Anti-CD3 inhibits circulatory and tissue-resident memory CD4 T cells that drive asthma exacerbations in mice.

Background: Exacerbations of asthma are thought to be strongly dependent on reactivation of allergen-induced lung tissue-resident and circulatory memory CD4 T cells. Strategies that broadly inhibit multiple T cell populations might then be useful to limit asthma. Accordingly, we tested whether targeting CD3 during exposure to inhaled allergen could prevent the accumulation of lung-localized effector memory CD4 T cells and block exacerbations of asthmatic inflammation.

Developmentally distinct CD4 T lineages shape the CD8 T cell response to acute infection.

SignificanceThe CD4 T response following acute infection is heterogeneous and deploys two distinct modes of suppression coinciding with initial pathogen exposure and resolution of infection. This bimodal suppression of CD8 T cells during priming and contraction is mediated by separate T lineages. These findings make a significant contribution to our understanding of the functional plasticity inherent within T, which allows these cells to serve as a sensitive and dynamic cellular rheostat for the immune system to prevent autoimmune pathology in the face of inflammation attendant to acute infection, enable expansion of the pathogen-specific response needed to control the infection, and reestablish immune homeostasis after the threat has been contained.

TWEAK functions with TNF and IL-17 on keratinocytes and is a potential target for psoriasis therapy.

TNF and IL-17 are two cytokines that drive dysregulated keratinocyte activity, and their targeting is highly efficacious in patients with psoriasis, but whether these molecules act with other inflammatory factors is not clear. Here, we show that mice having a keratinocyte-specific deletion of Fn14 (), the receptor for the TNF superfamily cytokine TWEAK (), displayed reduced imiquimod-induced skin inflammation, including diminished epidermal hyperplasia and less expression of psoriasis signature genes. This corresponded with Fn14 being expressed in keratinocytes in human psoriasis lesions and TWEAK being found in several subsets of skin cells.

Combination blockade of OX40L and CD30L inhibits allergen-driven memory T2 cell reactivity and lung inflammation.

Background: The selective reduction of memory T2 cell responses could be key to affording tolerance and protection from the recurrence of damaging allergic pathology.

Objective: We asked whether TNF family costimulatory molecules cooperated to promote accumulation and reactivity of effector memory CD4 T cells to inhaled complex allergen, and whether their neutralization could promote airway tolerance to subsequent reexposure to allergen.

Methods: Mice were sensitized intraperitoneally or intranasally with house dust mite and challenged with intranasal allergen after memory had developed.

Clearance of apoptotic cells by lung alveolar macrophages prevents development of house dust mite-induced asthmatic lung inflammation.

Background: Poor clearance of apoptotic cells has been suggested to contribute to severe asthma, but whether uptake of apoptotic cells by lung phagocytes might dampen house dust mite (HDM)-induced lung inflammation has not been shown.

Objectives: This study investigated whether apoptotic cell engulfment in the murine lung impacts the development of allergen-induced asthmatic airway inflammation and which immune modulating mechanisms were activated.

Methods: Apoptotic cells were infused into the lungs of mice challenged with HDM allergen and lung inflammation, expression of suppressive molecules, and induction of regulatory T cells were monitored.

The Transcription Factor T-Bet Is Regulated by MicroRNA-155 in Murine Anti-Viral CD8 T Cells SHIP-1.

We report here that the expression of the transcription factor T-bet, which is known to be required for effector cytotoxic CD8 T lymphocytes (CTL) generation and effector memory cell formation, is regulated in CTL by microRNA-155 (miR-155). Importantly, we show that the proliferative effect of miR-155 on CD8 T cells is mediated by T-bet. T-bet levels in CTL were controlled by miR-155 SH2 (Src homology 2)-containing inositol phosphatase-1 (SHIP-1), a known direct target of miR-155, and SHIP-1 directly downregulated T-bet.

TNF activity and T cells.

TNF (tumor necrosis factor) is both a pro-inflammatory and anti-inflammatory cytokine that is central to the development of autoimmune disease, cancer, and protection against infectious pathogens. As well as a myriad other activities, TNF can be a product of T cells and can act on T cells. Here we review old and new data on the importance of TNF produced by T cells and how TNF signaling via TNFR2 may directly impact alternate aspects of T cell biology.

Rapid Evolution of the CD8+ TCR Repertoire in Neonatal Mice.

Currently, there is little consensus regarding the most appropriate animal model to study acute infection and the virus-specific CD8(+) T cell (CTL) responses in neonates. TCRβ high-throughput sequencing in naive CTL of differently aged neonatal mice was performed, which demonstrated differential Vβ family gene usage. Using an acute influenza infection model, we examined the TCR repertoire of the CTL response in neonatal and adult mice infected with influenza type A virus.

Phosphatidylinositol 3-Kinase p110δ Isoform Regulates CD8+ T Cell Responses during Acute Viral and Intracellular Bacterial Infections.

The p110δ isoform of PI3K is known to play an important role in immunity, yet its contribution to CTL responses has not been fully elucidated. Using murine p110δ-deficient CD8(+) T cells, we demonstrated a critical role for the p110δ subunit in the generation of optimal primary and memory CD8(+) T cell responses. This was demonstrated in both acute viral and intracellular bacterial infections in mice.

Acute exposure to ZnO nanoparticles induces autophagic immune cell death.

The increasing risk of incidental exposure to nanomaterials has led to mounting concerns regarding nanotoxicity. Zinc oxide nanoparticles (ZnO NPs) are produced in large quantities and have come under scrutiny due to their capacity to cause cytotoxicity in vitro and potential to cause harm in vivo. Recent evidence has indicated that ZnO NPs promote autophagy in cells; however, the signaling pathways and the role of ion release inducing toxicity remain unclear.

Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection.

The role of Type I interferon (IFN) during pathogenic HIV and SIV infections remains unclear, with conflicting observations suggesting protective versus immunopathological effects. We therefore examined the effect of IFNα/β on T cell death and viremia in HIV infection. Ex vivo analysis of eight pro- and anti-apoptotic molecules in chronic HIV-1 infection revealed that pro-apoptotic Bak was increased in CD4+ T cells and correlated directly with sensitivity to CD95/Fas-mediated apoptosis and inversely with CD4+ T cell counts.

The microRNA miR-155 controls CD8(+) T cell responses by regulating interferon signaling.

We found upregulation of expression of the microRNA miR-155 in primary effector and effector memory CD8(+) T cells, but low miR-155 expression in naive and central memory cells. Antiviral CD8(+) T cell responses and viral clearance were impaired in miR-155-deficient mice, and this defect was intrinsic to CD8(+) T cells, as miR-155-deficient CD8(+) T cells mounted greatly diminished primary and memory responses. Conversely, miR-155 overexpression augmented antiviral CD8(+) T cell responses in vivo.

MicroRNAs: key components of immune regulation.

The regulation of gene expression at the posttranscriptional level has revealed important control levels for genes important to the immune system. MicroRNAs (miRNAs) are small RNAs that regulate gene expression by inhibiting protein translation or by degrading the mRNA transcript. A single miRNA can potentially regulate the expression of multiple genes and the proteins encoded.