authoritative, comprehensive and systematic

Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells

Phosphatase regulation of immunoreceptor signaling in T cells, B cells and mast cells

Th17 cell based vaccines in mucosal immunity

Human immune responses and potential for vaccine assessment in humanized mice

Controversy and consensus regarding myosin II function at the immunological synapse

Manipulating the PD-1 pathway to improve immunity

Dendritic cell-based nanovaccines for cancer immunotherapy

Leveraging fluorinated glucosamine action to boost antitumor immunity

T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment

The repertoire of human tumor-associated epitopes — identification and selection of antigens and their application in clinical trials

Adoptive cell therapy for the treatment of patients with metastatic melanoma

Adoptive cell therapy (ACT) is the best available treatment for patients with metastatic melanoma. In a recent series of three consecutive clinical trials using increasing lymphodepletion before infusion of autologous tumor infiltrating lymphocytes (TIL), objective response rates between 49% and 72% were seen. Persistence of infused cells in the circulation at one month was highly correlated with anti-tumor response as was the mean telomere length of the cells infused and the number of CD8+…

Volume 21, Issue 2, 01 April 2009, Pp 233-240
Rosenberg, S.A. | Dudley, M.E.

MDA5/RIG-I and virus recognition

The innate immune system initially recognizes RNA virus infection and evokes antiviral responses by producing type I interferons (IFNs). Toll-like receptors (TLRs) and cytoplasmic retinoic acid-inducible gene I (RIG-I)-like helicases (RLHs) are the two major receptor systems for detecting RNA viruses. The RLH signaling pathways play essential roles in the recognition of RNA viruses in various cells, with the exception of plasmacytoid dendritic cells, which utilize TLRs for virus recognition.…

Volume 20, Issue 1, 01 February 2008, Pp 17-22
Takeuchi, O. | Akira, S.

Macrophages, innate immunity and cancer: balance, tolerance, and diversity

Smouldering inflammation is a component of the tumor microenvironment and represents the 7 th hallmark of cancer. Tumor-associated macrophages (TAM) have served as a paradigm for cancer promoting inflammation. Tumor-associated macrophages orchestrate various aspects of cancer, including: diversion and skewing of adaptive responses; cell growth; angiogenesis; matrix deposition and remodelling; the construction of a metastatic niche and actual metastasis; response to hormones and chemotherapeutic…

Volume 22, Issue 2, 01 April 2010, Pp 231-237
Mantovani, A. | Sica, A.

γδ T cells: an important source of IL-17

IL-17 is a cytokine that plays an important role in orchestrating innate immune function. In addition, IL-17 has been shown to exacerbate autoimmune diseases. CD4+ αβ T cells, γδ T cells, and NK cells all produce IL-17. Th17 cells are a newly defined αβ+ T cell lineage characterized by IL-17 production. However, γδ T cells are often the major source of this cytokine. Their response can be very rapid during bacterial infections and has been shown to be protective, but IL-17-producing γδ T cells…

Volume 20, Issue 3, 01 June 2008, Pp 353-357
Roark, C.L. | Simonian, P.L. | Fontenot, A.P. | Born, W.K. | O'Brien, R.L.

Calcium signaling in lymphocytes

In cells of the immune system, calcium signals are essential for diverse cellular functions including differentiation, effector function, and gene transcription. After the engagement of immunoreceptors such as T-cell and B-cell antigen receptors and the Fc receptors on mast cells and NK cells, the intracellular concentration of calcium ions is increased through the sequential operation of two interdependent processes: depletion of endoplasmic reticulum Ca2+ stores as a result of binding of…

Volume 20, Issue 3, 01 June 2008, Pp 250-258
Oh-hora, M. | Rao, A.

Myeloid-derived suppressor cell heterogeneity and subset definition

Myeloid derived suppressor cells (MDSCs) are defined in mice on the basis of CD11b and Gr-1 marker expression and the functional ability to inhibit T lymphocyte activation. Nevertheless the term 'heterogeneous' remains the first, informal feature commonly attributed to this population. It is clear that CD11b+Gr-1+ cells are part of a myeloid macropopulation, which comprises at least two subsets of polymorphonuclear and monocytic cells with different immunosuppressive properties. While recent…

Volume 22, Issue 2, 01 April 2010, Pp 238-244
Peranzoni, E. | Zilio, S. | Marigo, I. | Dolcetti, L. | Zanovello, P. | Mandruzzato, S. | Bronte, V.

Recognition of viruses by cytoplasmic sensors

The immune response to virus infection is initiated when pathogen recognition receptors (PRRs) of the host cell recognize specific nonself-motifs within viral products (known as a pathogen-associated molecular pattern or PAMP) to trigger intracellular signaling events that induce innate immunity, the front line of defense against microbial infection. The replication program of all viruses includes a cytosolic phase of genome amplification and/or mRNA metabolism and viral protein expression.…

Volume 22, Issue 1, 01 February 2010, Pp 41-47
Wilkins, C. | Gale Jr., M.

Pattern-recognition receptors in plant innate immunity

Perception of pathogen-associated molecular patterns (PAMPs) constitutes the first layer of plant innate immunity and is referred to as PAMP-triggered immunity (PTI). For a long time, part of the plant community was sceptical about the importance of PAMP perception in plants. Genetic and biochemical studies have recently identified pattern-recognition receptors (PRRs) involved in the perception of bacteria, fungi and oomycetes. Interestingly, some of the structural domains present in PRRs are…

Volume 20, Issue 1, 01 February 2008, Pp 10-16
Zipfel, C.

The promise and potential pitfalls of chimeric antigen receptors

One important purpose of T cell engineering is to generate tumor-targeted T cells through the genetic transfer of antigen-specific receptors, which consist of either physiological, MHC-restricted T cell receptors (TCRs) or non MHC-restricted chimeric antigen receptors (CARs). CARs combine antigen-specificity and T cell activating properties in a single fusion molecule. First generation CARs, which included as their signaling domain the cytoplasmic region of the CD3ζ or Fc receptor γ chain,…

Volume 21, Issue 2, 01 April 2009, Pp 215-223
Sadelain, M. | Brentjens, R. | Rivière, I.

CD1d-restricted iNKT cells, the 'Swiss-Army knife' of the immune system

Natural Killer T cells are a distinct lymphocyte lineage that regulates a broad range of immune responses. NKT cells recognize glycolipids presented by the non-classical MHC molecule CD1d. Structural insight into the TCR/glycolipid/CD1d tri-complex has revealed an unusual and unexpected mode of recognition. Recent studies have also identified some of the signaling events during NKT cell development that give NKT cells their innate phenotype. Pathogen-derived glycolipid antigens continue to be…

Volume 20, Issue 3, 01 June 2008, Pp 358-368
Matsuda, J.L. | Mallevaey, T. | Scott-Browne, J. | Gapin, L.

Cytokine-producing B lymphocytes - key regulators of immunity

The successful use of B cell depletion therapy for the treatment of autoimmune disease has led to a resurgent appreciation of B cells as powerful regulators of immunity. However, to the surprise of many, B cells appear to regulate autoimmune conditions independently of their ability to produce autoantibodies. Indeed, disturbances in the ability of B cell subsets to present antigen, produce cytokines, and regulate the activities of T cells is emerging as a key feature in many inflammatory…

Volume 20, Issue 3, 01 June 2008, Pp 332-338
Lund, F.E.

Developmental plasticity of Th17 and Treg cells

The emergence of Th17 cells as a distinct subset of effector CD4 T cells has led to a revised model of the adaptive immune system. Whereas the Th1-Th2 paradigm revolutionized our understanding of adaptive immunity by introducing the concept of alternative developmental pathways for naïve CD4 T cells induced by distinct cytokine cues from microbe-activated innate immune cells, delineation of Th17 cell differentiation has extended this concept and has led to a greater appreciation of the…

Volume 21, Issue 3, 01 June 2009, Pp 274-280
Lee, Y.K. | Mukasa, R. | Hatton, R.D. | Weaver, C.T.

Mechanism of action of clinically approved adjuvants

Aluminum-containing adjuvants continue to be the most widely used adjuvants for human use. In the last year a major breakthrough has been the realization that alum adjuvant triggers an ancient pathway of innate recognition of crystals in monocytes and triggers them to become immunogenic dendritic cells, nature's adjuvant. This recognition can occur directly, via the triggering of the NALP3 inflammasome by alum crystals, or indirectly through release of the endogenous danger signal uric acid. It…

Volume 21, Issue 1, 01 February 2009, Pp 23-29
Lambrecht, B.N. | Kool, M. | Willart, M.A. | Hammad, H.

Peripheral B cell subsets

Our understanding of the origins and the biological functions of different peripheral B cell subsets continues to evolve. Some understanding has been obtained regarding the synergy between BCR-derived signals and other receptors and signaling pathways that drive the development of follicular, marginal zone, and B-1 B cells, but this remains a complex and poorly understood issue. More recent information regarding the origins of B-1 and B-2 B cells, the ability of follicular B cells to mature…

Volume 20, Issue 2, 01 April 2008, Pp 149-157
Allman, D. | Pillai, S.

Plasticity of CD4+ FoxP3+ T cells

Regulatory T (Treg) cells play an essential role in maintaining immunological tolerance. The discovery of FoxP3 as a key Treg transcription factor combined with recent advances in the development of functional reporter mice has enabled new insights into Treg biology and revealed unexpected features of this lineage. In this review, we address the stability of this population, focusing on studies that suggest that Tregs can downregulate FoxP3, lose regulatory activity and, under some conditions,…

Volume 21, Issue 3, 01 June 2009, Pp 281-285
Zhou, X. | Bailey-Bucktrout, S. | Jeker, L.T. | Bluestone, J.A.

NOD-like receptors (NLRs): bona fide intracellular microbial sensors

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) (nucleotide-binding domain leucine-rich repeat containing) family of proteins has been demonstrated to function as regulators of innate immune response against microbial pathogens. Stimulation of NOD1 and NOD2, two prototypic NLRs, results in the activation of MAPK and NF-κB. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of an inflammasome. This review discusses recent findings…

Volume 20, Issue 4, 01 August 2008, Pp 377-382
Shaw, M.H. | Reimer, T. | Kim, Y.-G. | Nuñez, G.

The inflammasomes: mechanisms of activation and function

In response to injurious or infectious agents caspase-1 activating multiprotein complexes, termed inflammasomes, assemble in the cytoplasm of cells. Activated caspase-1 cleaves the proforms of the interleukin-1 cytokine family members leading to their activation and secretion. The IL-1 family cytokines have multiple proinflammatory activities implicating them in the pathogenesis of many inflammatory diseases. While defined ligands have been identified for the NLRP1, IPAF, and AIM2…

Volume 22, Issue 1, 01 February 2010, Pp 28-33
Latz, E.

Terminal sugars of Fc glycans influence antibody effector functions of IgGs

IgG molecules contain glycans in the CH2 domain of the Fc fragment (N-glycosylation) which are highly heterogeneous, because of the presence of different terminal sugars. The heterogeneity of Fc glycans varies with species and expression system. Fc glycans influence the binding of IgG to Fc receptors and C1q, and are therefore important for IgG effector functions. Specifically, terminal sugars such as sialic acids, core fucose, bisecting N-acetylglucosamine, and mannose residues affect the…

Volume 20, Issue 4, 01 August 2008, Pp 471-478
Raju, T.S.

Regulatory T cells and treatment of cancer

CD4+CD25+FOXP3+ regulatory T cells (Tregs) are elevated in cancers and can thwart protective antitumor immunity. Recent human cancer trials suggest that depleting Tregs can be clinically beneficial. Additional types of deleterious regulatory cells are also increased in cancer. Tregs also play unanticipated roles in cancer therapy in that some drugs unexpectedly increase (e.g. cancer vaccines or IL-2 treatment) or decrease (e.g. antineoangiogenesis agents or receptor tyrosine kinase inhibitors)…

Volume 20, Issue 2, 01 April 2008, Pp 241-246
Curiel, T.J.

Molecular engineering and design of therapeutic antibodies

Since the first murine monoclonal antibody was approved for human therapeutic use over a decade ago, the realization that monoclonal antibody therapeutics could be engineered to improve their efficacy has inspired an astonishing array of novel antibody constructs. Early focus was on reducing the immunogenicity of rodent antibodies via humanization and generation of antibodies in transgenic mice; as those techniques were being established and then provided marketed therapeutic antibodies, the…

Volume 20, Issue 4, 01 August 2008, Pp 460-470
Presta, L.G.

Pattern recognition: recent insights from Dectin-1

The β-glucan receptor Dectin-1 is an archetypical non-toll-like pattern recognition receptor expressed predominantly by myeloid cells, which can induce its own intracellular signalling and can mediate a variety of cellular responses, such as cytokine production. Recent identification of the components of these signalling pathways, such as Syk kinase, CARD9 and Raf-1, has provided novel insights into the molecular mechanisms underlying Dectin-1 function. Furthermore, a broader appreciation of…

Volume 21, Issue 1, 01 February 2009, Pp 30-37
Reid, D.M. | Gow, N.A. | Brown, G.D.

Immunogenic cancer cell death: a key-lock paradigm

Physiological cell death, which occurs as a continuous byproduct of cellular turnover, is non-immunogenic or even tolerogenic, thereby avoiding autoimmunity. By contrast, cancer cell death elicited by radiotherapy and some chemotherapeutic agents such as anthracyclines is immunogenic. Recent data suggest that innate and cognate immune responses elicited by such anti-cancer agents are required for an optimal therapeutic outcome, underscoring the clinical relevance of immunogenic cell death. Here…

Volume 20, Issue 5, 01 October 2008, Pp 504-511
Tesniere, A. | Apetoh, L. | Ghiringhelli, F. | Joza, N. | Panaretakis, T. | Kepp, O. | Schlemmer, F. | Zitvogel, L. | Kroemer, G.

Rational antibody-based HIV-1 vaccine design: Current approaches and future directions

Many antiviral vaccines elicit neutralizing antibodies as a correlate of protection. For HIV, given the huge variability of the virus, it is widely believed that the induction of a broadly neutralizing antibody (bNAb) response will be crucial in a successful vaccine against the virus. Unfortunately, despite many efforts, the development of an immunogen that elicits bNAbs remains elusive. However, recent structural studies of HIV-1 Env proteins, generation of novel bNAbs, maturation of…

Volume 22, Issue 3, 01 June 2010, Pp 358-366
Walker, L.M. | Burton, D.R.

Endocytosis mechanisms and the cell biology of antigen presentation

Recent evidence revealed that presentation of soluble antigens is governed by the endocytosis mechanisms that determine the intracellular routing of the endocytosed antigens. Soluble antigens intended for classical exogenous MHC-II-restricted presentation are internalized into lysosomes. Soluble antigens destined for crosspresentation are taken up by distinct endocytosis mechanisms and are conveyed into stable early endosomes. Particulate antigens enter phagosomes, in which both…

Volume 20, Issue 1, 01 February 2008, Pp 89-95
Burgdorf, S. | Kurts, C.

Intracellular mechanisms of antigen cross presentation in dendritic cells

The induction of most CD8+ T cell responses by dendritic cells (DCs) requires the presentation of peptides from internalized antigen by class I MHC molecules. Increasing number of reports have shown that cross presentation is involved in transplant rejection, in immune responses to viral infections, in certain autoimmune diseases and cancer. The precise role of cross presentation in the initiation of immune responses in vivo, however, remains a matter of debate. This ongoing controversy is, at…

Volume 22, Issue 1, 01 February 2010, Pp 109-117
Amigorena, S. | Savina, A.

Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments

Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity

T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment

DNA recognition in immunity and disease

Regulation of NF-κB by ubiquitination

Macrophages, innate immunity and cancer: balance, tolerance, and diversity

Helper T cell diversity and plasticity

Innate immunity

Susceptibility and immunity to helminth parasites

The CD47–SIRPα pathway in cancer immune evasion and potential therapeutic implications