Seminars in Immunology最新文献

Population aging, a pervasive global demographic trend, is anticipated to challenge health and social systems worldwide. This phenomenon is due to medical advancements enabling longer lifespans, with 20% of the US population soon to be over 65 years old. Consequently, there will be a surge in age-related diseases. Senescence, characterized by the loss of biological maintenance and homeostasis at molecular and cellular levels, either correlates with or directly causes age-related phenotypic changes. Decline of the immune system is a critical factor in the senescence process, with cancer being a primary cause of death in elderly populations. Chimeric antigen receptor (CAR) T cell therapy, an innovative approach, has demonstrated success mainly in pediatric and young adult hematological malignancies but remains largely ineffective for diseases affecting older populations, such as late-in-life B cell malignancies and most solid tumor indications. This limitation arises because CAR T cell efficacy heavily relies on the fitness of the patient-derived starting T cell material. Numerous studies suggest that T cell senescence may be a key driver of CAR T cell deficiency. This review examines correlates and underlying factors associated with favorable CAR T cell outcomes and explores potential experimental and clinically actionable strategies for T cell rejuvenation.

Vaccines are among the greatest inventions in medicine, leading to the elimination or control of numerous diseases, including smallpox, polio, measles, rubella, and, most recently, COVID-19. Yet, the effectiveness of vaccines varies among individuals. In fact, while some recipients mount a robust response to vaccination that protects them from the disease, others fail to respond. Multiple clinical and epidemiological factors contribute to this heterogeneity in responsiveness. Systems immunology studies fueled by advances in single-cell biology have been instrumental in uncovering pre-vaccination immune cell types and genomic features (i.e., the baseline immune state, BIS) that have been associated with vaccine responsiveness. Here, we review clinical factors that shape the BIS, and the characteristics of the BIS associated with responsiveness to frequently studied vaccines (i.e., influenza, COVID-19, bacterial pneumonia, malaria). Finally, we discuss potential strategies to enhance vaccine responsiveness in high-risk groups, focusing specifically on older adults.

It is well-known that the functioning of the immune system gradually deteriorates with age, and we are increasingly confronted with its consequences as the life expectancy of the human population increases. Changes in the T-cell pool are among the most prominent features of the changing immune system during healthy ageing, and changes in the naive T-cell pool in particular are generally held responsible for its gradual deterioration. These changes in the naive T-cell pool are thought to be due to involution of the thymus. It is commonly believed that the gradual loss of thymic output induces compensatory mechanisms to maintain the number of naive T cells at a relatively constant level, and induces a loss of diversity in the T-cell repertoire. Here we review the studies that support or challenge this widely-held view of immune ageing and discuss the implications for vaccination strategies.

Aging leads to a decline in immune cell function, which leaves the organism vulnerable to infections and age-related multimorbidities. One major player of the adaptive immune response are T cells, and recent studies argue for a major role of disturbed proteostasis contributing to reduced function of these cells upon aging. Proteostasis refers to the state of a healthy, balanced proteome in the cell and is influenced by synthesis (translation), maintenance and quality control of proteins, as well as degradation of damaged or unwanted proteins by the proteasome, autophagy, lysosome and cytoplasmic enzymes. This review focuses on molecular processes impacting on proteostasis in T cells, and specifically functional or quantitative changes of each of these upon aging. Importantly, we describe the biological consequences of compromised proteostasis in T cells, which range from impaired T cell activation and function to enhancement of inflamm-aging by aged T cells. Finally, approaches to improve proteostasis and thus rejuvenate aged T cells through pharmacological or physical interventions are discussed.

Cells undergo an inflammatory programmed lytic cell death called ‘pyroptosis’ (with the Greek roots ‘fiery’), often featuring morphological hallmarks such as large ballooning protrusions and subsequent bursting. Originally described as a caspase-1-dependent cell death in response to bacterial infection, pyroptosis has since been re-defined in 2018 as a cell death dependent on plasma membrane pores by a gasdermin (GSDM) family member [1], [2]. GSDMs form pores in the plasma membrane as well as organelle membranes, thereby initiating membrane destruction and the rapid and lytic demise of a cell. The gasdermin family plays a profound role in the execution of pyroptosis in the context of infection, inflammation, tumor pathogenesis, and anti-tumor therapy. More recently, cell-death-independent functions for some of the GSDMs have been proposed. Therefore, a comprehensive understanding of gasdermin gene regulation, including mechanisms in both homeostatic conditions and during inflammation, is essential. In this review, we will summarize the role of gasdermins in pyroptosis and focus our discussion on the transcriptional and epigenetic mechanisms controlling the expression of GSDMs.

Inflammasomes are cytoplasmic organelles that stimulate inflammation upon cellular detection of infectious or non-infectious stress. While much foundational work has focused on the infection-associated aspects of inflammasome activities, recent studies have highlighted the role of inflammasomes in non-infectious cellular and organismal functions. Herein, we discuss the evolution of inflammasome components and highlight characteristics that permit inflammasome regulation of physiologic processes. We focus on emerging data that highlight the importance of inflammasome proteins in the regulation of reproduction, development, and malignancy. A framework is proposed to contextualize these findings.

Unconventional T cells include γδ T cells, invariant Natural Killer T cells (iNKT) cells and Mucosal Associated Invariant T (MAIT) cells, which are distinguished from conventional T cells by their recognition of non-peptide ligands presented by non-polymorphic antigen presenting molecules and rapid effector functions that are pre-programmed during their development. Here we review current knowledge of the effect of age on unconventional T cells, from early life to old age, in both mice and humans. We then discuss the role of unconventional T cells in age-associated diseases and infections, highlighting the similarities between members of the unconventional T cell family in the context of aging.

Siglecs (sialic acid-binding immunoglobulin-like lectins) are a family of vertebrate glycan-binding cell-surface proteins. The majority mediate cellular inhibitory activity once engaged by specific ligands or ligand-mimicking molecules. As a result, Siglec engagement is now of interest as a strategy to therapeutically dampen unwanted cellular responses. When considering allergic inflammation, human eosinophils and mast cells express overlapping but distinct patterns of Siglecs. For example, Siglec-6 is selectively and prominently expressed on mast cells while Siglec-8 is highly specific for both eosinophils and mast cells. This review will focus on a subset of Siglecs and their various endogenous or synthetic sialoside ligands that regulate eosinophil and mast cell function and survival. It will also summarize how certain Siglecs have become the focus of novel therapies for allergic and other eosinophil- and mast cell-related diseases.