Journal of immunology最新文献

African swine fever virus (ASFV) is a large DNA virus of the Asfarviridae family that causes a fatal hemorrhagic disease in domestic swine and wild boar. Infections with moderately virulent strains predominantly result in a milder clinical course and lower lethality. As target cells of ASFV, monocytes play a crucial role in triggering T-cell-mediated immune defense and ASF pathogenesis. We compared the effect of the highly virulent "Armenia2008" (ASFV-A) virus strain with that of the naturally attenuated "Estonia2014" (ASFV-E) on cellular immune activation in vivo and on primary monocytes ex vivo. Specifically, we asked whether antigen presentation of porcine monocytes is impaired upon ASFV-A infection. ASFV-A-infected monocytes are characterized by lower levels of swine leukocyte antigen (SLA) class I on the cell surface than ASFV-E-infected and uninfected monocytes. Despite stable steady-state SLA I mRNA/protein levels and expression of critical components of the antigen processing machinery, a marked decrease in maturation and reduced surface transport of SLA I were observed in ASFV-A-infected monocytes. The intracellular maturation block of SLA I was accompanied by a loss of functional rough ER structures and a pronounced formation of ER-associated aggresomes. This unsolved cellular stress resulted in a shutdown of overall host cell protein translation, mitochondrial dysfunction, and caspase-3-mediated apoptosis. In contrast, no such cellular subversion phenomenon was found in ASFV-E-infected monocytes. Our findings suggest that in domestic pigs infected with highly virulent ASFV-A, sequential subversion events occur in infected monocytes, likely leading to compromised T-cell activation and impaired downstream responses against ASFV.

Persistent systemic inflammation is associated with an elevated risk of cardiometabolic diseases. However, the characteristics of the innate and adaptive immune systems in individuals who develop these conditions remain poorly defined. Doublets, or cell-cell complexes, are routinely eliminated from flow cytometric and other immune phenotyping analyses, which limits our understanding of their relationship to disease states. Using well-characterized clinical cohorts, including participants with controlled human immunodeficiency virus (HIV) as a model for chronic inflammation and increased immune cell interactions, we show that circulating CD14+ monocytes complexed to CD3+ T cells are dynamic, biologically relevant, and increased in individuals with diabetes after adjusting for confounding factors. The complexes form functional immune synapses with increased expression of proinflammatory cytokines and greater glucose utilization. Furthermore, in persons with HIV, the CD3+ T cell: CD14+ monocyte complexes had more HIV copies compared to matched CD14+ monocytes or CD4+ T cells alone. Our results demonstrate that circulating CD3+ T-cell: CD14+ monocyte pairs represent dynamic cellular interactions that may contribute to inflammation and cardiometabolic disease pathogenesis. CD3+ T-cell: CD14+ monocyte complexes may originate or be maintained, in part, by chronic viral infections. These findings provide a foundation for future studies investigating mechanisms linking T cell-monocyte cell-cell complexes to developing immune-mediated diseases, including HIV and diabetes.

The humoral immune system influences the development of atherosclerosis, but the contributions of specific memory B cell subsets and IgG isotypes are poorly understood. We assessed the relationship between atherosclerosis and age-associated B cells (ABCs), a T-bet-expressing memory B cell subset that is enriched for IgG2c production and implicated in humoral autoimmunity. We found increased numbers of splenic CD11c+ ABCs in 6-mo-old, chow-fed Apoe-/- mice versus C57BL/6 control mice, which were exacerbated by high-fat diet. Deletion of T-bet in the B lineage in high-fat diet-fed Apoe-/- mice reduced aortic lesion area, and this correlated with decreased splenic CD11c+ B cells and reduced serum oxidized low-density lipoprotein-specific IgG2c. Our findings suggest that T-bet-expressing B cells are atherogenic agents in the Apoe-/- model and indicate that interventions to inhibit a T-bet-driven humoral response may improve atherosclerotic disease.

Immune memory is crucial for preventing hepatitis E virus (HEV) infection. Our study aims to investigate immunological memory characteristics and differences between vaccination and natural HEV infection, taking into account that both can induce immune memory. We recruited 60 HEV-infected patients, 58 contingency HEV-vaccinated individuals and 4 controls from an outbreak of hepatitis E in a nursing home between June and August 2023. Multicolor flow cytometry, ELISA, and quantitative polymerase chain reaction (qPCR) were employed to detect memory T-cell expression profiles, HEV-specific antibodies and cytokine expression. We observed that the level of HEV-specific IgM in acute jaundiced hepatitis E patients was greater than that in non-jaundiced patients (8.37 ± 1.27 vs. 4.27 ± 0.81, P < 0.05). No significant differences were detected in the HEV-specific IgG and memory T cell expression profiles among the different severities of hepatitis E. The percentage of CD8+ TEM at 6 months after recovery was significantly greater than that in acute jaundice patients (1.60% ± 0.30% vs. 1.15% ± 0.35%, P < 0.05). Compared with natural infection, three-dose vaccination increased the level of HEV-specific IgG (14.97 ± 0.21 vs. 12.75 ± 0.37, P < 0.05), IL-7 and IL-15 (28.50 ± 3.82 vs. 23.32 ± 6.37, 608.60 ± 143.30 vs. 257.50 ± 69.87, P < 0.05). Natural infection could effectively establish immune memory. During convalescence, infection severity impacted only HEV-specific IgM, while HEV-specific IgG and memory T-cell expression profiles were not affected. Compared with natural infection, three-dose vaccination results in equal effective humoral immune memory and weaker cellular immune memory with minimal side effects.

In naïve mice, a fraction of CD8 T cells displaying high affinity for self-MHC peptide complexes develop into virtual memory T (TVM) cells. Due to self-reactivity, TVM cells are exposed to persistent antigenic stimulation, a condition known to induce T cell exhaustion. However, TVM cells do not exhibit characteristics similar to exhausted CD8 T (TEX) cells. Here, we tested the role of the UFL1, E3 ligase of the ufmylation pathway in TVM cells. We show that UFL1 prevents the acquisition of epigenetic, transcriptional, and phenotypic changes in TVM cells that are similar to TEX cells and thus promote their survival and function. UFL1-deficient TVM cells failed to protect mice against Listeria infection. Epigenetic analysis showed higher BATF activity in UFL1-deficient TVM cells. Deletion of BATF and not PD1 decreased inhibitory molecules expression and restored the survival and function of UFL1-deficient TVM cells. Our findings demonstrate a key role of UFL1 in inhibiting the exhaustion of TVM cells and promoting their survival and function.

The relationship between sleep deprivation, obesity, and systemic inflammation is a critical area of investigation due to its significant impact on health. While it is established that poor sleep adversely affects obesity and metabolic syndromes, the specific mechanisms, particularly subclinical inflammation independent of obesity, remain unclear. This study investigates how sleep quality influences monocyte subclass distribution and its association with systemic inflammation across a spectrum of body mass index categories. In our cohort study, 237 healthy participants were categorized by body mass index. Participants' dietary intake, physical activity, and sleep patterns were objectively tracked through wearable ActiGraph GT3X accelerometer. The data showed that obese individuals had significantly lower sleep quality and higher chronic low-grade inflammation. Nonclassical monocytes increased significantly in obesity, correlating with reduced sleep quality and elevated proinflammatory cytokines. Although body mass index emerged as a significant factor in driving inflammation, mediation analyses further defined that sleep disruption independently contributes to inflammation, regardless of obesity status. Controlled sleep deprivation experiments confirmed these findings, demonstrating reversible increases in nonclassical monocytes expression. This study highlights the importance of sleep quality in regulating immune responses and inflammation in obesity, suggesting that improving sleep quality could reduce inflammation and improve health outcomes.

Endometriosis is a chronic disorder in which endometrial-like tissue presents outside the uterus. Patients with endometriosis have been shown to exhibit aberrant immune responses within the lesion microenvironment and in circulation which contribute to the development of endometriosis. Thymic stromal lymphopoietin (TSLP) is an alarmin involved in cell proliferation and the induction of T helper 2 (Th2) inflammation in various diseases, such as asthma, atopic dermatitis, and pancreatic and breast cancer. Recent studies have detected TSLP within endometriotic lesions and shown that its concentrations are elevated in the peritoneal fluid of patients compared with control subjects. However, its role in disease pathophysiology remains unclear. Here, we compared TSLP messenger RNA and protein expression between patient eutopic endometrium, endometriotic lesions, and control endometrial samples. We also assessed its effect on the proliferation and apoptosis of human endometriosis-representative cell lines, as well as on lesion development and inflammation in a mouse model of the disease. We demonstrated that TSLP expression was elevated in the stroma of patient endometriotic lesions compared with control endometrial samples. In cell lines, TSLP treatment reduced the apoptosis of endometrial stromal cells and promoted the proliferation of THP-1 cells. In mice induced with endometriosis, TSLP treatment induced a Th2 immune response within the lesion microenvironment, and led to TSLP receptor modulation in macrophages, dendritic cells, and CD4+ T cells. Furthermore, treatment increased murine endometriotic lesion proliferation. Overall, these results suggest that TSLP modulates the endometriotic lesion microenvironment and promotes a Th2 immune response that could support lesion development.

A gene encoding the transcription factor RTF1 has been associated with an increased risk of ulcerative colitis (UC). In this study, we investigated its function in modulating T cells expressing interleukin-17A (Th17 cells), a cardinal cell type promoting intestinal inflammation. Our results indicate that Rtf1 deficiency disrupts the differentiation of Th17 cells, while leaving regulatory T cells (Treg) unaffected. Mechanistically, RTF1 facilitates histone H2B monoubiquitination (H2Bub1), which requires its histone modification domain (HMD), for supporting Th17 cell function. Impaired Th17 differentiation was also observed in cells lacking the H2Bub1 E3 ligase subunit RNF40, an enzyme known to physically interact with RTF1. Thus, our study underscores the essential role of RTF1 in H2Bub1-mediated epigenetic regulation of Th17 cell differentiation. Understanding this process will likely provide valuable insights into addressing Th17-associated inflammatory disorders. (Images were created with BioRender).

While therapeutic vaccines are a promising strategy for inducing human immunodeficiency virus (HIV) control, HIV vaccines tested to date have offered limited benefit to people living with HIV. The barriers to success may include the use of vaccine platforms and/or immunogens that drive weak or suboptimal immune responses, immune escape and/or immune dysfunction associated with chronic infection despite effective antiretroviral therapy. Combining vaccines with immune modulators in a safe manner may address some of the challenges and thus increase the efficacy of therapeutic HIV vaccines. We evaluated the immunogenicity of a ChAd68/samRNA-based simian immunodeficiency virus (SIV) vaccine regimen alone and in combination with a series of immune modulators in a preclinical rhesus macaque (M. mulatta) model. The vaccine was co-delivered with the checkpoint inhibitors αPD-1 or αCTLA-4, or with a FLT3 receptor agonist (FLT3Ra) shown to differentiate and expand dendritic cells and improve T cell priming. We demonstrate that the magnitude, breadth and functionality of SIV-specific vaccine-elicited CD8+ T cell responses were enhanced by combination with either αPD-1, αCTLA-4, or FLT3Ra. Combination with FLT3Ra also expanded polyfunctional CD4+ T cell responses. Our data demonstrate enhanced and distinct shaping of vaccine-elicited immune responses by immune modulators with implications for developing a functional HIV cure.

The life cycle of effector T cells is determined by signals downstream of the T cell receptor (TCR) that induce activation and proinflammatory activity, or death as part of the process to resolve inflammation. We recently reported that T cell myeloid differentiation primary response 88 (MyD88) tunes down TCR activation and limits T cell survival in the cardiac and tumor inflammatory environments, in contrast to its proinflammatory role in myeloid cells upon toll-like receptor (TLR) recognition of pathogen- and damage-associated molecular patterns. However, the molecular mechanism remains unknown. Here, we report a central regulatory role for MyD88 in T cell apoptosis after TCR activation and Fas ligation through an association with the B cell adaptor for phosphoinositide 3-kinase (B cell activating protein [BCAP]). We show that TCR engagement upregulates MyD88 and BCAP and promotes their interaction, thereby limiting availability of BCAP for downstream TCR-BCAP-PI3K-AKT signaling required for T cell activation and survival, which are enhanced in MyD88-/- activated T cells. Further, MyD88 and BCAP association and localization to the TCR was prevented by lipopolysaccharide (LPS) activation of TLR4 and restored T cell survival in wild-type cells. The enhanced T cell activation markers, proinflammatory signals, and survival advantage observed in MyD88-/- T cells was fully eliminated upon BCAP knockdown in T cells. Our data demonstrate that MyD88 acts downstream of the TCR to regulate T cell fate through its association with BCAP and elucidate a novel molecular mechanism for MyD88 in T cell biology that could be targeted to fine-tune T cell effector function and survival therapeutically.