK) cells are bone marrow–derived granular lymphocytes that have a key role in immune defense against viral and bacterial infections and malignancies. NK cells are traditionally defined as cells of the innate immune response because they lack RAG recombinase–dependent clonal antigen receptors. However, evidence suggests that specific subsets of mouse NK cells can nevertheless develop long-lived and highly specific memory to a variety of antigens. Here we review published evidence of NK cell–mediated, RAG-independent adaptive immunity. We also compare and contrast candidate mechanisms for mammalian NK cell memory and antigen recognition with other examples of RAG-independent pathways that generate antigen receptor diversity in non-mammalian species and discuss NK cell memory in the context of lymphocyte evolution.

T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Recently, a clearer picture of the functional and phenotypic profile of exhausted T cells has emerged and T cell exhaustion has been defined in many experimental and clinical settings. Although the pathways involved remain to be fully defined, advances in the molecular delineation of T cell exhaustion are clarifying the underlying causes of this state of differentiation and also suggest promising therapeutic opportunities.

After infection, most antigen-specific memory T cells reside in nonlymphoid tissues. Tissue-specific programming during priming leads to directed migration of T cells to the appropriate tissue, which promotes the development of tissue-resident memory in organs such as intestinal mucosa and skin. Mechanisms that regulate the retention of tissue-resident memory T cells include transforming growth factor-β (TGF-β)-mediated induction of the E-cadherin receptor CD103 and downregulation of the chemokine receptor CCR7. These pathways enhance protection in internal organs, such as the nervous system, and in the barrier tissues--the mucosa and skin. Memory T cells that reside at these surfaces provide a first line of defense against subsequent infection, and defining the factors that regulate their development is critical to understanding organ-based immunity.

Weak T cell antigen receptor (TCR) signals from contact with self ligands act in synergy with antiapoptotic signals induced by interleukin 7 (IL-7) to promote the survival of naive T cells in a resting state. The amount of background TCR signaling in naive T cells is set by post-thymic TCR tuning and operates at an intensity just below that required to induce entry into the cell cycle. Costimulation from higher concentrations of IL-7 and other common γ-chain cytokines can induce T cells to undergo homeostatic proliferation and conversion into cells with a memory phenotype; many of these memory phenotype cells may be the progeny of cells responding to self antigens. The molecular mechanisms that control the conversion of naive resting T cells into memory-phenotype cells TCR-dependent in normal animals are beginning to be understood.

Humoral immunity requires interaction between specialized populations of B cells and CD4(+) T cells, called follicular helper T cells (T(FH) cells), in the germinal center (GC) to produce memory B cells and long-lived plasma cells. Molecular crosstalk between GC B cells and T(FH) cells influences the survival, proliferation and differentiation of each cell type. This pairing of GC B cells and T(FH) cells also occurs at the transcriptional level as the Bcl-6–IRF4–Blimp-1 axis, which is crucial for B cell differentiation, is also essential for the T(FH) cell identity. Less is known about the memory B cells that arise from the GC pool, as they seem to be distinctly 'programmed' on the basis of their antigen receptor affinity to enter the long-lived memory pool.

Lineage-committed effector CD4(+) T cells are generated at the peak of the primary response and are followed by heterogeneous populations of central and effector memory cells. Here we review the evidence that T helper type 1 (T(H)1) effector cells survive the contraction phase of the primary response and become effector memory cells. We discuss the applicability of this idea to the T(H)2 cell, T(H)17 helper T cell, follicular helper T cell (T(FH) cell) and induced regulatory T cell lineages. We also discuss how central memory cells are formed, with an emphasis on the role of B cells in this process.

Cytolytic T lymphocyte-associated antigen 4 (CTLA-4) is a critical down-regulatory molecule in T cells that plays a major role in peripheral tolerance. Although the CD45 protein tyrosine phosphatase is a potent immunomodulatory target, the mechanisms by which antibody against CD45RB isoforms (anti-CD45RB) induces allograft tolerance remain unclear. We show here that anti-CD45RB treatment alters CD45 isoform expression on T cells, which is associated with rapid up-regulation of CTLA-4 expression. These effects appear specific and occur without up-regulation of other activation markers. Administration of a blocking monoclonal antibody to CTLA-4 at the time of transplantation prevents anti-CD45RB therapy from prolonging islet allograft survival. In addition, treatment with cyclosporin A blocks anti-CD45RB-induced CTLA-4 expression and promotes acute rejection. These data suggest that anti-CD45RB acts through mechanisms that include CTLA-4 up-regulation and demonstrate a link between CD45 and CTLA-4 that depends on calcineurin-mediated signaling. They demonstrate also that CTLA-4 expression may be specifically targeted to enhance allograft acceptance.