authoritative, comprehensive and systematic

Vaccines against mucosal infections

Chronic inflammation and aging: DNA damage tips the balance

Homeostasis and function of regulatory T cells in aging

Properties of end-stage human T cells defined by CD45RA re-expression

Recombinant bacterial vaccines

The impact of CMV infection on survival in older humans

Malaria vaccine development: persistent challenges

Innate lymphoid cells: critical regulators of allergic inflammation and tissue repair in the lung

Development and function of intestinal innate lymphoid cells

Adjuvants for human vaccines

Differentiation and function of Th17 T cells

IL-17-producing T cells have recently been classified as a new effector T-cell subset, termed Th17, which is distinct from Th1, Th2 and Treg subsets. There has been much progress in the past year, leading to identification of the molecular mechanisms that drive differentiation of Th17 T cells. This has helped to clarify many aspects of their role in host defense as well as in autoimmunity. Nevertheless, many intriguing questions remain to be answered regarding the regulation of Th17-mediated…

Volume 19, Issue 3, 01 June 2007, Pp 281-286
Stockinger, B. | Veldhoen, M.

The inflammasome: a danger sensing complex triggering innate immunity

The NOD-like receptors (NLR) are a family of intracellular sensors of microbial motifs and 'danger signals' that have emerged as being crucial components of the innate immune responses and inflammation. Several NLRs (NALPs and IPAF) form a caspase-1-activating multiprotein complex, termed inflammasome, that processes proinflammatory cytokines including IL-1β. Amongst the various inflammasomes, the NALP3 inflammasome is particularly qualified to sense a plethora of diverse molecules, ranging…

Volume 19, Issue 6, 01 December 2007, Pp 615-622
Pétrilli, V. | Dostert, C. | Muruve, D.A. | Tschopp, J.

Th17: the third member of the effector T cell trilogy

T helper responses have now grown to include three T cell subsets: Th1, Th2 and Th17. Th17 cells have recently emerged as a third independent T cell subset that may play an essential role in protection against certain extracellular pathogens. However, Th17 cells with specificity for self-antigens are highly pathogenic and lead to the development of inflammation and severe autoimmunity. A combination of TGF-β plus IL-6 and the transcription factors STAT3 and RORγt were recently described to be…

Volume 19, Issue 6, 01 December 2007, Pp 652-657
Bettelli, E. | Korn, T. | Kuchroo, V.K.

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.

Bcl-2-regulated apoptosis: mechanism and therapeutic potential

Apoptosis is essential for tissue homeostasis, particularly in the hematopoietic compartment, where its impairment can elicit neoplastic or autoimmune diseases. Whether stressed cells live or die is largely determined by interplay between opposing members of the Bcl-2 protein family. Bcl-2 and its closest homologs promote cell survival, but two other factions promote apoptosis. The BH3-only proteins sense and relay stress signals, but commitment to apoptosis requires Bax or Bak. The BH3-only…

Volume 19, Issue 5, 01 October 2007, Pp 488-496
Adams, J.M. | Cory, S.

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.

Regulatory T cells and cancer

Increasing evidence indicates that T regulatory (Treg) cells have the potent ability to suppress host immune responses, thus preventing autoimmune diseases. However, recent studies demonstrate that tumor cells can recruit these Treg cells to inhibit antitumor immunity in the tumor microenvironment, thus limiting the efficiency of cancer immunotherapy. Tumor-specific Treg cells have recently been identified and characterized, providing compelling evidence that such antigen-specific Treg cells…

Volume 19, Issue 2, 01 April 2007, Pp 217-223
Wang, H.Y. | Wang, R.-F.

Expression and function of Toll-like receptors in T lymphocytes

Toll-like receptors (TLRs) are widely expressed in the innate immune system. They recognize conserved microbial ligands such as bacterial lipopolysaccharide, lipopeptides or viral and bacterial RNA and DNA. TLRs play an essential role in innate immune responses and in the initiation of adaptive immune responses. However, certain TLRs are also expressed in T lymphocytes, and the respective ligands can directly modulate T cell function. TLR2, TLR3, TLR5 and TLR9 act as co-stimulatory receptors to…

Volume 19, Issue 1, 01 February 2007, Pp 39-45
Kabelitz, D.

Humoral immunity, inflammation and cancer

Clinical and experimental data now clearly indicate that chronic inflammation significantly contributes to cancer development. Emerging out of these studies is an appreciation that persistent humoral immune responses exacerbate recruitment and activation of innate immune cells in neoplastic microenvironments where they regulate tissue remodeling, pro-angiogenic and pro-survival pathways that together potentiate cancer development. Population-based studies examining individuals with chronic…

Volume 19, Issue 2, 01 April 2007, Pp 209-216
Tan, T.-T. | Coussens, L.M.

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.

CD8 T cell dysfunction during chronic viral infection

Clearance of primary infection often leads to the development of highly functional memory T cells capable of rapid and long-lasting protective immunity. By contrast, chronic infections can result in T cell dysfunction and poor pathogen control. In this review, we will discuss recent work that highlights two main types of T cell dysfunction during chronic infection: exhaustion of effector functions and altered memory T cell development.

Volume 19, Issue 4, 01 August 2007, Pp 408-415
Shin, H. | Wherry, E.J.

Cytokines and T-cell homeostasis

Homeostasis of T cells can be defined as the ability of the immune system to maintain normal T-cell counts and to restore T-cell numbers following T-cell depletion or expansion. These processes are governed by extrinsic signals, most notably cytokines. Two members of the common γ chain family of cytokines, interleukin (IL)-7 and IL-15, are central to homeostatic proliferation and survival of mature CD4+ and CD8+ T cells. Recent evidence suggests that other cytokines, including IL-2, IL-10,…

Volume 19, Issue 3, 01 June 2007, Pp 320-326
Boyman, O. | Purton, J.F. | Surh, C.D. | Sprent, J.

B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling

B-cell activation factor from the tumor necrosis factor family (BAFF) is a key survival factor during B-cell maturation - a delicate immune checkpoint for B cells. Excessive BAFF production at this stage corrupts B-cell tolerance and leads to autoimmunity. Elevated serum BAFF levels have been detected in some patients suffering from various autoimmune conditions. The positive outcomes of currently ongoing clinical trials using BAFF-neutralising agents confirm that this factor plays a major…

Volume 19, Issue 3, 01 June 2007, Pp 327-336
Mackay, F. | Silveira, P.A. | Brink, R.

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.

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

Smouldering inflammation is a component of the tumor microenvironment and represents the 7th 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.

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.

PD-1 and its ligands in T-cell immunity

The past year has seen significant advances in our understanding of the critical roles of negative immunoregulatory signals delivered by the programmed death 1 (PD-1)-PD-1 ligand (PD-L) pathway in regulating T-cell activation and tolerance. Emerging evidence indicates that PD-Ls play an essential role on dendritic cells (DCs), both directly during DC-T cell interactions and indirectly through signaling into the DC. Recent studies point to a novel role for PD-L1 in maintaining tissue tolerance.…

Volume 19, Issue 3, 01 June 2007, Pp 309-314
Keir, M.E. | Francisco, L.M. | Sharpe, A.H.

Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes?

When immune cells and developing tumor cells localize to a common microenvironment, an assemblage of interactions takes place; this results in either tumor destruction by way of immunosurveillance or tumor outgrowth. These events put a functional imprint onto the emerging tumor repertoire because tumor cells arising in the presence of a fully functional immune system are less immunogenic than those that develop in the absence of immunity (i.e. in RAG2-/- and perforin-/- mice). However, other…

Volume 19, Issue 2, 01 April 2007, Pp 203-208
Bui, J.D. | Schreiber, R.D.

NKT cells: T lymphocytes with innate effector functions

Natural killer T (NKT) cells are innate-like T lymphocytes that recognize glycolipid antigens in the context of the MHC class I-related glycoprotein CD1d. Recent studies have identified multiple ways in which NKT cells can become activated during microbial infection. Mechanisms of CD1d-restricted antigen presentation are being unraveled, and a surprising connection has been made to proteins that control lipid metabolism and atherosclerosis. It appears that several microorganisms have developed…

Volume 19, Issue 3, 01 June 2007, Pp 354-364
Van Kaer, L.

Delivering the kiss of death: progress on understanding how perforin works

Killer lymphocytes release perforin and granzymes from cytotoxic granules into the immunological synapse to destroy target cells as a critical mechanism in the defense against viruses and cancer. Perforin, a Ca2+-dependent pore-forming protein that multimerizes in membranes, delivers granzymes into the target cell cytosol. The original model for perforin (acting by forming a cell membrane channel through which granzymes pass) does not fit the experimental data. Recently, an alternative model…

Volume 19, Issue 3, 01 June 2007, Pp 301-308
Pipkin, M.E. | Lieberman, J.

New and emerging roles for mast cells in host defence

Mast cells are highly effective sentinel cells, found close to blood vessels and especially common sites of potential infection, such as the skin, airways and gastrointestinal tract. Mast cells participate actively in the innate immune responses to many pathogens through a broad spectrum of mediators that can be selectively generated. They also have a role as innate effector cells in enhancing the earliest processes in the development of acquired immune responses. Studies of bacterial and…

Volume 19, Issue 1, 01 February 2007, Pp 31-38
Dawicki, W. | Marshall, J.S.

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.

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.

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.

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.

Autophagy as an innate immunity paradigm: expanding the scope and repertoire of pattern recognition receptors

Intracellular mechanisms of antigen cross presentation in dendritic cells

IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation

The many faces of Th17 cells

Advances in atopic dermatitis

The regulation of TNF signalling: what a tangled web we weave

Helper T cell diversity and plasticity

Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses

TH17 cytokines in autoimmune neuro-inflammation

Transcriptional drivers of the T-cell lineage program