Key Points Human CARD9 deficiency is characterized by a selective neutrophil killing defect, resulting in invasive candidiasis.

Cytotoxic CD4+CD28− T cells form a rare subset in human peripheral blood. The presence of CD4+CD28− cells has been associated with chronic viral infections, but how these particular cells are generated is unknown. In this study, we show that in primary CMV infections, CD4+CD28− T cells emerge just after cessation of the viral load, indicating that infection with CMV triggers the formation of CD4+CD28− T cells. In line with this, we found these cells only in CMV-infected persons. CD4+CD28− cells had an Ag-primed phenotype and expressed the cytolytic molecules granzyme B and perforin. Importantly, CD4+CD28− cells were to a large extent CMV-specific because proliferation was only induced by CMV-Ag, but not by recall Ags such as purified protein derivative or tetanus toxoid. CD4+CD28− cells only produced IFN-γ after stimulation with CMV-Ag, whereas CD4+CD28+ cells also produced IFN-γ in response to varicella-zoster virus and purified protein derivative. Thus, CD4+CD28− T cells emerge as a consequence of CMV infection.

IL-2 is crucial to T cell homeostasis, especially of CD4 + T regulatory cells and memory CD8 + cells, as evidenced by vigorous proliferation of these cells in vivo following injections of superagonist IL-2/anti-IL-2 antibody complexes. The mechanism of IL-2/anti-IL-2 antibody complexes is unknown owing to a lack of understanding of IL-2 homeostasis. We show that IL-2 receptor α (CD25) plays a crucial role in IL-2 homeostasis. Thus, prolongation of IL-2 half-life and blocking of CD25 using antibodies or CD25-deficient mice led in combination, but not alone, to vigorous IL-2-mediated T cell proliferation, similar to IL-2/anti-IL-2 antibody complexes. These data suggest an unpredicted role for CD25 in IL-2 homeostasis.CD25 | cytokine | cytokine/mAb complexes | T cell homeostasis | Fc receptor

Virus-specific CD8 ؉ T cells emerge after infection with herpesviruses and maintain latency to these persistent pathogens. It has been demonstrated that murine memory CD8 ؉ T-cell precursors specific for acute lymphocytic choriomeningitis virus express interleukin-7 receptor ␣ (IL-7R␣), and IL-7 is involved in maintaining memory populations after the clearance of antigen. To investigate whether human CD8 ؉ T cells reactive toward persistent viruses are maintained similarly, we analyzed IL-7R␣ expression and function on these virus-specific cells. During primary infection, all cytomegalovirus (CMV)-specific CD8 IntroductionAntiviral CD8 ϩ T-cell responses can be divided into 3 distinct phases. In the first phase, CD8 ϩ T cells clonally expand and differentiate into effector T cells that eliminate virus-producing cells. During the contraction phase that follows, most CD8 ϩ T cells die by apoptosis. Finally, in the third phase, the establishment of a CD8 ϩ T-cell memory pool takes place (for a review, see Kaech et al 1 ). The generation of a stable memory T-cell pool is a central feature of the adaptive immune system. On a second encounter with a virus, the immune system will be able to respond faster and more efficiently, thereby limiting cytopathic viral effects. This is achieved because the frequency of antigen-specific cells is greatly enhanced after the primary antigenic challenge, leading to higher numbers of responding T cells. 2 Moreover, on a per-cell basis, memory T cells are better equipped than naive T cells to respond to antigenic challenge because they can respond rapidly by producing in larger quantities important mediators such as interferon ␥ (IFN␥); regulated on activation, normal T-cell expressed and secreted (RANTES); and cytotoxic molecules perforin and granzyme. [3][4][5][6] Several studies have suggested that the expansion and differentiation program is imprinted shortly after antigenic stimulation. 7-9 Moreover, CD4 ϩ T-cell help, either during priming or during the memory phase, is required for CD8 ϩ T cells to be able to mount a proper secondary response. [10][11][12][13] The mechanism behind the development of long-lived memory cells is incompletely understood but depends on the survival of a few antigen-specific cells in the contraction phase. Two recent studies in mice infected with lymphocytic choriomeningitis virus (LCMV) or Listeria monocytogenes showed that during acute infection only a small population (5%-15%) of the effector cells expressed interleukin-7 receptor ␣ (IL-7R␣), whereas in the memory phase all specific CD8 ϩ T cells were IL-7R␣ ϩ . 14,15 The IL-7R␣ ϩ effector cells expressed higher levels of Bcl-2 than their IL-7R␣ Ϫ counterparts. Consistent with their antiapoptotic profile, IL-7R␣ ϩ cells had a superior recall response and showed enhanced proliferation in response to homeostatic signals compared with IL-7R␣ Ϫ cells. This indicated that IL-7R␣ ϩ effector T cells are the cells that survive and develop into long-lived memory CD8 ϩ T cells, which would make IL-7R␣ a us...

BackgroundThe genetic cause of primary immunodeficiency disease (PID) carries prognostic information.ObjectiveWe conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource–Rare Diseases cohort.MethodsIn the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses.ResultsBoth sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases.ConclusionWe show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

The lungs are frequently challenged by viruses, and resident CD8+ T cells likely contribute to the surveillance of these pathogens. To obtain insight into local T cell immunity to respiratory viruses in humans, we determined the specificity, phenotype, and function of lung-residing CD8+ T cells and peripheral blood CD8+ T cells in a paired analysis. The lung contained markedly higher frequencies of influenza (FLU)-specific and respiratory syncytial virus (RSV)-specific CD8+ T cells when compared with the circulation. This contrasted with an equal distribution of cytomegalovirus- and Epstein-Bar virus–specific CD8+ T cells. Noticeably, a substantial fraction of the lung-residing FLU- and RSV-specific CD8+ T cells had progressed to a relatively late differentiation phenotype, reflected by low expression of CD28 and CD27. Lung-derived FLU-specific CD8+ T cells had low activation requirements, as expansion of these cells could be initiated by cognate peptide in the absence of helper cell–derived signals. Thus, the human lung contains high numbers of differentiated FLU- and RSV-specific memory CD8+ T cells that can readily expand upon reexposure to virus. Resident lung T cells may provide immediate immunological protection against pulmonary virus infections.

Primary cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in recipients after solid organ transplantation (SOT). Widespread and prolonged use of antiviral drugs has changed the natural course of CMV disease by delaying its onset and causing drug resistance. CMV induces a strong cellular immune response, even in immunosuppressed patients, and has developed strategies to evade this immune surveillance. This review summarizes challenges in managing CMV infection in transplant recipients and highlights current insights in the cellular immune response against CMV.

Rotavirus vaccines (RVV) protect against childhood gastroenteritis caused by rotavirus (RV) but have decreased effectiveness in low- and middle-income settings. This proof-of-concept, randomized-controlled, open-label trial tested if microbiome modulation can improve RVV immunogenicity. Healthy adults were randomized and administered broad-spectrum (oral vancomycin, ciprofloxacin, metronidazole), narrow-spectrum (vancomycin), or no antibiotics and then vaccinated with RVV, 21 per group per protocol. Baseline anti-RV IgA was high in all subjects. Although antibiotics did not alter absolute anti-RV IgA titers, RVV immunogenicity was boosted at 7 days in the narrow-spectrum group. Further, antibiotics increased fecal shedding of RV while also rapidly altering gut bacterial beta diversity. Beta diversity associated with RVV immunogenicity boosting at day 7 and specific bacterial taxa that distinguish RVV boosters and RV shedders were identified. Despite the negative primary endpoint, this study demonstrates that microbiota modification alters the immune response to RVV and supports further exploration of microbiome manipulation to improve RVV immunogenicity.