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The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days). Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells. This open chromatin profile at effector genes was maintained in memory CD8 T cells isolated even a decade after vaccination, indicating that these cells retain an epigenetic fingerprint of their effector history and remain poised to respond rapidly upon re-exposure to the pathogen. In vivo deuterium labelling reveals a quiescent population of long-lived human virus-specific memory CD8 T cells that maintain the epigenetic landscape of effector cells, which facilitates rapid responses to pathogen re-exposure. A pathogen to remember Memory cells protect against reinfection, or protect against infection after vaccination, but whether they are derived from naive or effector T cells is unknown. Rafi Ahmed and colleagues study the generation, maintenance and characteristics of long-lived memory CD8 T cells in humans after yellow fever vaccination and deuterium labelling. The study demonstrates that long-lived memory CD8 T cells are derived from cells that have divided extensively during the effector phase of the infection. Quiescent memory cells appear to revert to a naive phenotype but maintain an upregulated pattern of gene regulation that resembles effector T cells. In a second paper in this issue, Rafi Ahmed and colleagues examine changes in DNA methylation during effector and memory CD8 T cell differentiation, providing support for a model in which long-lived memory cells arise from a precursor of effector cells.

The antibody response elicited after immunization with vaccinia virus (VacV) is known to be sufficient to confer host protection against VacV or smallpox. In humans it has been shown that such anti-VacV antibody production can be sustained for decades. Nevertheless, little is known about the kinetics and the role in protection of the early antibody response after vaccination. In this study we identify VacV neutralizing IgM antibodies as early as 4 days after infection of C57BL/6 mice. Most of this IgM production is T cell dependent and predominantly independent of the germinal center reaction (SAP/SH2D1A independent). Importantly, the IgM neutralized both infectious forms of VacV: the intracellular mature virion (MV, IMV) and the extracellular enveloped virion (EV, EEV). Moreover, in mice primed with MHCII restricted peptides, an increase in the total VacV neutralizing antibody titers was seen, a large component of which was neutralizing IgM against the same protein from which the priming peptide was derived. To further demonstrate the biological relevance of this early neutralizing response, we examined anti-VacV antibodies in humans after vaccination. Human subjects could be divided into two groups early after immunization: IgG hi and IgG lo. VacV IgM neutralizing antibodies were detected in the IgG lo group. Taken together these results indicate that both in a small animal model and in humans an early neutralizing IgM response after VacV immunization is present and likely contributes to control of the infection prior to the development of a robust IgG response.

Systemic lupus erythematosus (SLE) is a CD4+ T cell–dependent, immune complex–mediated, autoimmune disease that primarily affects women of childbearing age. Generation of high-titer affinity-matured IgG autoantibodies, specific for double-stranded DNA and other nuclear antigens, coincides with disease progression. Current forms of treatment of SLE including glucocorticosteroids are often inadequate and induce severe side effects. Immunological approaches for treating SLE in mice using anti-CD4 mAb’s or CTLA4-Ig and anti-CD154 mAb’s have proven to be effective. However, like steroid treatment, these regimens induce global immunosuppression, and their withdrawal allows for disease progression. In this report we show that lupus-prone NZB × NZW F1 mice given three injections of anti-CD137 (4-1BB) mAb’s between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the mice’s lifespan from 10 months to more than 2 years. Autoantibody production in recipients was rapidly suppressed without inducing immunosuppression. Successful treatment could be traced to the fact that NZB × NZW F1 mice, regardless of their age or disease status, could not maintain pathogenic IgG autoantibody production in the absence of continuous CD4+ T cell help. Our data support the hypothesis that CD137-mediated signaling anergized CD4+ T cells during priming at the DC interface.

Systemic lupus erythematosus (SLE) is a CD4(+) T cell-dependent, immune complex-mediated, autoimmune disease that primarily affects women of childbearing age. Generation of high-titer affinity-matured IgG autoantibodies, specific for double-stranded DNA and other nuclear antigens, coincides with disease progression. Current forms of treatment of SLE including glucocorticosteroids are often inadequate and induce severe side effects. Immunological approaches for treating SLE in mice using anti-CD4 mAb's or CTLA4-Ig and anti-CD154 mAb's have proven to be effective. However, like steroid treatment, these regimens induce global immunosuppression, and their withdrawal allows for disease progression. In this report we show that lupus-prone NZB x NZW F(1) mice given three injections of anti-CD137 (4-1BB) mAb's between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the mice's lifespan from 10 months to more than 2 years. Autoantibody production in recipients was rapidly suppressed without inducing immunosuppression. Successful treatment could be traced to the fact that NZB x NZW F(1) mice, regardless of their age or disease status, could not maintain pathogenic IgG autoantibody production in the absence of continuous CD4(+) T cell help. Our data support the hypothesis that CD137-mediated signaling anergized CD4(+) T cells during priming at the DC interface.

Background Detections of influenza A subtype‐specific antibody responses are often complicated by the presence of cross‐reactive antibodies. We developed two novel multiplex platforms for antibody detection. The multiplexed magnetic fluorescence microsphere immunoassay (MAGPIX) is a high‐throughput laboratory‐based assay. Chembio Dual Path Platform (DPP) is a portable and rapid test that could be used in the field. Methods Twelve recombinant globular head domain hemagglutinin (GH HA1) antigens from A(H1N1)pdm09 (pH1N1), A(H2N2), A(H3N2), A(H5N1), A(H7N9), A(H9N2), A(H13N9), B/Victoria lineage, B/Yamagata lineage viruses, and protein A control were used. Human sera from U.S. residents either vaccinated (with H5N1 or pH1N1) or infected with pH1N1 influenza viruses and sera from live bird market workers in Bangladesh (BDPW) were evaluated. GH HA1 antigens and serum adsorption using full ectodomain recombinant hemagglutinins from A(pH1N1) and A(H3N2) were introduced into the platforms to reduce cross‐reactivity. Results Serum adsorption reduced cross‐reactivity to novel subtype HAs. Compared to traditional hemagglutination inhibition or microneutralization assays, when serum adsorption and the highest fold rise in signals were used to determine positivity, the correct subtype‐specific responses were identified in 86%‐100% of U.S. residents exposed to influenza antigens through vaccination or infection (N=49). For detection of H5N1‐specific antibodies in sera collected from BDPW, H5 sensitivity was 100% (six of six) for MAGPIX, 83% (five of six) for DPP, H5 specificity was 100% (15/15), and cross‐reactivity against other subtype was 0% (zero of six) for both platforms. Conclusion MAGPIX and DPP platforms can be utilized for high‐throughput and in‐field detection of novel influenza virus infections.

CD137 (4-1BB), is an inducible T-cell costimulatory receptor and a member of the tumor necrosis factor receptor (TNFR) superfamily. It is expressed on activated T cells and activated natural killer (NK) cells, but is constitutively expressed on a population of splenic dendritic cells (DCs). The natural counter receptor for CD137 is 4-1BB ligand, a member of the TNF superfamily that is weakly expressed on naïve or resting B cells, macrophages, and DCs. Upon activation, the level of 4-1BBL expression increases on these cells. In T cells CD137-induced signals lead to the recruitment of TRAF family members and activation of several kinases, including ASK-1, MKK, MAPK3/ MAPK4, p38, and JNK/SAPK. Kinase activation is then followed by the activation and nuclear translocation of several transcription factors, including ATF-2, Jun, and NF-kappaB. CD137-mediated T-cell costimulation as measured by enhanced proliferation and cytokine production can be induced by anti-CD137 monoclonal antibodies (MAbs) or by employing immobilized 4-1BB ligand. In addition to augmenting suboptimal TCR-induced proliferation, CD137-mediated signaling protects T cells, and in particular, CD8+ T cells from activation-induced cell death (AICD). Although studies with CD137-deficient or 4-1BBL-deficient mice failed to demonstrate any loss of essential immunological function, or other noteworthy deficits, we have found that 4-1BBL-deficient mice failed to generate a strong antiviral immune response following lymphocytic choriomeningitis virus (LCMV) peptide vaccination. We further found that although compromised, the immune response to LCMV vaccination in these mice could be fully restored by injecting them with anti-CD137 MAbs at the time of vaccination. Finally, we have found that injecting normal mice with anti-CD137 MAbs had profound effects on their ability to develop immune responses to allo- and autoantigens. The results of these studies discussed in this article provide a rationale for assessing the potential use of anti-CD137 MAbs for therapeutic purposes.

Whole genome doubling (WGD) is a frequent event in cancer evolution associated with chromosomal instability, metastasis, and poor prognosis. While the genomic consequences of WGD are well documented, the effects of non-genetic alterations that accompany WGD, such as changes to cell and nuclear size, on tetraploid (4N) cancer cell physiology are less understood. Here, we show that cell and nuclear volume do not always scale with DNA content after WGD in cancer cells, resulting in 4N cells that differ in size. We find that small size is associated with enhanced cell fitness, mitotic fidelity, and tumorigenicity in 4N cancer cells and with poor patient survival in WGD-positive human cancers. Overall, these results suggest that cell and nuclear size contribute to the tumorigenic potential of 4N cancer cells and could be an important prognostic marker in human tumors that undergo WGD.