A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism . Previous studies showed that IL-2 is highly flexible 8,9 and exists in different conformations that favor either the high-affinity trimeric IL-2R or intermediate-affinity dimeric IL-2R, resulting in the activation of different immune cells 9 . This plasticity has complicated the use of the approved drug Proleukin at high doses to treat metastatic melanoma and renal cell carcinoma 10 , due to the role of IL-2 as an essential growth factor for T regs [11][12][13] . Moreover, adverse effects of high-dose IL-2 therapy have greatly limited its use 14,15 . Several studies have shown that low-dose IL-2 therapy preferentially activates T regs due to the constitutive high expression of IL-2Rα 16 and other cell-intrinsic factors that increase signal transduction sensitivity 17 . Treatment of mice and humans with low doses of IL-2 has been shown to ameliorate autoimmune diseases and graft-versus-host disease (GvHD) as well as delaying organ allograft rejection [18][19][20][21][22] . However, IL-2 therapy has some limitations, including difficulty in predicting the efficacious dose, off-target effects on different cell populations and a short in vivo half-life 23,24 . Thus, attempts have been made to engineer or modify the IL-2 structure to improve its therapeutic potential by modulating its ability to selectively target either T effs or T regs [25][26][27][28][29][30][31] . Selective antibodies against IL-2 can alter its conformation by binding a number of potential epitopes, thereby modifying the binding interaction of IL-2 to any of the IL-2R subunits and resulting in selective expansion of T regs or T eff cell subsets 32,33 . For example, it has been demonstrated that a rat anti-mouse IL-2 monoclonal antibody (JES6-1) can be administered in complex with wild-type mouse IL-2 and used to preferentially enhance T reg populations 26 . Binding of JES6-1 to IL-2 alters its conformation to lower the affinity of mIL-2 for CD25, such that CD25 high T regs compete favorably for IL-2 binding and expansion against T effs 33 . The therapeutic potential of IL-2 to selectively activate the tolerogenic immune response, combined with the imperative to develop a human T reg -selective IL-2 compound, led us to develop a mechanism-based screening strategy to identify human antibodies against human IL-2 that exhibit an in vivo T reg potentiation profile when complexed with hIL-2. This class of monoclonal antibody, exemplified by F5111.2, blocked IL-2Rβ binding and reduced IL-2Rα binding to IL-2, and, when administered in complex with hIL-2, preferentially promoted T reg expansion and was effective in models of autoimmune disease including type 1 diabetes and experimental autoimmune encephalomyelitis (EAE) in addition to GvHD. ResultsSelective IL-2 stimulation in T regs . To directly compare T reg and T eff sensitivity to IL-2, the pSTAT5 signaling response of T regs was analyzed in a mixed population of peripheral blood mononuclear cells (PBMCs).

Adaptive immune responses are defined as antigen-sensitization-dependent and antigen-specific responses leading to establishment of long-lived immunological memory. While natural killer (NK) cells have traditionally been considered cells of the innate immune system, mounting evidence in mice and non-human primates warrants reconsideration of the existing paradigm that B and T cells are the sole mediators of adaptive immunity. However, it is currently unknown whether human NK cells can exhibit adaptive immune responses. We therefore tested whether human NK cells mediate adaptive immunity to virally encoded antigens using humanized mice and human volunteers. We found that human NK cells displayed vaccination-dependent, antigen-specific recall responses in vitro, when isolated from livers of humanized mice previously vaccinated with human immunodeficiency virus (HIV)-encoded envelope protein. Furthermore, we discovered that large numbers of cytotoxic NK cells with a tissue-resident phenotype were recruited to sites of varicella-zoster virus (VZV) skin test antigen challenge in VZV-experienced human volunteers. These NK-mediated recall responses in humans occurred decades after initial VZV exposure, demonstrating that NK memory in humans is long-lived. Our data demonstrates that human NK cells exhibit adaptive immune responses upon vaccination or infection. The existence of human memory NK cells may allow for the development of vaccination-based approaches capable of establishing potent NK-mediated memory functions contributing to host protection.

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Graphical Abstract Highlights d IPEX mutation M370I leads to unrestrained Th2 immune response d M370I mutation generates Th2-like Treg cells expressing GATA3 and Th2 cytokines d M370I mutation induces de novo Foxp3 binding sites in the Th2 locus d M370I Treg cells have increased chromatin interaction at the Th2 locus

Influenza virus infection causes significant morbidity and mortality worldwide. Humans fail to make a universally protective memory immune response to influenza A. Hemagglutinin and Neuraminidase undergo antigenic drift and shift, resulting in new influenza A strains to which humans are naive. Seasonal vaccines are often ineffective and escape mutants have been reported to all treatments for influenza A. In the absence of a universal influenza A vaccine or treatment, influenza A will remain a significant threat to human health. The extracellular domain of the M2-ion channel (M2e) is an ideal antigenic target for a universal therapeutic agent, as it is highly conserved across influenza A serotypes, has a low mutation rate, and is essential for viral entry and replication. Previous M2e-specific monoclonal antibodies (M2e-MAbs) show protective potential against influenza A, however, they are either strain specific or have limited efficacy. We generated seven murine M2e-MAbs and utilized in vitro and in vivo assays to validate the specificity of our novel M2e-MAbs and to explore the universality of their protective potential. Our data shows our M2e-MAbs bind to M2e peptide, HEK cells expressing the M2 channel, as well as, influenza virions and MDCK-ATL cells infected with influenza viruses of multiple serotypes. Our antibodies significantly protect highly influenza A virus susceptible BALB/c mice from lethal challenge with H1N1 A/PR/8/34, pH1N1 A/CA/07/2009, H5N1 A/Vietnam/1203/2004, and H7N9 A/Anhui/1/2013 by improving survival rates and weight loss. Based on these results, at least four of our seven M2e-MAbs show strong potential as universal influenza A treatments. IMPORTANCE Despite a seasonal vaccine and multiple therapeutic treatments, Influenza A remains a significant threat to human health. The biggest obstacle is producing a vaccine or treatment for influenza A is their universality or efficacy against not only seasonal variances in the influenza virus, but also against all human, avian, and swine serotypes and, therefore, potential pandemic strains. M2e has huge potential as a target for a vaccine or treatment against influenza A. It is the most conserved external protein on the virus. Antibodies against M2e have made it to clinical trials, but not succeeded. Here, we describe novel M2e antibodies produced in mice that are not only protective at low doses, but that we extensively test to determine their universality and found to be cross protective against all strains tested. Additionally, our work begins to elucidate the critical role of isotype for an influenza A monoclonal antibody therapeutic.

Purpose of Review Inflammatory signals have emerged as critical regulators of hematopoietic stem cell (HSC) function. Specifically, HSCs are highly responsive to acute changes in systemic inflammation and this influences not only their division rate but also their lineage fate. Identifying how inflammation regulates HSCs and shapes the blood system is crucial to understanding the mechanisms underpinning these processes, as well as potential links between them. Recent Findings A widening array of physiologic and pathologic processes involving heightened inflammation are now recognized to critically affect HSC biology and blood lineage production. Conditions documented to affect HSC function include not only acute and chronic infections but also autoinflammatory conditions, irradiation injury, and physiologic states such as aging and obesity. Summary Recognizing the contexts during which inflammation affects primitive hematopoiesis is essential to improving our understanding of HSC biology and informing new therapeutic interventions against maladaptive hematopoiesis that occurs during inflammatory diseases, infections, and cancer-related disorders.