Immunosenescence influences many components of the immune system. Most
importantly, profound changes in T cell function are evident in older
individuals. The impact of aging on specific T cell subsets has been difficult
to examine, but recent advances in murine model systems and new insights into T
cell function have allowed for the more precise examination of how T cell
responses change with aging. Importantly, recent studies have shown that
age-related enhancement of both Th17 generation and regulatory T cell function
may contribute to significant changes in immune function. In this review, we
summarize the current views on how aging influences the factors that impact T
cell function and how this can affect the immune response to infections,
vaccinations, and tumors.
There has been considerable progress in our understanding of the genetic architecture of susceptibility to inflammatory diseases in recent years: several hundred susceptibility loci have been discovered in genome-wide association studies (GWAS) of human populations. This success has created an important challenge in identifying the functional consequences of these risk-associated variants and in elucidating how the repercussions of individual susceptibility loci integrate to yield dysregulation of immune pathways and, ultimately, syndromic clinical phenotypes. The integration of GWAS association signals with high-resolution transcriptome and other genomic data that capture the dynamics of cellular state and function in the context of individual's collection of susceptibility alleles has proven to be a successful avenue of investigation. The rapid pace of methodological development in this area has been coupled with an accumulation of experimental data that makes the elucidation of complex biological networks underlying susceptibility to these common inflammatory diseases a reasonable goal in the near future.
It is well recognized that allospecific T cell activation is required for rejection. However, the process of allospecific T cell activation is largely controllable with current agents. Accordingly, short-term outcomes in allotransplantation have uniformly improved, a testament to the importance of the T cell-centric view of current therapy; thus, the field’s attention has turned toward lagging long-term outcomes. The inexorable chronic graft destruction that continues to define clinical transplantation suggests that there are important aspects of alloimmunity that are un-mollified by simple T cell-directed immunosuppression. Indeed, in the past decade it has become clear that the full biological phenomenon collectively recognized as rejection incorporates an almost Gordian network of factors, both inflammatory and regulatory, that shape the phenotype of allorecognition. T cell responses, including the T cell dependent allograft response, are contextually determined by the state of innate immunity in which T cells interact with antigen. Organs utilized for transplantation are usually obtained from deceased donors by a surgical procedure and then placed into cold preservation solutions before surgery implantation into the recipient. Brain death, ischemia reperfusion, hypoxia and hemostasis related injuries dramatically influence the state of innate immunity within the transplant. Overall, each of these processes activates innate immunity into a pro-inflammatory mode that is known to promote tissue destructive forms of adaptive immunity. These pathways and cell types have been left largely untargeted, or at least under recognized, and it is these finer points of rejection that serve as the focus of this issue of Current Opinion in Immunology…
HIV/AIDS remains a chronic and incurable disease, in spite of the notable successes of highly active antiretroviral therapy. Gene therapy offers the prospect of creating genetic resistance to HIV that supplants the need for antiviral drugs. In sight of this goal, a variety of anti-HIV genes have reached clinical testing, including gene-editing enzymes, protein-based inhibitors, and RNA-based therapeutics. Combinations of therapeutic genes against viral and host targets are designed to improve the overall antiviral potency and reduce the likelihood of viral resistance. In cell-based therapies, therapeutic genes are expressed in gene modified T lymphocytes or in hematopoietic stem cells that generate an HIV-resistant immune system. Such strategies must promote the selective proliferation of the transplanted cells and the prolonged expression of therapeutic genes. This review focuses on the current advances and limitations in genetic therapies against HIV, including the status of several recent and ongoing clinical studies.
HIV; gene therapy; HSCs
Many common genetic variants have been identified to be associated with autoimmune diseases such as Type I diabetes. Methods to identify these genetic loci have become powerful, but deciphering the functional effects of these variants in disease progression remains a major challenge. Recent studies have shown that single nucleotide polymorphisms are associated with altered DNA methylation and chromatin accessibility, suggesting that genetic variants can alter epigenetic features and epigenetic variations can mediate genetic variability. In this review, we highlight recent studies that have examined the relationship between genetics and epigenetics, and how epigenetic studies may complement genetic studies in understanding the impact of common disease causing alleles.
The advent of reprogramming technology has greatly advanced the field of stem cell biology and nurtured our hope to create patient specific renewable stem cell sources. While the number of reports of disease specific induced pluripotent stem cells is continuously rising, the field becomes increasingly more aware that induced pluripotent stem cells are not as similar to embryonic stem cells as initially assumed. Our state of the art understanding of human induced pluripotent stem cells, their capacity, their limitations and their promise as it pertains to the study and treatment of primary immunodeficiencies, is the content of this review.
The genetics of human autoimmune diseases remain incompletely understood, despite significant progress from genome-wide association studies (GWAS). In this review we outline how mouse studies may help filling these knowledge gaps. Forward genetic approaches including mutagenesis screens and quantitative trait locus mapping can be used to identify candidate genes for in depth analysis in human patient populations. Reverse genetic approaches utilize genetically engineered mice to analyze the function of disease-associated genes and their variants. Inbred strains are a distinctive feature of mouse genetics and we discuss their history, advantages and disadvantages. Three factors need to be considered when comparing experimental results from studies in mice and humans. In addition to species-specific differences, phenotypes are affected by the genetic background of the mouse strain being analyzed, as well as by microbial factors. Despite of these complexities, mice are essential discovery tools in the post GWAS era.
How expression of canonical semi-invariant TCRs leads to innate-like effector differentiation is a central enigma of NKT cell development. NKT thymic precursors undergo elevated TCR signals leading to increased Egr2, which directly induces their signature transcription factor, PLZF. PLZF is necessary and sufficient to induce a multipotent, unbiased effector program that precedes terminal differentiation into T-bethigh NK1.1+ (NKT1) cells and recently identified NKT2 and NKT17 sublineages. Major variations in polarized NKT sublineages have been uncovered in different mouse strains and in several mutants, with direct impact on NKT cell function but also, unexpectedly, on the development and function of conventional T cells.
The proper choice of the CD4-helper or CD8-cytotoxic lineages by developing T cells is crucial for the generation of an antigen-responsive and functionally fit T cell repertoire. Here we present a brief overview of the transcriptional control of this process, with emphasis on two issues. The study of Cd4 expression, that had previously generated important paradigms for transcriptional regulation in eukaryotic cells, now brings new twists to the concept of ‘epigenetic memory’. On the other hand, connections are emerging between transcriptional regulators critical for commitment to either lineage. The present review attempts to integrate these findings and discusses the still elusive mechanisms that match CD4-CD8 lineage differentiation to MHC specificity.
The various clinical manifestations of chronic mucocutaneous candidiasis (CMC) often result from acquired T-cell immunodeficiencies. More rarely, CMC results from inborn errors of immunity, the recent dissection of which has shed light on the molecular mechanisms of mucocutaneous immunity to Candida albicans. CMC may accompany various other infectious diseases in patients with almost any broad and profound T-cell primary immunodeficiency. By contrast, CMC is one of the few key infections in patients with autosomal dominant hyper IgE syndrome (mutations in STAT3), and in rare patients with autosomal recessive predisposition to mucocutaneous and invasive fungal infections (mutation in CARD9). In patients with mutations in STAT3 and CARD9 the development of IL-17-producing T cells is impaired. Moreover, CMC is the principal, if not only infection in patients with autosomal recessive autoimmune polyendocrinopathy syndrome-I (mutations in AIRE). Patients with this condition have high titers of neutralizing autoantibodies (auto-Abs) against the IL-17 cytokines IL-17A, IL-17F, and IL-22. Collectively, these data suggest that human IL-17A, IL-17F, and IL-22 are essential for mucocutaneous immunity to Candida albicans. They also suggest that the distinct syndrome of isolated CMC, without autoimmunity or other infections, may be caused by inborn errors of IL-17 immunity.
In short, manipulation of cytokine pathways shows promise as a mean to tilt the balance of immunity toward tolerance. Effective and regulatory T cells vary in their response to a variety of cytokines. In particular, the ability of certain cytokines, for example, IL-2, to provide vital survival signals to regulatory cells and to trigger death of effector T cells or impede IL-15 driven expansion of memory cells has spurred several trials. The ability of IFNγ, IL-4, TNFα, and lymphotoxin to exert selective effects upon crucial lymphocyte subset populations in vivo may also enable translation into potent therapies.
Advances in experimental tools have allowed for the systematic identification of components and biological processes as well quantification of their activities over time. Together with computational analysis, these measurement and perturbation technologies have given rise to the field of systems biology, which seeks to discover, analyze and model the interactions of physical components in a biological system. Although in its infancy, recent application of this approach has resulted in novel insights into the machinery that regulates and modifies innate immune cell functions. Here, we summarize contributions that have been made through the unbiased interrogation of the mammalian innate immune system, emphasizing the importance of integrating orthogonal datasets into models. To enable application of approaches more broadly, however, a concerted effort across the immunology community to develop reagent and tool platforms will be required.
An effective vaccine usually requires more than one time immunization in the form of prime-boost. Traditionally the same vaccines are given multiple times as homologous boosts. New findings suggested that prime-boost can be done with different types of vaccines containing the same antigens. In many cases such heterologous prime-boost can be more immunogenic than homologous prime-boost. Heterologous prime-boost represents a new way of immunization and will stimulate better understanding on the immunological basis of vaccines.
The logistic problem of B cell antigen encounter in the lymph node has recently been studied by dynamic imaging using two-photon microscopy. These studies combined with early studies of antigen transport have yielded a more complete picture of the orchestration of B cell activation in vivo. Here we summarize the recent advances and focus on the specialized macrophages that are critical to this process and the role of B cells themselves as antigen transporting cells.
A hallmark of aging is the progressive deterioration of immune function. Age-related immune suppression increases susceptibility to infectious diseases and cancer, significant causes of morbidity and mortality in the elderly. In particular, age-related T cell dysfunction is a major contributor to “immune-senescence”. Recently, it has become clear that the frequency of regulatory T cells (Treg) significantly increases in aged mice and humans. As Treg control the intensity of T cell responses, their accrual likely contributes to age-related immune dysfunction. This review will focus on mechanisms underlying Treg homeostasis and function in aging.
The aged immune system, typically hyporesponsive to infection and vaccination, can be hyperresponsive in the context of inflammatory pathology. Here we review current work examining the mechanisms behind the amplified inflammatory profile of aged adaptive immunity, and the reciprocal relationship between chronic inflammation and immune aging. Aged hematopoietic stem cells are driven to differentiate following accumulated DNA damage, thus depleting the stem cell pool and increasing the number of damaged effector cells in the circulation. Chronic DNA damage responses in lymphocytes as well as senescent cells of other lineages initiate the production of inflammatory mediators. In addition, aged lymphocytes become less reliant on specific antigen for stimulation and more prone to activation through innate receptors. When these lymphocytes are exposed to inflammatory signals produced by senescent tissues, the bias toward inflammation exacerbates destruction without necessarily improving immunity.
The commensal bacteria normally resident in the gastrointestinal tract represent an enormous pool of foreign antigen within the body. Although mechanical barriers limit entry of bacteria into the host, recent data suggest that T cells routinely interact with commensal bacteria using both antigen-specific and non-specific receptors. Depending on the bacterial species, either regulatory or effector T cell responses can be generated. For example, segmented filamentous bacteria (SFB) favor effector Th17 responses whereas Bacteroides fragilis and certain Clostridium species favor Foxp3+ regulatory T (Treg) cell responses. Thus, in contrast with the notion that only tolerogenic responses are required to self, gut homeostasis may require both tolerance and immunity to various constituents of the commensal microbiota.
This review explores the recent advances that have been made in our understanding of host viral interactions in the intestine. Technical advances have allowed the initial definition of intestinal viromes in a number of species including humans. Important advances in our knowledge of the host response to viral infection have shown that interferon lambda has a role that is unique from type I interferons in the intestine. Lastly, our understanding of virally induced phenotypes has expanded through new studies that show bacteria can play an important role in the outcome of viral infection in the intestine.
Telomeres are essential for the integrity of chromosomes and for cellular replication. Attrition of telomeres occurs during DNA replication due to the inability of conventional DNA polymerase to replicate chromosomal termini and the insufficient compensation for telomere loss by telomerase, an enzyme that synthesizes telomeric DNA. A number of genetic defects have been described in humans and in animal models which cause accelerated telomere attrition, in turn leading to severe phenotypes of hematopoietic and other proliferating cells. Telomere length, most frequently measured as an average value in heterogeneous peripheral blood leukocyte populations in humans, has been associated with a wide range of health conditions and diseases of immune and non-immune cells. Here, we review recent studies of telomere length dynamics with particular relevance to immune function.
A vast majority of human vaccines rely on neutralizing antibodies for protection. With the exception of vaccines against human papillomavirus, despite a great amount of dedicated effort by the scientific community, development of vaccines against sexually transmitted viruses has generally been unsuccessful. Understanding the immunobiology of the genital tract is key to designing vaccines that prevent spreading of these viruses. Recent studies demonstrate that adaptive immunity in the vaginal mucosa is uniquely regulated compared to other mucosal organs. In particular, development of virus-specific CD4+ and CD8+ T cells is critically important for antiviral defense in vagina. In this review, we provide an overview of our current understanding of a wide spectrum of immune responses in vagina - from innate viral sensing to memory development.
Recent studies have revisited the roles of prime players in the immune response to tuberculosis (TB) and have highlighted novel functions of players. Specifically, immunoregulatory mechanisms mediated by IFNγ have been delineated as well as a novel role for neutrophils in promoting antigen presentation. New insights into the interaction between the bacterium and phagocyte indicate that the bacterium actively promotes phagocyte necrosis rather than apoptosis and that this impacts generation of the acquired response. There are also many new examples of how the phagocyte responds to the bacteria and how it mediates control. The phenotype of protective T cells is also being re-examined. These developments provide promise for improved vaccine design and highlight the complexity of this disease.
Polymicrobial interactions on mucosal surfaces can influence inflammation, immunity, and disease outcome. Here, we review how host responses to colonization in the upper respiratory tract with the bacterial pathogen Streptococcus pneumoniae can be altered by co-infection. Recent advances provide a mechanistic understanding of how mucosal immunity can be subverted at distinct immunological time-points during pneumococcal colonization by other pathogens such as Haemophilus influenzae, influenza type A and Staphylococcus aureus. These examples use animal models of co-infection to highlight how otherwise effective host responses can be rendered ineffective by co-infection, and vice versa. The complex microbial ecology of mucosal sites must be considered to fully understand how immune responses in a natural setting influence the outcome of host-pathogen interactions.
The intestine serves as the primary site of nutrient absorption in the body while also harboring the highest burden of commensal microflora and representing a major portal of pathogen exposure. As such, the immune network of the intestine relies on both dietary and commensal derived signals to guide appropriate function. Recent advances highlight the role of dietary derived nutrients and commensal derived metabolites in shaping gastrointestinal immunity. In particular, Vitamin A has been shown to have dominant and pleiotropic effects in the intestine. In addition, dietary derived AHR ligands and commensal derived metabolites are now emerging as important players in mucosal immunity. Thus nutrition, commensal microflora and the mucosal immune system are all intimately connected.
The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human STAT1 define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes.