Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis.

Background: Differences in immune responses between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect women, such as multiple sclerosis (MS). MS manifests in more than twice as many women, making sex one of the most important risk factor. However, it is incompletely understood which genes contribute to sex differences in autoimmune incidence.

Magnitude of Type I Interferon Responses by Plasmacytoid Dendritic Cells After TLR7 Stimulation Is Associated With Human Immunodeficiency Virus Type 1 (HIV-1) Reservoir Sizes in Cisgender Women With HIV-1 on Antiretroviral Therapy.

Human immunodeficiency virus type 1 (HIV-1) disease manifestations differ between cisgender women and men, including better control of viral replication during primary infection and less frequent residual HIV-1 replication on antiretroviral therapy (ART) in cisgender women with HIV-1 (WWH). Investigating plasmacytoid dendritic cell (pDC) functions and HIV-1 reservoir sizes in 20 WWH on stable ART, we observed inverse correlations between interferon-α and tumor necrosis factor responses of pDCs to Toll-like receptor 7/8 stimulation and intact/total proviral HIV-1 DNA levels. Additionally, ISG15 mRNA levels in peripheral blood mononuclear cells correlated with cytokine responses of pDCs.

Reduction of IFN-I responses by plasmacytoid dendritic cells in a longitudinal trans men cohort.

Type I interferons (IFN-I) are important mediators of antiviral immunity and autoimmune diseases. Female plasmacytoid dendritic cells (pDCs) exert an elevated capacity to produce IFN-I upon toll-like receptor 7 (TLR7) activation compared to male pDCs, and both sex hormones and X-encoded genes have been implicated in these sex-specific differences. Using longitudinal samples from a trans men cohort receiving gender-affirming hormone therapy (GAHT), the impact of testosterone injections on TLR7-mediated IFN-I production by pDCs was assessed.

Expanded ILC2s in human infant intestines promote tissue growth.

Early life is characterized by extraordinary challenges, including rapid tissue growth and immune adaptation to foreign antigens after birth. During this developmental stage, infants have an increased risk of immune-mediated diseases. Here, we demonstrate that tissue-resident, interleukin (IL)-13- and IL-4-producing group 2 innate lymphoid cells (ILC2s) are enriched in human infant intestines compared to adult intestines.

The co-inhibitory receptor TIGIT regulates NK cell function and is upregulated in human intrahepatic CD56 NK cells.

The crosstalk between NK cells and their surrounding environment is enabled through activating and inhibitory receptors, which tightly control NK cell activity. The co-inhibitory receptor TIGIT decreases NK cell cytotoxicity and is involved in NK cell exhaustion, but has also been associated with liver regeneration, highlighting that the contribution of human intrahepatic CD56 NK cells in regulating tissue homeostasis remains incompletely understood. A targeted single-cell mRNA analysis revealed distinct transcriptional differences between matched human peripheral blood and intrahepatic CD56 NK cells.

Assessment of escape from X chromosome inactivation and gene expression in single human immune cells.

X-chromosomal genes escaping from X chromosome inactivation (XCI) in immune cells can contribute to sex-specific differences in immune responses. This protocol describes the specific steps to determine escape from XCI and to simultaneously quantify mRNA expression of multiple genes at the single immune cell level using a single-nucleotide polymorphism approach. The protocol furthermore allows the analysis of allele-specific expression of X-chromosomal genes.

Androgens predispose males to monocyte-mediated immunopathology by inducing the expression of leukocyte recruitment factor CXCL1.

Hepatic amebiasis, predominantly occurring in men, is a focal destruction of the liver due to the invading protozoan Entamoeba histolytica. Classical monocytes as well as testosterone are identified to have important functions for the development of hepatic amebiasis in mice, but a link between testosterone and monocytes has not been identified. Here we show that testosterone treatment induces proinflammatory responses in human and mouse classical monocytes.

In-depth characterization of monocyte subsets during the course of healthy pregnancy.

Pregnancy represents an immunological challenge for the maternal immune system. Pregnancy augments innate immune responses, and particularly monocytes contribute to maintaining the balance between pro- and anti-inflammatory immune responses required for the successful sequence of distinct immunological phases throughout pregnancy. Nonetheless, studies that focus on the heterogeneity of monocytes and analyze the alteration of monocyte subsets in a longitudinal approach throughout healthy pregnancies have remained scarce.

The Transcription Factor Promyelocytic Leukemia Zinc Finger Protein Is Associated With Expression of Liver-Homing Receptors on Human Blood CD56 Natural Killer Cells.

The transcription factor promyelocytic leukemia zinc finger protein (PLZF) is involved in the development of natural killer (NK) cells and innate lymphoid cells, including liver-resident NK cells in mice. In human NK cells, the role of PLZF in liver residency is still unknown. Expression of PLZF in matched human peripheral blood- and liver-derived NK cells and the association of PLZF expression with surface molecules and transcription factors relevant for tissue residency were investigated using multiparameter flow cytometry and assessing single-cell messenger RNA (mRNA) levels.

rAAV Engineering for Capsid-Protein Enzyme Insertions and Mosaicism Reveals Resilience to Mutational, Structural and Thermal Perturbations.

Recombinant adeno-associated viruses (rAAV) provide outstanding options for customization and superior capabilities for gene therapy. To access their full potential, facile genetic manipulation is pivotal, including capsid loop modifications. Therefore, we assessed capsid tolerance to modifications of the structural VP proteins in terms of stability and plasticity.

Innate immune responses to toll-like receptor stimulation are altered during the course of pregnancy.

During pregnancy the maternal immune system has to develop tolerance towards the developing fetus. These changes in maternal immunity can result in increased severity of certain infections, but also in amelioration of autoimmune diseases. Pregnancy-related hormones have been suggested to play a central role in the adaptation of the maternal immune system, but their specific effects on innate immune function is not well understood.

Human pDCs display sex-specific differences in type I interferon subtypes and interferon α/β receptor expression.

The outcomes of many diseases differ between women and men, with women experiencing a higher incidence and more severe pathogenesis of autoimmune and some infectious diseases. It has been suggested that this is partially due to activation of plasmacytoid dendritic cells (pDCs), the main producers of interferon (IFN)-α, in response to toll-like receptor (TLR)7 stimulation. We investigated the induction of type I IFN (IFN-I) subtypes upon TLR7 stimulation on isolated pDCs.

The X awakens: multifactorial ramifications of sex-specific differences in HIV-1 infection.

Sex-specific differences have been described for a variety of infectious and autoimmune diseases. In HIV-1 infection women present with significantly lower viral loads during early infection, but during chronic infection women progress faster to AIDS for the same amount of viral replication. Recent studies have shown that sex differences during HIV-1 infection might also include the size of the latent viral reservoir, which represents a major obstacle towards a cure for HIV-1.

Characterization and inhibition of AF10-mediated interaction.

The non-random chromosomal translocations t(10;11)(p13;q23) and t(10;11)(p13;q14-21) result in leukemogenic fusion proteins comprising the coiled coil domain of the transcription factor AF10 and the proteins MLL or CALM, respectively, and subsequently cause certain types of acute leukemia. The AF10 coiled-coil domain, which is crucial for the leukemogenic effect, has been shown to interact with GAS41, a protein previously identified as the product of an amplified gene in glioblastoma. Using sequential synthetic peptides, we mapped the potential AF10/GAS41 interaction site, which was subsequently be used as scaffold for a library targeting the AF10 coiled-coil domain.

Modular adeno-associated virus (rAAV) vectors used for cellular virus-directed enzyme prodrug therapy.

The pre-clinical and clinical development of viral vehicles for gene transfer increased in recent years, and a recombinant adeno-associated virus (rAAV) drug took center stage upon approval in the European Union. However, lack of standardization, inefficient purification methods and complicated retargeting limit general usability. We address these obstacles by fusing rAAV-2 capsids with two modular targeting molecules (DARPin or Affibody) specific for a cancer cell-surface marker (EGFR) while simultaneously including an affinity tag (His-tag) in a surface-exposed loop.

A monoclonal antibody for the detection of SNAP/CLIP-tagged proteins.

SNAP/CLIP-tag technology is a novel approach that allows tagged proteins to be covalently coupled to diverse labels, such as fluorochromes and particles, using a convenient and specific enzymatic reaction. A monoclonal antibody (mAb) that binds to the SNAP/CLIP-tag would be useful to determine labeling efficiency, and to achieve reproducible detection in a variety of experimental formats. We therefore generated the murine mAb M2D11 by standard immunization and hybridoma technology.