Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

Neutrophil recruitment and function in health and inflammation

The impact of the gut microbiota on human health: an integrative view.

Epstein-Barr virus.

Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Here, we show that in response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells. Strikingly, CD8 memory T cells isolated from nonlymphoid tissues exhibited effector levels of lytic activity directly ex vivo, in contrast to their splenic counterparts. These results point to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection.

https://science.sciencemag.org/content/sci/291/5512/2413.full.pdf

Preferential Localization of Effector Memory Cells in Nonlymphoid Tissue

The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can mount resistance to reinfection, a phenomenon termed "trained immunity" or "innate immune memory." Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, new therapeutic strategies for the treatment of immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases.

http://science.sciencemag.org/content/sci/352/6284/aaf1098.full.pdf

Trained immunity: A program of innate immune memory in health and disease

Based on T cell subset depletion studies and the analysis of gene knockout mice, it is evident that CD8(+) T cells contribute to resistance against intracellular infections with certain viral, protozoan, and bacterial pathogens. Although they are known primarily for their capacity to kill infected cells, CD8(+) T cells elaborate a variety of effector mechanisms with the potential to defend against infection. Microbes use multiple strategies to cause infection, and the nature of the pathogenhost interaction may determine which CD8(+) T cell effector mechanisms are required for immunity. In this review, we summarize our current understanding of the effector functions used by CD8(+) T cells in resistance to pathogens. Analyses of mice deficient in perforin and/or Fas demonstrate that cytolysis is critical for immunity against some, but not all, infections and also reveal the contribution of cytolysis to the pathogenesis of disease. The role of CD8(+) T cell-derived cytokines in resistance to infection has been analyzed by systemic treatment with neutralizing antibodies and cytokine gene knockout mice. These studies are complicated by the fact that few, if any, cytokines are uniquely produced by CD8(+) T cells. Thus, the requirement for CD8(+) T cell- derived cytokines in resistance against most pathogens remains to be defined. Finally, recent studies of human CD8(+) T cells reveal the potential for novel effector mechanisms in resistance to infection.

CD8+ T cell effector mechanisms in resistance to infection.

All humans become infected with multiple herpesviruses during childhood. After clearance of acute infection, herpesviruses enter a dormant state known as latency. Latency persists for the life of the host and is presumed to be parasitic, as it leaves the individual at risk for subsequent viral reactivation and disease. Here we show that herpesvirus latency also confers a surprising benefit to the host. Mice latently infected with either murine gammaherpesvirus 68 or murine cytomegalovirus, which are genetically highly similar to the human pathogens Epstein-Barr virus and human cytomegalovirus, respectively, are resistant to infection with the bacterial pathogens Listeria monocytogenes and Yersinia pestis. Latency-induced protection is not antigen specific but involves prolonged production of the antiviral cytokine interferon-gamma and systemic activation of macrophages. Latency thereby upregulates the basal activation state of innate immunity against subsequent infections. We speculate that herpesvirus latency may also sculpt the immune response to self and environmental antigens through establishment of a polarized cytokine environment. Thus, whereas the immune evasion capabilities and lifelong persistence of herpesviruses are commonly viewed as solely pathogenic, our data suggest that latency is a symbiotic relationship with immune benefits for the host.

Herpesvirus latency confers symbiotic protection from bacterial infection

CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions.

Objectives Twenty-eight genetic loci are associated with serum urate levels in Europeans. Evidence for association with gout at most loci is absent, equivocal or not replicated. Our aim was to test the loci for association with gout meeting the American College of Rheumatology gout classification criteria in New Zealand European and Polynesian case-control sample sets. Methods 648 European cases and 1550 controls, and 888 Polynesian (Maāori and Pacific) cases and 1095 controls were genotyped. Association with gout was tested by logistic regression adjusting for age and sex. Power was adequate (>0.7) to detect effects of OR>1.3. Results We focused on 24 loci without previous consistent evidence for association with gout. In Europeans, we detected association at seven loci, one of which was the first report of association with gout ( IGF1R ). In Polynesian, association was detected at three loci. Meta-analysis revealed association at eight loci—two had not previously been associated with gout ( PDZK1 and MAF ). In participants with higher Polynesian ancestry, there was association in an opposing direction to Europeans at PRKAG2 and HLF ( HLF is the first report of association with gout). There was obvious inconsistency of gout association at four loci ( GCKR , INHBC , SLC22A11 , SLC16A9 ) that display very similar effects on urate levels. Conclusions We provide the first evidence for association with gout at four loci ( IGF1R , PDZK1 , MAF , HLF ). Understanding why there is lack of correlation between urate and gout effect sizes will be important in understanding the aetiology of gout.

https://ard.bmj.com/content/annrheumdis/75/1/124.full.pdf

Twenty-eight loci that influence serum urate levels: analysis of association with gout

Nearly all human beings, by the time they reach adolescence, are infected with multiple herpesviruses. At any given time, this family of viruses accounts for 35–40 billion human infections worldwide, making herpesviruses among the most prevalent pathogens known to exist. Compared to most other viruses, herpesviruses are also unique in that infection lasts the life of the host. Remarkably, despite their prevalence and persistence, little is known about how these viruses interact with their hosts, especially during the clinically asymptomatic phase of infection referred to as latency. This review explores data in human and animal systems that reveal the ability of latent herpesviruses to modulate the immune response to self and environmental antigens. From the perspective of the host, there are both potentially detrimental and surprisingly beneficial effects of this lifelong interaction. The realization that latent herpesvirus infection modulates immune responses in asymptomatic hosts forces us to reconsider what constitutes a ‘normal’ immune system in a healthy individual.

/pdf/immune-modulation-during-latent-herpesvirus-infection-5aigb7oojs.pdf

Douglas W. White

Papers

CD8+ T cell effector mechanisms in resistance to infection.

Herpesvirus latency confers symbiotic protection from bacterial infection

CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions.

Twenty-eight loci that influence serum urate levels: analysis of association with gout

Immune Modulation During Latent Herpesvirus Infection