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- Volume 36, 2018
Annual Review of Immunology - Volume 36, 2018
Volume 36, 2018
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Multidomain Control Over TEC Kinase Activation State Tunes the T Cell Response
Vol. 36 (2018), pp. 549–578More LessSignaling through the T cell antigen receptor (TCR) activates a series of tyrosine kinases. Directly associated with the TCR, the SRC family kinase LCK and the SYK family kinase ZAP-70 are essential for all downstream responses to TCR stimulation. In contrast, the TEC family kinase ITK is not an obligate component of the TCR cascade. Instead, ITK functions as a tuning dial, to translate variations in TCR signal strength into differential programs of gene expression. Recent insights into TEC kinase structure have provided a view into the molecular mechanisms that generate different states of kinase activation. In resting lymphocytes, TEC kinases are autoinhibited, and multiple interactions between the regulatory and kinase domains maintain low activity. Following TCR stimulation, newly generated signaling modules compete with the autoinhibited core and shift the conformational ensemble to the fully active kinase. This multidomain control over kinase activation state provides a structural mechanism to account for ITK's ability to tune the TCR signal.
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CD4 Helper and CD8 Cytotoxic T Cell Differentiation
Vol. 36 (2018), pp. 579–601More LessA fundamental question in developmental immunology is how bipotential thymocyte precursors generate both CD4+ helper and CD8+ cytotoxic T cell lineages. The MHC specificity of αβ T cell receptors (TCRs) on precursors is closely correlated with cell fate–determining processes, prompting studies to characterize how variations in TCR signaling are linked with genetic programs establishing lineage-specific gene expression signatures, such as exclusive CD4 or CD8 expression. The key transcription factors ThPOK and Runx3 have been identified as mediating development of helper and cytotoxic T cell lineages, respectively. Together with increasing knowledge of epigenetic regulators, these findings have advanced our understanding of the transcription factor network regulating the CD4/CD8 dichotomy. It has also become apparent that CD4+ T cells retain developmental plasticity, allowing them to acquire cytotoxic activity in the periphery. Despite such advances, further studies are necessary to identify the molecular links between TCR signaling and the nuclear machinery regulating expression of ThPOK and Runx3.
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The Immune Response to Mycobacterium tuberculosis in HIV-1-Coinfected Persons
Vol. 36 (2018), pp. 603–638More LessGlobally, about 36.7 million people were living with HIV infection at the end of 2015. The most frequent infection co-occurring with HIV-1 is Mycobacterium tuberculosis—374,000 deaths per annum are attributable to HIV-tuberculosis, 75% of those occurring in Africa. HIV-1 infection increases the risk of tuberculosis by a factor of up to 26 and alters its clinical presentation, complicates diagnosis and treatment, and worsens outcome. Although HIV-1-induced depletion of CD4+ T cells underlies all these effects, more widespread immune deficits also contribute to susceptibility and pathogenesis. These defects present a challenge to understand and ameliorate, but also an opportunity to learn and optimize mechanisms that normally protect people against tuberculosis. The most effective means to prevent and ameliorate tuberculosis in HIV-1-infected people is antiretroviral therapy, but this may be complicated by pathological immune deterioration that in turn requires more effective host-directed anti-inflammatory therapies to be derived.
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The Formation and Function of Granulomas
Vol. 36 (2018), pp. 639–665More LessGranulomas are organized aggregates of macrophages, often with characteristic morphological changes, and other immune cells. These evolutionarily ancient structures form in response to persistent particulate stimuli—infectious or noninfectious—that individual macrophages cannot eradicate. Granulomas evolved as protective responses to destroy or sequester particles but are frequently pathological in the context of foreign bodies, infections, and inflammatory diseases. We summarize recent findings that suggest that the granulomatous response unfolds in a stepwise program characterized by a series of macrophage activations and transformations that in turn recruit additional cells and produce structural changes. We explore why different granulomas vary and the reasons that granulomas are protective and pathogenic. Understanding the mechanisms and role of granuloma formation may uncover new therapies for the multitude of granulomatous diseases that constitute serious medical problems while enhancing the protective function of granulomas in infections.
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RIG-I and Other RNA Sensors in Antiviral Immunity
Vol. 36 (2018), pp. 667–694More LessPattern recognition receptors (PRRs) survey intra- and extracellular spaces for pathogen-associated molecular patterns (PAMPs) within microbial products of infection. Recognition and binding to cognate PAMP ligand by specific PRRs initiates signaling cascades that culminate in a coordinated intracellular innate immune response designed to control infection. In particular, our immune system has evolved specialized PRRs to discriminate viral nucleic acid from host. These are critical sensors of viral RNA to trigger innate immunity in the vertebrate host. Different families of PRRs of virus infection have been defined and reveal a diversity of PAMP specificity for wide viral pathogen coverage to recognize and extinguish virus infection. In this review, we discuss recent insights in pathogen recognition by the RIG-I-like receptors, related RNA helicases, Toll-like receptors, and other RNA sensor PRRs, to present emerging themes in innate immune signaling during virus infection.
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Exploiting Nanobodies’ Singular Traits
Vol. 36 (2018), pp. 695–715More LessThe unique class of heavy chain–only antibodies, present in Camelidae, can be shrunk to just the variable region of the heavy chain to yield VHHs, also called nanobodies. About one-tenth the size of their full-size counterparts, nanobodies can serve in applications similar to those for conventional antibodies, but they come with a number of signature advantages that find increasing application in biology. They not only function as crystallization chaperones but also can be expressed inside cells as such, or fused to other proteins to perturb the function of their targets, for example, by enforcing their localization or degradation. Their small size also affords advantages when applied in vivo, for example, in imaging applications. Here we review such applications, with particular emphasis on those areas where conventional antibodies would face a more challenging environment.
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Regulation of the Cell Biology of Antigen Cross-Presentation
Vol. 36 (2018), pp. 717–753More LessAntigen cross-presentation is an adaptation of the cellular process of loading MHC-I molecules with endogenous peptides during their biosynthesis within the endoplasmic reticulum. Cross-presented peptides derive from internalized proteins, microbial pathogens, and transformed or dying cells. The physical separation of internalized cargo from the endoplasmic reticulum, where the machinery for assembling peptide–MHC-I complexes resides, poses a challenge. To solve this problem, deliberate rewiring of organelle communication within cells is necessary to prepare for cross-presentation, and different endocytic receptors and vesicular traffic patterns customize the emergent cross-presentation compartment to the nature of the peptide source. Three distinct pathways of vesicular traffic converge to form the ideal cross-presentation compartment, each regulated differently to supply a unique component that enables cross-presentation of a diverse repertoire of peptides. Delivery of centerpiece MHC-I molecules is the critical step regulated by microbe-sensitive Toll-like receptors. Defining the subcellular sources of MHC-I and identifying sites of peptide loading during cross-presentation remain key challenges.
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Translating Immunology into Therapeutic Concepts for Inflammatory Bowel Disease
Vol. 36 (2018), pp. 755–781More LessInflammatory bowel disease (IBD) defines a spectrum of complex disorders. Understanding how environmental risk factors, alterations of the intestinal microbiota, and polygenetic and epigenetic susceptibility impact on immune pathways is key for developing targeted therapies. Mechanistic understanding of polygenic IBD is complemented by Mendelian disorders that present with IBD, pharmacological interventions that cause colitis, autoimmunity, and multiple animal models. Collectively, this multifactorial pathogenesis supports a concept of immune checkpoints that control microbial-host interactions in the gut by modulating innate and adaptive immunity, as well as epithelial and mesenchymal cell responses. In addition to classical immunosuppressive strategies, we discuss how resetting the microbiota and restoring innate immune responses, in particular autophagy and epithelial barrier function, might be key for maintaining remission or preventing IBD. Targeting checkpoints in genetically stratified subgroups of patients with Mendelian disorder–associated IBD increasingly directs treatment strategies as part of personalized medicine.
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Molecular and Functional Neuroscience in Immunity
Vol. 36 (2018), pp. 783–812More LessThe nervous system regulates immunity and inflammation. The molecular detection of pathogen fragments, cytokines, and other immune molecules by sensory neurons generates immunoregulatory responses through efferent autonomic neuron signaling. The functional organization of this neural control is based on principles of reflex regulation. Reflexes involving the vagus nerve and other nerves have been therapeutically explored in models of inflammatory and autoimmune conditions, and recently in clinical settings. The brain integrates neuro-immune communication, and brain function is altered in diseases characterized by peripheral immune dysregulation and inflammation. Here we review the anatomical and molecular basis of the neural interface with immunity, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus. Clinical advances stemming from this knowledge within the framework of bioelectronic medicine are also briefly outlined.
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Systems Immunology: Learning the Rules of the Immune System
Vol. 36 (2018), pp. 813–842More LessGiven the many cell types and molecular components of the human immune system, along with vast variations across individuals, how should we go about developing causal and predictive explanations of immunity? A central strategy in human studies is to leverage natural variation to find relationships among variables, including DNA variants, epigenetic states, immune phenotypes, clinical descriptors, and others. Here, we focus on how natural variation is used to find patterns, infer principles, and develop predictive models for two areas: (a) immune cell activation—how single-cell profiling boosts our ability to discover immune cell types and states—and (b) antigen presentation and recognition—how models can be generated to predict presentation of antigens on MHC molecules and their detection by T cell receptors. These are two examples of a shift in how we find the drivers and targets of immunity, especially in the human system in the context of health and disease.
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Rebooting Human Immunology
Vol. 36 (2018), pp. 843–864More LessRecent progress in both conceptual and technological approaches to human immunology have rejuvenated a field that has long been in the shadow of the inbred mouse model. This is a healthy development both for the clinical relevance of immunology and for the fact that it is a way to gain access to the wealth of phenomenology in the many human diseases that involve the immune system. This is where we are likely to discover new immunological mechanisms and principals, especially those involving genetic heterogeneity or environmental influences that are difficult to model effectively in inbred mice. We also suggest that there are likely to be novel immunological mechanisms in long-lived, less fecund mammals such as human beings since they must remain healthy far longer than short-lived rodents in order for the species to survive.
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Previous Volumes
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Volume 41 (2023)
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Volume 40 (2022)
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Volume 39 (2021)
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Volume 38 (2020)
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Volume 37 (2019)
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Volume 36 (2018)
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Volume 35 (2017)
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Volume 34 (2016)
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Volume 33 (2015)
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Volume 32 (2014)
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Volume 31 (2013)
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Volume 30 (2012)
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Volume 29 (2011)
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Volume 28 (2009)
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Volume 27 (2009)
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Volume 25 (2007)
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Volume 24 (2006)
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Volume 26 (2005)
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Volume 23 (2005)
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Volume 22 (2004)
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Volume 21 (2003)
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Volume 20 (2002)
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Volume 19 (2001)
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Volume 18 (2000)
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Volume 17 (1999)
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Volume 16 (1998)
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Volume 15 (1997)
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Volume 14 (1996)
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Volume 13 (1995)
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Volume 12 (1994)
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Volume 11 (1993)
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Volume 10 (1992)
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Volume 9 (1991)
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Volume 8 (1990)
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Volume 7 (1989)
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Volume 6 (1988)
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Volume 5 (1987)
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Volume 4 (1986)
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Volume 3 (1985)
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Volume 2 (1984)
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Volume 1 (1983)
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Volume 0 (1932)