Discovery immunology最新文献

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.

Introduction: Programmed death-1 (PD-1) is a negative regulator of immune responses. Upon deletion of PD-1 in mice, symptoms of autoimmunity developed only after they got old. In a model experiment in cancer immunotherapy, PD-1 was shown to prevent cytotoxic T lymphocytes from attacking cancer cells that expressed neoantigens derived from genome mutations. Furthermore, the larger number of genome mutations in cancer cells led to more robust anti-tumor immune responses after the PD-1 blockade. To understand the common molecular mechanisms underlying these findings, we hypothesize that we might have acquired PD-1 during evolution to avoid/suppress autoimmune reactions against neoantigens derived from mutations in the genome of aged individuals.

Methods: To test the hypothesis, we introduced random mutations into the genome of young PD-1^-/- and PD-1^+/+ mice. We employed two different procedures of random mutagenesis: administration of a potent chemical mutagen N-ethyl-N-nitrosourea (ENU) into the peritoneal cavity of mice and deletion of MSH2, which is essential for the mismatch-repair activity in the nucleus and therefore for the suppression of accumulation of random mutations in the genome.

Results: We observed granulomatous inflammatory changes in the liver of the ENU-treated PD-1 knockout (KO) mice but not in the wild-type (WT) counterparts. Such lesions also developed in the PD-1/MSH2 double KO mice but not in the MSH2 single KO mice.

Conclusion: These results support our hypothesis about the physiological function of PD-1 and address the mechanistic reasons for immune-related adverse events observed in cancer patients having PD-1-blockade immunotherapies.

Immunotherapy, the medicinal modulation of a host's immune response to better combat a pathogen or disease, has transformed cancer treatments in recent decades. T-cells, an important component of the adaptive immune system, are further paramount for therapy success. Recent immunotherapeutic modalities have therefore more frequently targeted T-cells for cancer treatments and other pathologies and are termed adoptive T-cell (ATC) therapies. ATC therapies characterize various types of immunotherapies but predominantly fall into three established techniques: tumour-infiltrating lymphocyte, chimeric antigen receptor T-cell, and engineered T-cell receptor therapies. Despite promising clinical results, all ATC therapy types fall short in providing long-term sustained tumour clearance while being particularly ineffective against solid tumours, with substantial developments aiming to understand and prevent the typical drawbacks of ATC therapy. Optogenetics is a relatively recent development, incorporating light-sensitive protein domains into cells or tissues of interest to optically tune specific biological processes. Optogenetic manipulation of immunological functions is rapidly becoming an investigative tool in immunology, with light-sensitive systems now being used to optimize many cellular therapeutic modalities and ATC therapies. This review focuses on how optogenetic approaches are currently utilized to improve ATC therapy in clinical settings by deepening our understanding of the molecular rationale behind therapy success. Moreover, this review further critiques current immuno-optogenetic systems and speculates on the expansion of recent developments, enhancing current ATC-based therapeutic modalities to pave the way for clinical progress.

Background: Immunometabolism is a crucial determinant of immune cell function, influencing cellular activation and differentiation through metabolic pathways. The intricate interplay between metabolism and immune responses is highlighted by the distinct metabolic programs utilized by immune cells to support their functions. Of particular interest is the pentose phosphate pathway (PPP), a key metabolic pathway branching out of glycolysis that plays a pivotal role in generating NADPH and pentose sugars crucial for antioxidant defense and biosynthesis. The sedoheptulose kinase Carbohydrate Kinase-like protein (CARKL), an enzyme involved in the PPP, emerges as a critical regulator of cell metabolism and was previously shown to play a role in macrophage function.

Methods: This study delves into the impact of CARKL expression on T-cell functionality, revealing dynamic alterations in response to cellular activation. Notably, CARKL overexpression leads to significant metabolic shifts in T cells, affecting mitochondrial respiration, ATP production, and inflammatory cytokine profiles. Furthermore, CARKL modulation influences T-cell motility by regulating chemokine receptor expression, particularly compromising CXCR3 expression and impairing T-cell migration in response to specific chemokine signals.

Conclusions: These findings underscore the multifaceted role of CARKL as a metabolic regulator shaping T-cell responses. Overall, our data reveal the complex regulatory mechanisms orchestrated by CARKL in T-cell function, with implications for immune regulation. Further exploration of the molecular interactions between CARKL and metabolic reprogramming in T cells could provide valuable insights into immune regulation and potential therapeutic strategies.

Graphical Abstract.

Monocytes are a key component of the innate immune system. They undergo intricate developmental processes within the bone marrow, leading to diverse monocyte subsets in the circulation. In a state of healthy homeostasis, monocytes are continuously released into the bloodstream, destined to repopulate specific tissue-resident macrophage pools where they fulfil tissue-specific functions. However, under pathological conditions monocytes adopt various phenotypes to resolve inflammation and return to a healthy physiological state. This review explores the nuanced developmental pathways and functional roles that monocytes perform, shedding light on their significance in both physiological and pathological contexts.