Signals for antigen-independent differentiation of memory CD8+ T cells

Conventional CD8+ memory T cells develop upon stimulation with foreign antigen and provide increased protection upon re-challenge. Over the past two decades, new subsets of CD8+ T cells have been identified that acquire memory features independently of antigen exposure. These antigen-inexperienced memory T cells (TAIM) are described under several names including innate memory, virtual memory, and memory phenotype. TAIM cells exhibit characteristics of conventional or true memory cells, including antigen-specific responses. In addition, they show responsiveness to innate stimuli and have been suggested to provide additional levels of protection toward infections and cancer. Here, we discuss the current understanding of TAIM cells, focusing on extrinsic and intrinsic molecular conditions that favor their development, their molecular definitions and immunological properties, as well as their transcriptional and epigenetic regulation.

Context-dependent miR-21 regulation of TLR7-mediated autoimmune and foreign antigen driven antibody-forming cell and germinal center responses

MicroRNAs (miRNAs) are involved in healthy B cell responses and the loss of tolerance in systemic lupus erythematosus (SLE), though the role of many miRNAs remains poorly understood. Dampening miR-21 activity was previously shown to reduce splenomegaly and blood urea nitrogen levels in SLE-prone mice, but the detailed cellular responses and mechanism of action remains unexplored. Herein, using the TLR7 agonist imiquimod-induced SLE model, we observed that loss of miR-21 in Sle1b mice prevented the formation of plasma cells and autoantibody forming cells (AFC), without a significant effect on the magnitude of the germinal center (GC) response. We further observed reduced dendritic cell and monocyte numbers in the spleens of miR-21 deficient Sle1b (Sle1b.miR-21KO) mice that were associated with reduced interferon, proinflammatory cytokines, and effector CD4+ T cell responses. RNAseq analysis on B cells from Sle1b.miR-21KO mice revealed reduced activation and response to interferon and cytokine and target array analysis revealed modulation of numerous miR-21 target genes in response to TLR7 activation and type I interferon stimulation. Our findings in the B6.Sle1b.Yaa spontaneous model recapitulated the miR-21 role in TLR7-induced responses with an additional role in autoimmune GC and Tfh responses. Finally, immunization with T-dependent antigen revealed a role for miR-21 in foreign antigen driven GC and Ab, but not AFC responses. Our data suggest a potential multifaceted, context-dependent role for miR-21 in autoimmune and foreign antigen driven AFC and GC responses. Further study is warranted to delineate the cell-intrinsic requirements and mechanisms of miR-21 during infection and SLE development.Key PointsmiR-21 has context dependent effects on AFC and GC responsesmiR-21 promotes TLR7-driven autoimmunity with activation of multiple B cell pathwaysmiR-21 is required for optimal B cell responses to T-dependent foreign antigen

Strategies for Enhancement of Live-Attenuated Salmonella-Based Carrier Vaccine Immunogenicity

The use of live-attenuated bacterial vaccines as carriers for the mucosal delivery of foreign antigens to stimulate the mucosal immune system was first proposed over three decades ago. This novel strategy aimed to induce immunity against at least two distinct pathogens using a single bivalent carrier vaccine. It was first tested using a live-attenuated Salmonella enterica serovar Typhi strain in clinical trials in 1984, with excellent humoral immune responses against the carrier strain but only modest responses elicited against the foreign antigen. Since then, clinical trials with additional Salmonella-based carrier vaccines have been conducted. As with the original trial, only modest foreign antigen-specific immunity was achieved in most cases, despite the incorporation of incremental improvements in antigen expression technologies and carrier design over the years. In this review, we will attempt to deconstruct carrier vaccine immunogenicity in humans by examining the basis of bacterial immunity in the human gastrointestinal tract and how the gut detects and responds to pathogens versus benign commensal organisms. Carrier vaccine design will then be explored to determine the feasibility of retaining as many characteristics of a pathogen as possible to elicit robust carrier and foreign antigen-specific immunity, while avoiding over-stimulation of unacceptably reactogenic inflammatory responses.

İMMUNPROFILAKTIKANIN TƏŞKILININ ƏSASLARI, ONUN EFFEKTIVLIYININ VƏ TƏHLÜKƏSIZLIYININ QIYMƏTLƏNDIRILMƏSI

The purpose of this article is to investigate the growing number of viral diseases, to gather information on what measures should be taken against them and to educate the population. The immunological structure of the population is formed due to increased insensitivity to pathogenic microorganisms, which occurs through the formation of natural immunity (inherited or acquired as a result of an infectious process) and artificial immunity (created through immunoprophylaxis). The level of the immunological structure of the population affects the direction (trend) of the epidemic process. The higher the AID for a particular infectious disease, the lower the incidence, as well as the risk of group illnesses or outbreaks Key words: immunology, prophylaxis, natural immunity, artificial immunity, vaccination, vaccine, acquired immunity, serum, foreign antigen, organism, hereditary, physiological feature, anatomical feature

Introduction to the Principles of Immunology

This chapter discusses how the human immune system combats viruses, either by spontaneously eliminating infections or by becoming stimulated via vaccination to prevent viral diseases. The proteins in viruses and bacteria that trigger an immune response are called antigens or immunogens, and the result of a satisfactory immune response to these antigens is immunity—long-term protection from repeated disease caused by a specific type of virus or bacteria. Similarly, a vaccine primes the immune response by programming it to anticipate and resist future pathogens like those in that particular vaccine. The immune system has evolved to deal with enormous numbers and varieties of every conceivable foreign antigen. However, the immune system must discriminate between foreign antigens, such as viral proteins, that are non-self and those antigens that are self, one’s own proteins (i.e., hormones such as insulin and cell proteins that make up muscle or nerve cells). Ultimately, the success of this system defines an organism’s capacity for survival.

Recombinant vector vaccines and within-host evolution

Many recombinant vector vaccines are capable of replication within the host. They consist of a fully competent vector backbone engineered to express an antigen from a foreign transgene. From the perspective of viral replication, the transgene is not only dispensable but may even be intrinsically detrimental. Thus vaccine revertants that delete the transgene may evolve to dominate the within-host population and in doing so reduce the antigenicity of the vaccine. We apply mathematical and computational models to study this process, including the dynamics of vaccine and revertant growth plus the dynamics of innate and adaptive immunity. Although the selective basis of vaccine evolution is easy to comprehend, the immunological consequences are not. One complication is that, despite possible fitness differences between vaccine and revertant, the opportunity for vaccine evolution is limited by the short period of growth before the viral population is cleared. Even less obvious, revertantper sedoes not interfere with immunity to vaccine except as the revertant suppresses vaccine abundance; the magnitude of this interference depends on mechanisms and timing of viral suppression. Adaptive immunity targeting the foreign antigen is also a possible basis of vaccine inferiority, but it is not worsened by vaccine evolution. Overall, we find that within-host vaccine evolution can sometimes matter to the adaptive immune response targeting the foreign antigen, but even when it does matter, simple principles of vaccine design and the control of inoculum composition can largely mitigate the effects.Author SummaryRecombinant vector vaccines are live replicating viruses that are engineered to carry extra genes derived from a pathogen – and these produce proteins against which we want to generate immunity. These genes may evolve to be lost during the course of replication within an individual, and there is a concern that this can severely limit the vaccine’s efficacy. The dynamics of this process are studied here with mathematical models. The potential for vaccine evolution is somewhat reduced by the short-term growth of the vaccine population before it is suppressed by the immune response. Even when within-host evolution can be a problem, the models show that increasing the vaccine inoculum size or ensuring that the inoculum is mostly pure vaccine can largely avoid the loss of immunity arising from evolution.

Antibody specificity and promiscuity

The immune system is capable of making antibodies against anything that is foreign, yet it does not react against components of self. In that sense, a fundamental requirement of the body's immune defense is specificity. Remarkably, this ability to specifically attack foreign antigens is directed even against antigens that have not been encountered a priori by the immune system. The specificity of an antibody for the foreign antigen evolves through an iterative process of somatic mutations followed by selection. There is, however, accumulating evidence that the antibodies are often functionally promiscuous or multi-specific which can lead to their binding to more than one antigen. An important cause of antibody cross-reactivity is molecular mimicry. Molecular mimicry has been implicated in the generation of autoimmune response. When foreign antigen shares similarity with the component of self, the antibodies generated could result in an autoimmune response. The focus of this review is to capture the contrast between specificity and promiscuity and the structural mechanisms employed by the antibodies to accomplish promiscuity, at the molecular level. The conundrum between the specificity of the immune system for foreign antigens on the one hand and the multi-reactivity of the antibody on the other has been addressed. Antibody specificity in the context of the rapid evolution of the antigenic determinants and molecular mimicry displayed by antigens are also discussed.