Discovery immunology最新文献

Introduction: Cell metabolism plays an important role in immune effector responses and through responding to metabolic signals, immune cells can adapt and regulate their function. Arginine metabolism in dendritic cells (DC) has been shown to reduce T cell activation; however, it is unclear how this immunosuppressive state is induced.

Method: To address this issue, we examined the immunomodulatory capacity of various metabolites from arginine metabolism.

Results: Through the use of a recently described DC:T cell interaction assay and flow cytometry we demonstrated that spermidine most significantly inhibited DC activation, preventing subsequent interactions with CD4 T cells. DC function could be restored by addition of inhibitors of spermidine metabolism via the eIF5A-hypusine axis, required for expression of some mitochondrial enzymes. We also demonstrated that the spermidine induced-immunosuppressive state protected DC against activation-induced loss of mitochondrial capacity for energy generation, which was also hypusination dependent.

Conclusion: Taken together, these data demonstrate that spermidine is the key immunomodulatory component downstream of arginine metabolism and that it mediates this effect by stimulating hypusination-dependent protection of OXPHOS in DC, which in turn results in a reduced ability of DC to activate and interact with T cells. This pathway may be utilized by the immune system to regulate excessive immune responses but could also be exploited by pathogens as a method of immune evasion.

Oligodendrocytes are responsible for the myelination of axons and providing trophic and metabolic support to the myelinated axon. They also interact with immune effector cells, including microglia and T cells, hence, are involved in central nervous system immune regulation. Given the crucial roles for oligodendrocytes and myelin in axonal function and maintenance, dysfunction, whether through cell death, myelin injury and loss, or failure in normal myelin formation, impairs neurological function. In diseases such as multiple sclerosis, the leukodystrophies, and viral infection, neuroinflammation is an important effector of myelin injury, having secondary consequences for the myelinated axon. In this review, we discuss the role of oligodendrocytes in health and inflammatory disease, with a focus on the interplay between inflammation and oligodendrocyte-axon interactions.

Oligodendrocytes (OGDs) are well-established cells in the central nervous system (CNS), primarily recognized for their role in myelination. However, emerging evidence suggests intrinsic differences among OGDs that may lead to diverse functions. OGDs heterogeneity could depend on their origin, location, age, and the presence of pathology. These variations indicate that specific populations of OGDs can modulate local immune responses and interact with other immune cells beyond their role in myelination. OGDs express major histocompatibility complex class I and class II molecules and can thus present endogenous and exogenous antigens to CD8 + and CD4 + T cells, respectively. In physiological conditions, OGDs release factors that maintain microglial quiescence and support homeostatic functions. However, during neuroinflammation, OGDs interact with microglia, astrocytes, and peripheral immune cells infiltrating the CNS, which may change their signaling profiles. In inflammatory conditions, OGDs demonstrate their active role in CNS immunology by producing a range of pro-inflammatory cytokines and chemokines. These factors are critical to the regulation of immune cell migration and activation within the CNS. Conversely, OGDs can also release anti-inflammatory factors, such as brain-derived neurotrophic factors, which help mitigate excessive inflammatory responses. Research into how OGDs affect and are affected by neighboring cells may unveil new therapeutic targets and strategies. The dual roles of OGDs in immunology and CNS function present both opportunities and challenges for advancing our understanding and treatment of CNS disorders.

Manipulating CD28 co-stimulation is a key element of anti-tumour immune responses and treating autoimmune diseases. CD28 can reduce the T cell activation threshold but has a complex relationship with T cell receptor (TCR) signalling and an unclear role in specific T cell subsets. Using a series of in vitro stimulation assays, we have studied the relative contribution of CD28 and TCR signals in human CD4 + T cell responses. We show that not only the quantity of CD28 co-stimulation but also its intensity relative to TCR differentially impacts the division of naïve and memory T cells. We show that CD28 co-stimulation can have TCR-independent effects on memory T cell phenotype and cytokine production and in some settings can antagonize TCR-driven functions. These data highlight the complex relationship between CD28 co-stimulation and TCR signals and expose clear differences in their use by naïve and memory T cells.

Tissue-resident memory (TRM) T cells play an important role in protection against respiratory infection but whether this memory is maintained by long-lived or dividing cells remains controversial. To address the rate of division of lung TRM T cells, deuterium-enriched water was administered orally to young pigs to label dividing lymphocytes. T-cell subsets were separated from blood, lymph nodes, and airways [bronchoalveolar lavage (BAL)], the latter comprising almost exclusively TRM. We show that, as in other species, circulating memory T-cell subsets divide more rapidly than naïve T cells. Rates of labelling of memory subsets were similar in blood and lymph nodes, consistent with the rapid and free exchange. Strikingly, the fraction of label in BAL was similar to those in blood/lymph nodes after 5-21 days of labelling, suggesting replacement with recently divided cells, but this was preceded at Day 2 by a phase when labelling was lower in BAL than blood/lymph node in some memory subsets. Our data exclude long-lived TRM as the source of BAL memory cells leaving three possible hypotheses: blood/airway exchange, in situ proliferation, or proliferation in the lung interstitium followed by migration to BAL. When considered in the context of other information, we favour the latter interpretation. These results indicate the dynamic nature of memory in the lung and have implications for harnessing immune responses against respiratory pathogens.

Background: Innate lymphoid cells (ILCs) are prominent in the human uterine mucosa and play physiological roles in pregnancy. ILC3 are the second-most common ILC subset in the uterine mucosa, but their role remains unclear.

Methods: Here we define two subsets of lineage-negative CD56+ CD117+ CRTH2-uterine ILC3, distinguished by their expression of CD127.

Results: The CD127- subset is most numerous and active during menstruation and immediately after parturition, suggesting a role in the repair of the uterine mucosa (called endometrium outside of pregnancy); the CD127+ subset is most numerous and active immediately after menstruation, as the endometrium regenerates. In healthy endometrium, ILC3 are spatially associated with glandular epithelial and endothelial cells, which both express receptors for the ILC3-derived cytokines, IL-22 and IL-8. In the eutopic endometrium of people with endometriosis, ILC3 are located further from glandular epithelial and endothelial cells suggesting that these cells may be less exposed to ILC3 products, potentially with negative consequences for endometrial regeneration.

Conclusion: Our findings highlight the dynamic nature of ILC3 in the uterine mucosa and suggest their primary role is in repair and regeneration. An improved understanding of uterine ILC3 will inform future research on endometrial health and disease.

Background: T-helper (Th) cells co-ordinate immune responses to ensure that infections with diverse parasites are controlled effectively. Helminth parasites such as gastrointestinal nematodes (GIN) are generally associated with T-helper type 2 (Th2) responses, while intracellular parasites are associated with Th1 responses. Although laboratory models have reported that Th1 and Th2 can be antagonistic, this has been challenged by studies of natural infections.

Methods: Between 2019 and 2022 we completed 759 captures of 538 wild Soay sheep (1-4 captures per animal) and monitored body weight, parasite egg counts, Th phenotypes, cytokines, and GIN-specific antibodies.

Results: While different Th cell counts, cytokines and antibody isotypes were generally positively correlated with each other, no strong positive associations were observed between these measurements. Cell counts had low repeatability (among-individual variation) across 4 years, while antibody levels were highly repeatable. The Th1 and Th2 cytokines Interferon-gamma (IFN-γ) and Interleukin-4 (IL-4) were moderately repeatable and were positively correlated at both the between- and within-individual levels independent of body condition or parasite exposure. IL-4 was negatively associated with GIN faecal egg count, while IFN-γ was negatively associated with coccidian faecal oocyst count, suggesting that these cytokines reflect resistance to these parasites. None of our immune markers were strongly associated with lamb survival.

Conclusions: Our results provide insights into how different aspects of immune function interact to produce effective responses to complex infections but suggest longer-term data collection is required to address the causes of these interactions and to detect fitness consequences of variation in T cell phenotypes under natural conditions.

Introduction: Obesity is a worldwide epidemic, with over 1 billion people worldwide living with obesity. It is associated with an increased risk of over 200 chronic co-morbidities, including an increased susceptibility to infection. Numerous studies have highlighted the dysfunction caused by obesity on a wide range of immune cell subsets, including dendritic cells (DCs). DCs are innate immune sentinels that bridge the innate and adaptive immune systems. DCs provide critical signals that instruct and shape the immune response. Our group has previously reported that DCs from people with obesity display defective cytokine production; however, the mechanisms underpinning these defects are unclear.

Methods: We investigated the functional responses of DCs using a murine-specific single-stranded RNA virus, Sendai virus, in mice on a standard diet and in a model of diet-induced obesity.

Results: Here, we demonstrate that GM-CSF cultured bone marrow-derived DCs (GM-DCs) from mice on a high-fat diet (HFD) have reduced cytokine production following viral challenge. This was associated with a dysfunctional metabolism through reduced translation in the HFD GM-DCs.

Conclusions: We propose that obesity-mediated effects on DCs have downstream consequences on their ability to effectively mediate subsequent immune responses, especially during viral infection.

Introduction: Concerns regarding the translational value of preclinical mouse models have been addressed by introducing various approaches of 'naturalizing' research mice, which provide them with more diverse microbiomes and physiological immune responses. We have previously shown that 'feralized' mice, that is, inbred laboratory mice raised in a farmyard-like, microbe-rich environment exhibit a shifted gut microbiota, matured immunophenotype, and reduced severity of colorectal cancer. Similar studies occasionally involve co-housing with wild or pet-store-raised mice as microbial donors integrating species-specific commensals and pathogens. To what extent these different practices of microbial exposure are crucial for the resulting mouse phenotype remains unclear.

Methods: Here, we present the first side-by-side comparison of different methods to naturalize laboratory mice: co-housing with wild-caught house mice, feralization in a farmyard-like habitat only, or a combination of the two, with conventional clean laboratory mice as a reference.

Results: Independent of the method, the naturalized colon-mucosa microbiota, was colonized by several Helicobacter species, and the colonic intestinal epithelial cells of naturalized mice displayed elevated expression of genes encoding antimicrobial peptides, mucus components, and reactive-oxygen-species-producing enzymes. They further showed significantly increased resident memory T cells in the colonic lamina propria and effector memory T cells in the mesenteric lymph nodes. The most pronounced changes of these parameters occurred in mice co-housed with wild-caught mice, while feralized mice displayed phenotypes that were intermediate between laboratory and co-housed mice.

Conclusion: These findings enhance our understanding of naturalization model setups and effects on the gut barrier and immune system, thereby aiding future decisions on the utilization of naturalized mouse models.