Interleukin-10 (IL-10) is arguably the most potent anti-inflammatory cytokine. It is produced by almost all the innate and adaptive immune cells. These cells also serve as its targets, indicating that IL-10 secretion and action is highly regulated and perhaps compartmentalized. Consistent with this notion, various efforts directed at systemic administration of IL-10 to modulate autoimmune diseases (type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis) have produced conflicting and largely inconsequential effects. On the other hand, IL-10 can promote humoral immune responses, enhancing class II expression on B cells and inducing immunoglobulin (Ig) production. Consequently, the high IL-10 level in systemic lupus erythematosus (SLE) patients is considered pathogenic and its blockade ameliorates the disease. In this perspective, we review preclinical findings and results of recent clinical studies using exogenous IL-10 to treat the aforementioned autoimmune diseases. In addition, given the limited success of IL-10 supplementation, we suggest that future studies should be expanded beyond modulating the delivery modes to include developing new strategies to protect and replenish the endogenous sources of IL-10. As an example, we provide evidence that aberrant Fas-mediated deletion of IL-10-producing B cells subverts the immunoregulatory role of IL-10 in autoimmune diabetes and that modulation of the Fas pathway preserves the IL-10-producing B cells and completely protects NOD mice from developing the disease.

ABSTRACT

CD4−CD8− double negative (DN) αβ T cells are legitimate components of the normal immune system. However, they are poorly understood and largely ignored by immunologists because of their historical association with the lymphoproliferation that occurs in mice (lpr and gld) and humans (ALPS patients) with impaired Fas-mediated apoptosis where they are considered abnormal T cells. We believe that the traditional view that DN T cells that cause lymphoproliferation (hereafter referred to as lpr DN T cells) are CD4 and CD8 T cells that lost their coreceptor, conceived more than two decades ago, is flawed and that conflating lpr DN T cells with DN T cells found in normal immune system (hereafter referred to as nDN T cells) is unnecessarily dampening interest of this potentially important cell type. To begin rectifying these misperceptions, we will revisit the traditional view of lpr DN T cells and show that it does not hold true in light of recent immunological advances. In lieu of it, we offer a new model proposing that Fas-mediated apoptosis actively removes normally existing DN T cells from the periphery and that impaired Fas-mediated apoptosis leads to accumulation of these cells rather than de novo generation of DN T cells from activated CD4 or CD8 T cells. By doing so, we hope to provoke a new discussion that may lead to a consensus about the origin of lpr DN T cells and regulation of their homeostasis by the Fas pathway and reignite wider interest in nDN T cells.

Summary Invariant natural killer T (iNKT) cells recognize glycolipids as antigens and diversify into NKT1 (IFN-γ), NKT2 (IL-4), and NKT17 (IL-17) functional subsets while developing in the thymus. Mechanisms that govern the balance between these functional subsets are poorly understood due partly to the lack of distinguishing surface markers. Here we identified the heparan sulfate proteoglycan syndecan-1 (sdc1) as a specific marker of naïve thymic NKT17 cells and that sdc1 deficiency significantly increased thymic NKT17 cells at the expense of NKT1 cells, leading to impaired iNKT cell-derived IFN-γ, both in vitro and in vivo. Using surface expression of sdc1 to identify NKT17 cells, we confirmed differential tissue localization and interstrain variability of NKT17 cells and uncovered that NKT17 cells expressed high TCRβ, preferentially use Vβ8, and display high sensitivity to ɑ-GalCer than to CD3/CD28 stimulation. These findings provide a novel non-invasive simple method for identification and viable sorting of naïve NKT17 cells from unmanipulated mice and suggest that sdc1 expression negatively regulates homeostasis iNKT cells. In addition, they lay the groundwork for investigating the mechanisms by which sdc1 regulates NKT17 cells.

Intermittent fasting blunts inflammation in asthma 1 and rheumatoid arthritis 2 , suggesting that fasting may be exploited as an immune-modulatory intervention. However, mechanisms underpinning anti-inflammatory effects of fasting remain poorly characterized 3 , 4 , 5 . Here, we show that fasting in humans is sufficient to blunt CD4 + T helper cell responsiveness. RNA-seq and flow cytometric immunophenotyping of peripheral blood mononuclear cells (PBMCs) from volunteers subjected to overnight or 24-hour fasting, and 3-hours of refeeding implicate that fasting blunts CD4 + T helper cell activation and differentiation. Transcriptomic analysis reveal that the longer fast-duration has a more robust effect on CD4 + T cell biology. Through bioinformatic analyses, we identify the transcription factor FOXO4 and its canonical target FKBP5 as a potential fasting-responsive regulatory axis. Genetic gain- or loss-of-function of FOXO4 and FKBP5 is sufficient to modulate Th1 and Th17 cytokine production. Moreover, we find that fasting-induced or genetic overexpression of FOXO4 and FKBP5 is sufficient to downregulate mTORC1 signaling and suppress STAT1/3 activation. Our results identify FOXO4-FKBP5 as a novel fasting-induced, STAT-mediated, regulatory pathway to blunt human CD4 + T helper cell responsiveness.

Th17 cells are a discrete subset of T cell subpopulation, which produce IL-17 and certain other pro-inflammatory cytokines. A regulatory role of Th17 cells have been proposed in several autoimmune diseases including psoriasis, psoriatic arthritis (PsA), ankylosing spondylitis (AS), rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis. Psoriatic disease is an autoimmune disease which mainly involves skin and joints. Until recently, psoriasis and PsA were thought to be Th1 mediated disease, but after the discovery of IL-17 and IL-17 knockout animal studies as well as human experimental data indicate a crucial role of the Th17 cells in the pathogenesis of psoriasis and PsA. Our research group have not only found abundance of CD4(+)IL-17(+) T cells, mainly the memory phenotype (CD4RO(+)CD45RA(-)CD11a(+)) in the synovial fluid, but also have shown the existence of a functional IL-17 receptor in synovial fibroblast of psoriatic arthritis patients. Similarly, both animal and human studies indicate a regulatory role of the Th17 cells in AS; most critical observations are that Th17 cytokines (IL-17 and IL-22) can contribute to bone erosion, osteitis and new bone formation the hall mark skeletal features associated with the pathophysiology of AS. In this review article, we have discussed the contributing role of the IL-23/IL-17 axis in the pathogenesis of PsA and AS.

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No licensed vaccine exists against visceral leishmaniasis (VL), a disease caused by the Leishmania donovani parasite. We have previously reported both macrophages and dendritic cells play important role in the protection induced by a live attenuated centrin gene-deleted L. donovani (LdCen 2/2 ) parasite vaccine. The role of neutrophils in orchestrating the initial innate response to pathogens is widely recognized. To investigate the early interaction of LdCen 2/2 with neutrophils, we immunized mice intradermally in the ear pinna with LdCen 2/2 . Compared with LdWT infection, LdCen 2/2 parasites induced higher recruitment of neutrophils to the ear dermis and ear draining lymph nodes (dLN) as early as 6-18 h after immunization, which were predominantly proinflammatory in nature. Neutrophils from ear dLN of LdCen 2/2 -immunized mice exhibited heightened expression of costimulatory molecules and attenuated expression of coinhibitory molecules necessary for higher T cell activation. Further phenotypic characterization revealed heterogeneous neutrophil populations containing Na and Nb subtypes in the ear dLN. Of the two, the parasitized Na subset from LdCen 2/2 -immunized mice exhibited much stronger Ag-specific CD4 + T cell proliferation ex vivo. Adoptive transfer of neutrophils bearing LdCen 2/2 parasites induced an increased Th1 response in naive mice. Importantly, neutrophil depletion significantly abrogated Ag-specific CD4 + T cell proliferation in LdCen 2/2 -immunized mice and impaired protection against virulent challenge. Conversely, replenishing of neutrophils significantly restored the LdCen 2/2 -induced host-protective response. These results suggest that neutrophils are indispensable for protective immunity induced by LdCen 2/2 parasite vaccine.