TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation.

CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8+-exhausted T (Tex) cells expressing PD1, Lag-3, and Tim-3 inhibitory receptors. T cell-intrinsic, TCR-independent CD137 signaling stimulated the proliferation and the terminal differentiation of Tex precursor cells through a mechanism involving the RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. While Tex cell accumulation induced by prophylactic CD137 agonists favored tumor growth, anti-PD1 efficacy was improved with subsequent CD137 stimulation in pre-clinical mouse models. Better understanding of T cell exhaustion has crucial implications for the treatment of cancer and infectious diseases. Our results identify CD137 as a critical regulator of Tex cell expansion and differentiation that holds potential for broad therapeutic applications.

NK cells with adhesion defects and reduced cytotoxic functions are associated with a poor prognosis in Multiple Myeloma.

The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as Natural Killer (NK) cells that are mandatory for MM surveillance and therapy. In this study, we performed a single cell RNA sequencing analysis of NK cells from 10 MM patients and 10 age/sex matched healthy donors (HD) that revealed important transcriptomic changes in NK cell landscape affecting both the bone marrow and peripheral blood compartment. The frequency of mature cytotoxic "CD56dim" NK cell subsets was reduced in MM patients at the advantage of late-stage NK cell subsets expressing NFB and IFN-I inflammatory signatures. These NK cell subsets accumulating in MM patients were characterized by a low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced LFA-1 integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM infiltrating NK cells in a retrospective cohort of 177 MM patients from the IFM 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively impact patients' clinical outcome. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.

Targeting androgen signaling in ILC2s protects from IL-33-driven lung inflammation, independently of KLRG1.

BACKGROUND: Allergic asthma is more severe and frequent in women than in men. In male mice, androgens negatively control group 2 innate lymphoid cell (ILC2) development and function by yet unknown mechanisms. OBJECTIVES: We sought to investigate the impact of androgen on ILC2 homeostasis and IL-33-mediated inflammation in female lungs. We evaluated the role of androgen receptor (AR) signaling and the contribution of the putative inhibitory receptor killer cell lectin-like receptor G1 (KLRG1). METHODS: Subcutaneous pellets mimicking physiological levels of androgen were used to treat female mice together with mice expressing a reporter enzyme under the control of androgen response elements and mixed bone marrow chimeras to assess the cell-intrinsic role of AR activation within ILC2s. We generated KLRG1-deficient mice. RESULTS: We established that lung ILC2s express a functionally active AR that can be in vivo targeted with exogenous androgens to negatively control ILC2 homeostasis, proliferation, and function. Androgen signaling upregulated KLRG1 on ILC2s, which inhibited their proliferation on E-cadherin interaction. Despite evidence that KLRG1 impaired the competitive fitness of lung ILC2s during inflammation, KLRG1 deficiency neither alters in vivo ILC2 numbers and functions, nor did it lead to hyperactive ILC2s in either sexes. CONCLUSIONS: AR agonists can be used in vivo to inhibit ILC2 homeostatic numbers and ILC2-dependent lung inflammation through cell-intrinsic AR activation. Although androgen signals in ILC2s to upregulate KLRG1, we demonstrate that KLRG1 is dispensable for androgen-mediated inhibition of pulmonary ILC2s.

ILC precursors differentiate into metabolically distinct ILC1-like cells during Mycobacterium tuberculosis infection.

Tissue-resident innate lymphoid cells (ILCs) regulate tissue homeostasis, protect against pathogens at mucosal surfaces, and are key players at the interface of innate and adaptive immunity. How ILCs adapt their phenotype and function to environmental cues within tissues remains to be fully understood. Here, we show that Mycobacterium tuberculosis (Mtb) infection alters the phenotype and function of lung IL-18Rα+ ILC toward a protective interferon-γ-producing ILC1-like population. This differentiation is controlled by type 1 cytokines and is associated with a glycolytic program. Moreover, a BCG-driven type I milieu enhances the early generation of ILC1-like cells during secondary challenge with Mtb. Collectively, our data reveal how tissue-resident ILCs adapt to type 1 inflammation toward a pathogen-tailored immune response.

Sex hormone regulation of innate lymphoid cells.

Innate lymphoid cell (ILC) subsets at barrier surfaces contribute to maintain tissue homeostasis and appropriate responses to infection. ILCs respond to environmental factors produced by non-hematopoietic cells within tissues, but also circulating cytokines or dietary compounds which allow them to adapt to organ milieu. Among these extrinsic signals, evidence is emerging that sex steroid hormones may act in a cell-intrinsic manner to regulate the development, maintenance in tissues and effector functions of specific subsets of ILCs. Understanding the nature and molecular mechanisms of sex steroid hormone actions on ILCs is important to unravel the cause of sexual disparity in human diseases and could lead to new drug development for the treatment of chronic inflammatory diseases or cancers. This review discusses the recent development in our understanding of the cell-intrinsic actions of sex steroid hormones on ILCs and their consequences on tissue-specific immunity with a particular focus on group 2 innate lymphoid cells and NK cells.

[Sex-bias in allergic asthma: androgens and group 2 innate lymphoid cells]. / Biais de sexe dans l'asthme allergique - Androgènes et cellules lymphoïdes innées de groupe 2.

Allergic asthma is a chronic pulmonary inflammatory disease initiated by exposure to normally harmless allergens and marked by bronchial hyperreactivity. It affects more than 300 million people worldwide. Asthma often starts in childhood. Epidemiological studies show that there are sexual disparities in the prevalence and severity of asthma. Before the age of 10, the disease is more common in boys. This tendency reverses at puberty suggesting a regulating role of the sex hormones. In this synthesis, we summarize current knowledge on the role of sex hormones in allergic inflammation, with a particular focus on the impact of androgens on the development and function of recently introduced group 2 innate lymphoid cell subsets (ILC2) as critical actors in the initiation of allergic responses.♢.

Sex Differences in Asthma: A Key Role of Androgen-Signaling in Group 2 Innate Lymphoid Cells.

Infectious diseases, autoimmune diseases, and also allergy differentially affect women and men. In general, women develop strongest immune responses and thus the proportion of infected individuals and the severity of many viral, bacterial, or parasitic infections are increased in men. However, heightened immunity in women makes them more susceptible than men to autoimmunity and allergy. While sex differences in immunity are well documented, little is known about the cellular and molecular mechanisms underlying these immunological differences, particularly in allergic asthma. Asthma is a chronic inflammation of the airways mediated by exacerbated type 2 immune responses. Sex differences have been reported in the incidence, prevalence, and severity of asthma. While during childhood, males are more susceptible to asthma than females, there is a switch at the onset of puberty as for many other allergic diseases. This decrease of asthma incidence around puberty in males suggests that hormonal mediators could play a protective role in the susceptibility to allergic responses in male. Group 2 innate lymphoid cells (ILC2s) have recently emerged as critical players in the initiation of allergic responses, but also in the resolution of parasitic infection, through their capacity to rapidly and potently produce type 2 cytokines. This review will cover the current understanding of the impact of sex-linked factors in allergic inflammation, with a particular focus on the role of sex hormones on the development and function of tissue-resident ILC2s.

Androgen signaling negatively controls group 2 innate lymphoid cells.

Prevalence of asthma is higher in women than in men, but the mechanisms underlying this sex bias are unknown. Group 2 innate lymphoid cells (ILC2s) are key regulators of type 2 inflammatory responses. Here, we show that ILC2 development is greatly influenced by male sex hormones. Male mice have reduced numbers of ILC2 progenitors (ILC2Ps) and mature ILC2s in peripheral tissues compared with females. In consequence, males exhibit reduced susceptibility to allergic airway inflammation in response to environmental allergens and less severe IL-33-driven lung inflammation, correlating with an impaired expansion of lung ILC2s. Importantly, orchiectomy, but not ovariectomy, abolishes the sex differences in ILC2 development and restores IL-33-mediated lung inflammation. ILC2Ps express the androgen receptor (AR), and AR signaling inhibits their differentiation into mature ILC2s. Finally, we show that hematopoietic AR expression limits IL-33-driven lung inflammation through a cell-intrinsic inhibition of ILC2 expansion. Thus, androgens play a crucial protective role in type 2 airway inflammation by negatively regulating ILC2 homeostasis, thereby limiting their capacity to expand locally in response to IL-33.