Immunological Reviews最新文献

Accumulating evidence suggests that the immune system shows subtle but relevant differences between men and women. These differences may have an impact on cancer development and TME composition as well as responses to and adverse events elicited by immunotherapies. Several, albeit not all, clinical trials indicate a greater benefit from mono-immunotherapies over chemotherapies for male patients than for female patients, especially in non-small cell lung cancer and melanoma. Vice versa, female patients might benefit more from chemo-immunotherapies. In human as well as animal models, sex differences in cancer microenvironment composition were described, with partially divergent results. Sex-specific factors such as the levels of hormones, in particular testosterone and estrogen, or X- or Y-chromosome associated genes are likely to drive the observed differences, but are often confounded by external influences such as smoking behavior, diet, or UV exposure. Therefore, large clinical and mechanistic knowledge gaps remain regarding the influence of sex on cancer immunotherapies and strategies to optimize response in either sex. More clinical as well as experimental research in this field is required to close these knowledge gaps, and clinical trials should include large enough groups of male and/or female patients to allow robust sex-specific analyses.

The solid tumor microenvironment is a highly complex system shaped by dynamic interactions among immune and non-immune cell populations. The formation and organization of tumor-associated tertiary lymphoid structures (TA-TLS) have been observed in patients and linked to favorable prognosis and improved response to immunotherapy against a variety of cancers. Since then, preclinical mouse models have been extensively used to recapitulate TA-TLS formation, dissect the underlying mechanisms, and define the cellular interactions licensing TLS anti-tumor activity. Importantly, mouse models allow temporal dissection of TA-TLS development and progression, an aspect that is difficult to capture in humans where analyses are typically limited to endpoint surgical material. Although many steps leading to TLS formation mirror secondary lymphoid organogenesis, a lot is left unknown about what initiates TA-TLS formation and how these transient immune hubs can be manipulated therapeutically in cancer. Notably, while the persistence of TA-TLS in the tumor microenvironment provides a prolonged local anti-tumor immune response, it also enables the accumulation of regulatory cell components (regulatory T and B cells), thus making TLS the sites of both promotion and regulation of the ongoing endogenous immune response. The disruption of germinal centers and the progressive disaggregation of TLS following tumor regression and neoantigen clearance is also an important point where TLS differ from lymph nodes. Whether a form of local tissue memory exists following TA-TLS resolution, and whether this memory allows for faster and more efficient response upon tumor rechallenge, remain open questions. Different preclinical tumor models used to address these questions have their own strengths and limitations. These models are empowered by advances in high-dimensional imaging and spatial profiling technologies. The field of TA-TLS is now reaching a turning point, where emerging techniques promise to help shift from mostly descriptive studies toward a more mechanistic and functional understanding of TLS biology in cancer. Here, we review insights gained from mouse models into TA-TLS formation, persistence, and function, and highlight experimental and technological advances shaping future TLS research.

Tuberculosis (TB) remains a leading cause of infectious mortality worldwide, disproportionately affecting vulnerable populations and posing significant challenges for global health. Sex profoundly influences TB susceptibility, disease progression, treatment outcomes, and drug pharmacokinetics. While biological factors such as sex hormones and, to some extent, sex chromosomes are suspected drivers, the mechanisms behind these sex-based differences remain poorly understood. Emerging evidence indicates that males experience higher TB incidence, more severe disease, and worse treatment outcomes, including higher rates of relapse, treatment failure, and death, while females often achieve better drug exposure and display stronger immune responses. Differences in adverse drug reactions and pharmacokinetics also vary greatly by sex, suggesting potential for personalized, optimized therapy. These findings raise important questions: How does sex intersect with TB pathogenesis, drug metabolism, and resistance? Could integrating sex-specific strategies improve TB management and global control efforts? Understanding these differences is crucial to unravel the hidden drivers of TB vulnerability and to develop sex-specific, tailored therapies and precision interventions.

Sex is a fundamental yet underexplored determinant of human neuroinflammation. Across autoimmune, neurodegenerative, and post-infectious neurological syndromes, males and females exhibit consistent differences in disease vulnerability, progression, and immune tone. While sex hormones and chromosomes strongly shape immune development and function in health and disease, they do not fully explain the magnitude or disease-specific patterns of these disparities, nor do they provide sufficient mechanistic information for developing novel therapeutics. Emerging evidence suggests that sex-defining factors interact with age and environment to shape downstream metabolite-immune circuits, networks in which metabolic enzymes, metabolites, and immune cells tune inflammatory set points. Pathways spanning purine metabolism, glycolytic remodeling, lipid sensing, mitochondrial stress, and nucleic-acid sensing can recalibrate microglial activation thresholds, T-cell cytokine programs, innate type I interferon antiviral responses, and shape overall CNS resilience in a sex-dependent manner. Here, we synthesize mechanistic and human systems-level studies to propose an integrated framework in which sex-biased immunometabolism serves as a mechanistic bridge between biological sex and neuroimmune disease risk, progression, and responses to injury. We highlight key knowledge gaps and discuss how targeting metabolite-immune pathways may enable sex-informed biomarkers and therapeutic strategies in neuroinflammatory disease.

Immune responses are key in controlling viral infections such as HIV-1, which remains a global challenge to public health. X/Y-chromosome-encoded genes and sex steroid hormones can modulate immune cells and drive distinct patterns of gene and protein expression involved in antiviral function, impacting sex-dependent immune responses and altering the balance of specific immune pathways. These sex-specific differences in antiviral immune responses have significant consequences for the outcome of HIV-1 infection. A better understanding of sex differences in HIV-1-specific antiviral immunity is required to implement and develop new strategies for prevention, treatment and ultimately a functional cure against HIV-1. Here we review the impact of X- and Y-encoded genes and the role of sex steroid hormones on modulating antiviral immune responses against HIV-1 and the consequences for disease manifestations in people living with HIV-1.

Biological sex has a significant impact on how the immune system develops and responds to foreign and self-antigens. Sex differences exist in innate and adaptive immune cells, both at homeostasis and in the context of infection and inflammatory diseases such as asthma, cancer, and autoimmune disorders. Women generate stronger immune responses and are more susceptible to developing autoimmune conditions, while males are more prone to acute viral infections and developing certain cancers. Some immunological differences persist throughout life, while others emerge only after puberty and before reproductive senescence. Additionally, environmental exposures can affect the influence of biological sex in regulating immune function. This is particularly pertinent at mucosal surfaces such as the lungs, where lung immune defenses are constantly exposed to foreign material during respiration. Consequently, environmental factors together with genetics, age and sex hormones play a vital role in governing lung tissue immune responses between the sexes. In this context, we highlight studies that support the need for considering sex as an important biological variable in lung immunological research. This knowledge will provide a benchmark for understanding sex-driven immunological mechanisms that underpin disease development and may inform new avenues targeted for generating sex-specific therapies in lung disease.

The thymus is emerging as a model for studying organ regeneration and stem cell biology. While research has long focused on how antigen-presenting cells shape the T cell repertoire, recent discoveries unveil a far richer cellular landscape that challenges long-held views of thymus structure and function. This review traces the history of early thymic reconstitution assays, the paradigm of clonal stem cells and serial transplantation, assessing evidence for “stemness” within the thymus. A key focus is the paradox that an involuting thymus retains cells able to expand in culture and reconstitute organ function. We differentiate embryonic/fetal thymus development from postnatal homeostasis, emphasizing how the potency of epithelial progenitor/stem cells shifts with age or upon injury. The role of mesenchymal/interstitial cells and the extracellular milieu is considered alongside advances in organ reconstruction. We outline major unsolved questions in the field: thymus regeneration after childhood; the minimal components required to generate functional naïve T cells outside the body; and the potential of next-generation humanized mouse models to interrogate immune tolerance and novel immunotherapies. We argue that thymus research is entering a new era, one in which understanding and harnessing thymus regenerative potential could yield transformative advances in both basic science and clinical applications.

Urinary tract infections possess substantial sex disparities in the incidence, immune response, and progression of infection. Some of these distinctions may be due to sexual dimorphism in mucosal barriers or sex differences in the initial immune response to infection. Mucosal organs are protected by a mucus barrier, however, there is little knowledge of the impact of biological sex on this layer in homeostasis and infection. Notably, despite the incidence of infection, there is a paucity of even fundamental research on bladder mucus in homeostasis and infectious disease. When bacteria encounter mucosal epithelia, they must bind and potentially invade these surfaces to initiate an infection. Whether differences in mucosal epithelia have an impact on bacterial-epithelial interactions between the sexes is not known. When bacteria are sensed by the host, they initiate transcription factor activation, which may differ by sex of the host. Finally, sex steroid hormone receptor signaling likely also impacts innate immunity between the sexes, leading to the divergence between the sexes observed in mucosa infection.