Adaptive from Innate: Human IFN-γ+CD4+ T Cells Can Arise Directly from CXCL8-Producing Recent Thymic Emigrants in Babies and Adults.

We recently demonstrated that the major effector function of neonatal CD4+ T cells is to produce CXCL8, a prototypic cytokine of innate immune cells. In this article, we show that CXCL8 expression, prior to proliferation, is common in newly arising T cells (so-called "recent thymic emigrants") in adults, as well as in babies. This effector potential is acquired in the human thymus, prior to TCR signaling, but rather than describing end-stage differentiation, such cells, whether isolated from neonates or adults, can further differentiate into IFN-γ-producing CD4+ T cells. Thus, the temporal transition of host defense from innate to adaptive immunity is unexpectedly mirrored at the cellular level by the capacity of human innate-like CXCL8-producing CD4+ T cells to transition directly into Th1 cells

Inhibition of TNF Receptor Shedding by a Synthetic Matrix Metalloproteinase Inhibitor Paradoxical Effects of a Synthetic Metalloproteinase Inhibitor That Blocks Both P55 and P75 TNF Receptor Shedding and TNF ␣ Processing in RA Synovial Membrane Cell Cultu

Abstract We have previously hypothesized that the pro-inflammatory cytokine TNF ␣ has a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It mediates its effects by crosslinking surface p55 or p75 TNF receptors (TNF-R), which can be proteolytically cleaved to yield soluble fragments. Upon binding TNF ␣ soluble TNF-R (sTNF-R) can inhibit its function. We investigated the enzymatic nature of the proteases involved in TNF-R cleavage, and found that this process is blocked by a synthetic inhibitor of matrix metalloproteinase activity (MMP), BB-2275. Inhibition of TNF-R cleavage was observed in a number of different cell types, as detected by retention of surface bound TNF receptor and by less sTNF-R released into the cell supernatant. The augmentation of surface TNF-R expression was of biological relevance as TNF ␣ -mediated necrosis of human KYM.1D4 rhabdosarcoma cells was enhanced ‫ف‬ 15-fold in the presence of BB-2275. The addition of BB-2275 to rheumatoid synovial membrane cell cultures totally inhibited MMP activity and also significantly reduced the levels of soluble TNF ␣ ( P Ͻ 0.006), p55 sTNF-R ( P Ͻ 0.006), and p75 sTNF-R ( P Ͻ 0.004). Paradoxically, despite the reduction in soluble TNF ␣ levels, the production of IL-1 ␤ , IL-6, and IL-8, cytokines whose production was previously demonstrated to be inhibited by the addition of a neutralizing anti-TNF ␣ antibody were not down-regulated by BB-2275. These results raise the interesting possibility that a close relationship exists between the enzyme(s) which process membranebound TNF ␣ , and those involved in surface TNF-R cleavage. Furthermore our observations suggest that hydroxamate inhibitors of MMP activity which block TNF ␣ secretion and TNF-R cleavage may not modulate down-stream effects of TNF ␣ , and as such suggest that the precise specificity of these compounds will be highly relevant to their clinical efficacy in inflammatory diseases. ( J. Clin. Invest. 1996. 97: 2833-2841.) Key words: rheumatoid arthritis • tumor necrosis factor • TNF receptor • matrix metalloproteinas

Innate responsiveness of CD8 memory T-cell populations nonspecifically inhibits allergic sensitization

Background: Infection or stimulation of the innate immune system by nonspecific microbial antigens is thought to educate the immune system to respond appropriately to allergens, preventing allergy. Objective: To determine the immunologic pathways that might explain how infection/microbial exposure inhibits allergic sensitization. Methods: Immunologic studies of non-antigen-specific functions of CD8 memory cells, their maturation in vivo, and their effects in a mouse asthma model, to test the hypothesis that CD8 memory is shaped by innate immunity in a way that can inhibit allergic disease. Results: We found that CD8 memory T-cell (CD8 Tm) populations bridge innate and adaptive immunity by responding to either antigen or cytokines alone. CD8 Tm populations partially subvert the clonal selection process by activating their neighbors through induction of dendritic cell IL-12. Stimulation of innate or acquired immunity in the lung or gut causes expansion/maturation of CD8 Tm populations, which provide an early source of cytokines, enhance T1 immunity, and inhibit allergic sensitization and airway inflammation/hyperresponsiveness in a non-antigen-specific fashion. Conclusion: CD8 T-cell-mediated immune memory is long-lived and can retain its capacity for rapid cytokine release in a nonantigen-specific fashion. This novel type of memory enhances T1 over T2 immunity and prevents allergic sensitization after exposure to environmental antigens or infection

Neutrophils Dominate the Cervical Immune Cell Population in Pregnancy and Their Transcriptome Correlates With the Microbial Vaginal Environment

The cervicovaginal environment in pregnancy is proposed to influence risk of spontaneous preterm birth. The environment is shaped both by the resident microbiota and local inflammation driven by the host response (epithelia, immune cells and mucous). The contributions of the microbiota, metabolome and host defence peptides have been investigated, but less is known about the immune cell populations and how they may respond to the vaginal environment. Here we investigated the maternal immune cell populations at the cervicovaginal interface in early to mid-pregnancy (10–24 weeks of gestation, samples from N = 46 women), we confirmed neutrophils as the predominant cell type and characterised associations between the cervical neutrophil transcriptome and the cervicovaginal metagenome (N = 9 women). In this exploratory study, the neutrophil cell proportion was affected by gestation at sampling but not by birth outcome or ethnicity. Following RNA sequencing (RNA-seq) of a subset of neutrophil enriched cells, principal component analysis of the transcriptome profiles indicated that cells from seven women clustered closely together these women had a less diverse cervicovaginal microbiota than the remaining three women. Expression of genes involved in neutrophil mediated immunity, activation, degranulation, and other immune functions correlated negatively with Gardnerella vaginalis abundance and positively with Lactobacillus iners abundance; microbes previously associated with birth outcome. The finding that neutrophils are the dominant immune cell type in the cervix during pregnancy and that the cervical neutrophil transcriptome of pregnant women may be modified in response to the microbial cervicovaginal environment, or vice versa, establishes the rationale for investigating associations between the innate immune response, cervical shortening and spontaneous preterm birth and the underlying mechanisms

Cutting Edge: Regulator of G protein signaling-1 selectively regulates gut T cell trafficking and colitic potential

The Regulator of G Protein Signaling 1 [RGS1] gene is associated with celiac disease, multiple sclerosis (MS) and Type I diabetes (T1D), which are all T cell-mediated pathologies. And yet there is no reported analysis of RGS1 biology in human T cells. This study shows that RGS1 expression is substantially higher in T cells from human gut versus peripheral blood, and that this can be exaggerated in intestinal inflammation. Elevated RGS1 levels profoundly reduce T cell migration to lymphoid-homing chemokines, whereas RGS-1 depletion selectively enhances such chemotaxis in gut T cells, and impairs their colitogenic potential. These findings provide a revised framework in which to view the linkage of RGS1 to inflammatory disease

Receptor for Advanced Glycation End Products Contributes to Postnatal Pulmonary Development and Adult Lung Maintenance Program in Mice

The role of the receptor for advanced glycation end products (RAGE) in promoting inflammatory response through activation of NF-kB pathway is well established. Recent findings indicate that RAGE may have also regulative function in apoptosis, as well as in proliferation, differentiation and cell adhesion. Unlike other organs, lung tissue in adult age and during organ development shows relatively high levels of RAGE expression. Thus a role for the receptor in lung organogenesis and homeostasis may be supposed. To evaluate the role of RAGE in lung development and adult lung homeostasis we generated hemizygous and homozygous transgenic mice overexpressing human RAGE and analyzed their lungs from 4th postnatal day to adult age. Moderate RAGE hyper-expression during lung development influences the secondary septation resulting in an impairment of alveolar morphogenesis leading to significant changes in morphometric parameters such as air spaces number and size of alveolar ducts. An increase of alveolar cell apoptosis and a decrease of cell proliferation is demonstrated by TUNEL reaction, active caspase3 and Ki67 immunohistochemistry. Alteration in elastin organization and deposition, and in TGFβ expression is observed. In homozygous mice, the hyper-expression of RAGE results in histological changes resembling those characterizing human Bronchopulmonary Dysplasia (BPD). RAGE hyper-expression in adult lung is associated with an increase of the alveolar destructive index and a persistent inflammatory status leading to "destructive" emphysema. These results suggest an important role for RAGE in both alveolar development and lung homeostasis, and open new ways for working hypothesis on the pathogenesis of BPD and COPD