Trends in Immunology最新文献

Multiomics advances have led to breakthroughs in understanding human early life immunity. Adaptive memory immune cells have been detected in fetal tissue extremely early in gestation, where they may respond to maternal exposures. These promising findings lay the groundwork for future research on the lifelong impact of early immune development.

Active regulation of T cell quiescence is important to sustain immune responses to vaccination and infection while preventing inappropriate responses such as autoimmunity. Recent studies highlight that quiescence in naïve T cells is actively regulated by transcription factors and tonic signaling. Loss of quiescence in aged T cells has significant consequences because the cells are less responsive to infection or vaccination. This review covers the current state of knowledge about transcriptional regulation of naïve T cell quiescence and how quiescence is lost in aged hosts and during chronic infection. Finally, we discuss the need for a deeper understanding of the factors involved in cell quiescence to identify targets to restore cell quiescence in dysfunctional T cells.

Exploiting specific T cell subset properties bears potential for T cell therapies but is complicated by inconsistencies in T cell subset definitions and markers. Here, we discuss causes for the definition and classification complexities to provide a handle for how to navigate the T cell subset jungle.

Although DNA damage is a common cellular event, T cells experience significant genotoxic stresses because of rapid antigen-stimulated expansion and their presence in various nonlymphoid microenvironments. In addition to the well-established link between genomic instability and malignancy, recent genomic studies have uncovered a substantial mutational burden in nonmalignant T cells in both normal aging and disease contexts. Furthermore, genomic damage in T cells is accelerated in autoimmune diseases and in older individuals because of both intrinsic and extrinsic factors. This review highlights the different genotoxic stressors affecting T cells and the detrimental effects of persistent DNA damage and identifies the most critical knowledge gaps.

Lassa virus (LASV), which causes deadly Lassa fever (endemic in Western Africa), is a priority pathogen and a global health threat. Current vaccine candidates protect LASV-challenged animals through T cell immunity or non-neutralizing IgG/Fc receptor-mediated functions in the absence of potent neutralization. Neutralizing antibodies (nAbs), applied through passive immunization, also provide broad and complete protection against LASV. Rational design of LASV glycoprotein complex (GPC), the primary target for adaptive immunity, overcomes prior challenges to elicitation of nAbs caused by the dense glycan shield, metastability, and heterogeneity of GPC. Well-engineered GPC immunogens, in combination with advanced immunization methods and existing clinical trial phase vaccine candidates, provide a possibility to infuse neutralizing activity into complementary mechanisms of immune protection delivered by LASV vaccination.

Two recent studies, by Ely et al. and Apavaloaei et al., revealed that non-canonical antigens derived from unmutated, noncoding regions dominate the immunopeptidome of many cancers. Here, we discuss how this challenges conventional mutation-centric immunotherapies and highlight emerging strategies, including cryptic antigen- and TCR-targeted vaccines, as promising new clinically relevant paths in personalised and off-the-shelf cancer immunotherapy.

Organisms must adapt to unpredictable environmental perturbations. We propose that the immune system, which can be redistributed across tissues ('immune innervation'), cooperates with the nervous system to form a larger integrative network that can maximize the number of adaptive physiologic states to a given perturbation.

N⁶-methyladenosine (m⁶A) is a key mRNA modification influencing mRNA stability and translation. YTHDF2, a major m⁶A 'reader', was initially recognized for promoting mRNA decay but is now also known to enhance translation by binding to methylated mRNAs. YTHDF2 maintains the function of immune suppressive cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), while also supporting cytotoxic immune cells, including natural killer (NK) and CD8⁺ T cells. Additionally, YTHDF2 acts as a tumor-intrinsic regulator orchestrating tumor immune evasion. Its multifaceted roles in tumor immunity make YTHDF2 a promising yet challenging therapeutic target. This review explores the complex roles and mechanisms of YTHDF2 in cancers, immune regulation, and tumor immune evasion and highlights emerging therapeutic strategies that target YTHDF2.

Microglia replacement is reshaping neurodegenerative disease therapy, yet its key prerequisites remain unclear. In the current issue of Immunity, Aisenberg et al. and Bastos et al. reveal how developmental origin influences monocyte engraftment into the brain, and demonstrate the therapeutic potential of monocyte-based interventions in a monogenic neurological disease.

Recently, Kondo et al. engineered the coexpression of a T cell receptor (TCR) and a chimeric antigen receptor (CAR) and developed an antagonism-enforced braking system where TCR signals both enhance and inhibit CAR activation. This work may enable rational design of CAR-T agents that limit toxicity to healthy tissue.