Neuropilin-1: The Glue between Regulatory T Cells and Dendritic Cells?

The interaction between dendritic cells and regulatory T cells is critical for the maintenance of self-tolerance. In this issue of Immunity, Sarris et al. (2008) find that Neuropilin-1 contributes to the prolonged interaction of regulatory T cells with dendritic cells.     

How do T cells mediate autoimmune thyroiditis?

Susceptibility to experimental autoimmune thyroiditis (EAT) is linked to the mouse H-2 complex¹. Initiation of the condition by the thyroid antigen, thyroglobulin (Tg), requires T cells from susceptible mice². These T cells are autoreactive in that they recognize Tg and proliferate in vitro in response to it³. The 1980s have brought forth confirmatory data from several laboratories on T-cell autoreactivity to mouse Tg both in vivo^4,5 and in vitro^6–13, and its correlation with EAT susceptibility. T cells from patients with Hashimoto's thyroiditis (HT), may proliferate in response to stimulation in vitro with human Tg^14–16. The capacity of murine T cells to expand and differentiate in vitro^17,18 and to serve as effector cells causing thyroiditis in vivo^{7,8, 11,12} is strongly indicative of their pathogenic role. We are now in a position to discuss not only if T cells mediate autoimmune thyroiditis, but how they might contribute to the pathogenic process. At least two antigen-activated T-cell subsets seem to participate in initiating and perpetuating thyroid destruction. In this article, Yi-chi Kong and her colleagues present a synopsis of the supporting data from the mouse model and parallel findings from HT patients.     

How many mechanisms do regulatory T cells need?

A plethora of new regulatory T cell (Treg) mechanisms have recently emerged. This raises two important questions. First, how many molecules or mechanisms are required for Treg to work? Second, how should we evaluate the contribution of any given Treg molecule/mechanism and how is this likely to relate (or not) to the phenotype seen in Scurfy/Foxp3‐deficient mice? In this discussion piece, I will briefly outline our current understanding of the Treg arsenal and address these important questions. See accompanying commentary: http://dx.doi.org/10.1002/eji.200838143     

How do animals actually solve the T maze?

Rats were trained on a reinforced, delayed alternation T-maze task in the presence (cue group) or absence (no-cue group) of salient extramaze landmarks. A surprising finding was that the acquisition and memory performance of the 2 groups did not differ. Manipulations of the extramaze landmarks for the cue group suggested that, although landmarks were used to guide behavior, other sources of information were also used normally. The no-cue group was able to perform the task at above-chance levels even when extramaze, intramaze, and inertial sources of orientation were manipulated. These results suggest that memory performance on the T maze does not rely exclusively on the processing of allocentric spatial relationships in the maze environment.     

Do Regulatory T Cells Play a Role in the Control of Homeostatic Proliferation?

The control of peripheral lymphocyte numbers is a fundamental aspect of the immune system. Regulatory T cells are involved in the suppression of autoimmune, antitumor, allergic, and other inflammatory responses, as well as in facilitating graft acceptance. In this paper, we discuss whether the control of homeostatic proliferation is another facet of the immune system that is controlled by regulatory T cells. A review of the published data connecting regulatory T cells with the control of homeostatic proliferation indicates that several key questions remain open. One of these relates to the stage at which regulatory T cells could play a role (i.e., T-cell proliferation vs. survival).     

Generation and Regulation of CD8＋ Regulatory T Cells

Research into the suppressive activity of CD4＋FoxP3＋ T regulatory cells （Treg） has defined a sublineage of CD4＋ cells that contribute to self-tolerance and resistance to autoimmune disease. Much less attention has been given to the potential contribution of regulatory sublineages of CD8＋ cells. Analysis of a small fraction of CD8＋ cells that target autoreactive CD4＋ cells through recognition of the MHC class Ib molecule Qa-1 in mouse and HLA-E in human has revitalized interest in CD8＋ Treg. Here we summarize recent progress and future directions of research into the role of this CD8＋ sublineage in resistance to autoimmune disease. Cellular ＆ Molecular Immunology. 2008; 5（6）：401-406.     

How do I manage nocardiosis?

BackgroundNocardiosis is a rare infection that is often difficult to treat and may be life-threatening. There is no consensus on its management.ObjectivesOur aim was to provide the current evidence for the diagnosis and management of individuals with nocardiosis, and to propose a management approach for this uncommon infection.SourcesWe systematically searched the medical literature on nocardiosis for studies published between 2010 and 2020 and describing ten or more individuals.ContentNocardiosis, a primarily opportunistic infection which may occur in immunocompetent persons, most commonly involves the lungs and frequently disseminates to other sites including the central nervous system. The reference standard for Nocardia species identification is molecular biology, and the preferred method for antibiotic susceptibility testing (AST) is broth microdilution. Monotherapy seems appropriate for patients with primary skin nocardiosis or non-severe pulmonary disease; we reserve a multidrug regimen for more severe infections. Species identification and AST results are often missing at initiation of antibiotics. Trimethoprim-sulfamethoxazole is the preferred agent for initial therapy, because Nocardia is very often susceptible to this agent, and because it has been the keystone of nocardiosis treatment for years. Linezolid, to which Nocardia is almost always susceptible, may be an alternative. When combination therapy is required, the repertoire of companion drugs includes third-generation cephalosporins, amikacin and imipenem. Therapeutic modifications should take into account clinical response to initial therapy and AST results. Treatment duration of 6 months is appropriate for most situations, but longer durations are preferred for disseminated nocardiosis and shorter durations are reasonable in low-risk situations. Secondary prophylaxis may be considered in selected individuals with permanent immunosuppression.ImplicationsWe hereby provide the clinician with an easy-to-use algorithm for the management of individuals with nocardiosis. We also illuminate gaps in evidence and suggest future research directions.     

How do inhibitory phosphatases work?

We present a hypothesis regarding the mode of induction of the inhibitory phosphatases SHP-1 and SHIP in hematopoietic cells. One mode is a general one in which the phosphatase regulates but does not abort signal transduction and biology. Regulator phosphatases are induced by directly or indirectly engaging the amino acid motifs present in the activating receptor, and act to control the biochemical and biological output. The other mode of induction is a specific one, which critically involves paired co-clustering of activating and inhibitory receptors. Phosphatases working in this way act only under conditions of paired co-clustering of activating and inhibitory receptors, and directly bind amino acid motifs present in the inhibitory receptor. However, this mode of induction is apparently more efficient, as cellular activation is completely aborted. This review presents several examples of each mode of inhibition and speculates on their mechanisms.     

COVID-19 and T Cells: Do T Cells Really Matter?

How to cite this article: Gajjala C, Jindal, A. COVID-19 and T Cells: Do T Cells Really Matter? Indian J Crit Care Med 2023;27(1):75.     

How do we monitor asthma control?

The present consensus on asthma management includes avoidance of triggers, education, regular follow-up, and an action plan that relies on symptoms and lung function measurements for the monitoring of disease severity. Inclusion of objective measurements for monitoring seems to be important because patients and physicians may not always recognize asthma symptoms or their severity. However, the additional value of monitoring peak flow and symptoms in guiding asthma therapy has not been well established. Furthermore, it can be questioned whether a treatment strategy which is solely based on optimizing symptoms and lung function leads to optimal control of asthma in each individual patient, since airway hyperresponsiveness (AHR) and airways inflammation may persist. The chronicity of such abnormalities may lead to airways remodelling, thereby worsening the long-term outcome of asthma. It has been shown that AHR provides prognostic information on asthma control, because it can serve as a valuable noninvasive surrogate marker of airways inflammation when added to the guides of asthma therapy. A limited increase in dose of inhaled steroids, instead of applying an increased dose indiscriminately, can be successfully tailored to the needs of the individual patient based on the degree of AHR. Such a strategy leads to both a better clinical outcome and a better histologic outcome. The present worldwide effort is to find alternative markers of airways inflammation in asthma that can be easily implemented in routine practice. In the near future, longitudinal studies will determine which parameter is potentially most useful in guiding asthma management.     

Understanding the Regulatory Roles of Natural Killer T Cells in Rheumatoid Arthritis: T Helper Cell Differentiation Dependent or Independent?

Rheumatoid arthritis (RA) is the most common chronic systemic autoimmune disease. This disease is thought to be caused by pathogenic T cells. Th1, Th2, Th17 and Treg cells have been implicated in the pathogenesis of RA. These Th cells differentiate from CD4+ T cells primarily due to the effects of cytokines. Natural killer T (NKT) cells are a distinct subset of lymphocytes that can rapidly secrete massive amount of cytokines, including IL‐2, IL‐4, IL‐12 and IFN‐γ. Numerous studies showed that NKT cells can influence the differentiation of CD4+ T cells via cytokines in vitro. These findings suggest that NKT cells play an important role in RA by polarizing Th1, Th2, Th17 and Treg cells. In view of the complexity of RA, we discussed whether NKT cells really influence the development of RA through regulating the differentiation of Th cells.     

How do dendrites take their shape?

Recent technical advances have made possible the visualization and genetic manipulation of individual dendritic trees. These studies have led to the identification and characterization of molecules that are important for different aspects of dendritic development. Although much remains to be learned, the existing knowledge has allowed us to take initial steps toward a comprehensive understanding of how complex dendritic trees are built. In this review, we describe recent advances in our understanding of the molecular mechanisms underlying dendritic morphogenesis, and discuss their cell-biological implications.     

Regulatory T cells: magic bullets for immunotherapy?

In the past few years it has been become increasingly clear that T cells capable of actively suppressing immune responses are thought to be in part responsible for the maintenance of peripheral self tolerance. In healthy rodents and humans, CD4(+) T cells constitutively expressing the interleukin (IL)-2 receptor alpha-chain (CD25) are able to exert such suppressive function in vitro and in vivo. Despite great efforts in our understanding of the biology of such immunoregulatory T cells, there are still certain points incompletely understood. Although some authors suggest that immunoregulatory cytokines such as IL-10 or transforming growth factor-beta are critical for the suppressive effect of these cells, this is controversial and the exact molecular nature and the targets of suppression are largely unknown. Thus far, until regulatory T cells can be used for diagnostic or therapeutic purposes many questions have to be answered. In this review we summarize the current knowledge on the function and properties of this T cell subset and discuss their potential role in human autoimmune or chronic inflammatory diseases.     

How do CD4+CD25+ regulatory T cells control autoimmunity?

Any scientist opening up an immunology journal today will observe immediately that suppressor T cells, renamed 'regulatory T cells' (Tregs) have become a central concept in the immunology lexicon. Hundreds of Treg publications over the past few years have validated the existence of this unique T cell lineage armed with an ability to regulate autoimmunity. The CD4(+)CD25(+)Foxp3(+) Treg subset develops in the thymus, can be induced in the periphery during the course of normal immune responses and utilizes a T cell repertoire skewed towards autoantigens. Despite these advances, however, there is still controversy over their mechanism of action. This confusion stems from the differences observed in in vitro versus in vivo studies. Recent in vivo analyses support a model in which Tregs directly or indirectly alter the activation and differentiation of pathogenic T cells through an effect on antigen presenting cells.     

IL-9 Contributes to Immunosuppression Mediated by Regulatory T Cells and Mast Cells in B-Cell Non-Hodgkin’s Lymphoma

It has been known that regulatory T (Treg) cells and mast cells (MCs) are involved in tumor immunity regulation, but the exact roles and mechanisms of Treg cells and MCs in B-cell non-Hodgkin’s lymphoma (NHL) are incompletely defined. In the present study, we found that the number of Foxp3⁺ Treg cells and CD117⁺ MCs increased in B-cell NHL patients. Concomitantly, a high level of interleukin (IL)-9 was observed in the sera from B-cell NHL patients. Neutralizing IL-9 significantly inhibited tumor growth in the lymphoma model of murine, and this process was associated with down-regulation of Treg cells and MCs. Furthermore, IL-9 was also demonstrated to induce expression of MC-related genes and proliferation of MCs from the bone marrow stem cells. Collectively, our results indicate that Treg cell and MCs are involved in immunosuppression in B-cell NHL, and IL-9 is a key mediator of Treg cells and MCs in that process. These findings provide novel insight for the pathogenesis and possible therapeutic strategy of B-cell NHL.     

(How) do aluminium adjuvants work?

The aluminium compounds, originally identified as adjuvants over 70 years ago, remain unique in their widespread application to human vaccines. Given this history, it is surprising that the physicochemical interactions between aluminium compounds and antigens are relatively poorly understood. This has clearly been a contributing factor to vaccine failures, for example, through inappropriate selection of aluminium species or buffers. Similarly, the mechanism(s) of action of aluminium adjuvants are relatively unstudied, although it appears that these agents fail to fit within the current principles underlying activation of the immune response. This review aims to examine recent developments in our understanding of the physicochemical and biological aspects of research into aluminium adjuvants.     

How do DCs interact with intestinal antigens?

Recent evidence demonstrates that dendritic cells (DCs) can insert dendrites between the epithelial cells that form the barrier protecting the body from the gut contents. Although first observed almost a decade ago, this is a controversial area of DC biology and the physiological importance of this phenomenon is only now being clarified. A recent study by Niess and colleagues shows that this behaviour enables efficient sampling of both invasive and non-invasive bacteria and might enhance the ability of an organism to resist infections by a pathogenic strain of Salmonella.