Highlight of 2023: Unraveling the complexity of T cell aging - insights from recent advances.

Unraveling the complexities of T cell aging is essential for developing targeted interventions to enhance immune function in the elderly. This article for the Highlights of 2023 Series integrates recent findings published in 2023, offering a panoramic view of the current understanding of T cell aging and its implications.

Single-Cell Profiling of Bone Marrow B Cells and Early B Cell Developmental Disorders Associated With Systemic Lupus Erythematosus.

OBJECTIVE: The peripheral B cell compartment is heavily disturbed in systemic lupus erythematosus (SLE), but whether B cells develop aberrantly in the bone marrow (BM) is largely unknown. METHODS: We performed single-cell RNA/B cell receptor (BCR) sequencing and immune profiling of BM B cells and classified patients with SLE into two groups: early B cell (Pro-B and Pre-B) normal (EBnor) and EB defective/low (EBlo) groups. RESULTS: The SLE-EBlo group exhibited more severe disease activity and proinflammatory status, overaction of type I interferon signaling and metabolic pathways within the B cell compartment, and aberrant BCR repertoires compared with the SLE-EBnor group. Moreover, in one patient with SLE who was initially classified in the SLE-EBlo group, early B cell deficiency and associated abnormalities were largely rectified in a second BM sample at the remission phase. CONCLUSION: In summary, this study suggests that early B cell loss in BM defines a unique pathological state in a subset of patients with SLE that may play an active role in the dysregulated autoimmune responses.

T cell proliferation requires ribosomal maturation in nucleolar condensates dependent on DCAF13.

T cells require rapid proliferation to initiate adaptive immunity to prevent pathogen attacks. The nucleolus, a distinct subnuclear membrane-less compartment for ribosomal biogenesis, is indispensable for cell proliferation. However, specific nucleolar proteins involved in rapid T cell proliferation and their underlying molecular regulatory mechanism remain elusive. Here, we identified an essential nucleolar protein, DCAF13, in T cells and revealed its significant regulation of rapid T cell proliferation. Its depletion drastically impairs T cell proliferation due to severe 18S rRNA maturation failure, consequent abnormal ribosome assembly in nucleoli, and insufficient production of nascent proteins. Mechanistically, we propose that DCAF13 promotes NPM1 phase separation to accelerate pre-RNA enrichment and its endonuclease UTP23 for 18S rRNA maturation during T cell proliferation. Our findings reveal the modulatory effect of nucleolar NPM1/DCAF13 phase separation on ribosomal maturation to ensure rapid T cell proliferation and further pathogen clearance for the first time.

Single-Cell Transcriptomics Reveals Longevity Immune Remodeling Features Shared by Centenarians and Their Offspring.

Centenarians, who show mild infections and low incidence of tumors, are the optimal model to investigate healthy aging. However, longevity related immune characteristics has not been fully revealed largely due to lack of appropriate controls. In this study, single-cell transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) derived from seven centenarians (CEN), six centenarians' offspring (CO), and nine offspring spouses or neighbors (Control, age-matched to CO) are performed to investigate the shared immune features between CEN and CO. The results indicate that among all 12 T cell clusters, the cytotoxic-phenotype-clusters (CPC) and the naïve-phenotype-clusters (NPC) significantly change between CEN and ontrol. Compared to Control, both CEN and CO are characterized by depleted NPC and increased CPC, which is dominated by CD8+ T cells. Furthermore, CPC from CEN and CO share enhanced signaling pathways and transcriptional factors associated with immune response, and possesse similar T-cell-receptor features, such as high clonal expansion. Interestingly, rather than a significant increase in GZMK+ CD8 cells during aging, centenarians show accumulation of GZMB+ and CMC1+ CD8 T cells. Collectively, this study unveils an immune remodeling pattern reflected by both quantitative increase and functional reinforcement of cytotoxic T cells which are essential for healthy aging.

Expression of ICOS in the salivary glands of patients with primary Sjogren's syndrome and its molecular mechanism.

The present study aimed to explore latent markers for identifying primary Sjogren's syndrome (pSS), as well as their expression and molecular mechanism. Hub inducible T cell co­stimulator genes were retrieved from the Gene Expression Omnibus. A total of 95 patients with pSS and 68 healthy individuals from Affiliated Hospital of Nantong University (Nantong, China) were included in the study. The expression of inducible T cell co­stimulator (ICOS) in whole blood and saliva was evaluated using ELISA. Western blotting was performed to investigate aquaporin 5 (AQP5) protein expression, as well as the inflammatory effects of ICOS in patients with pSS compared with healthy individuals. Differentially expressed mRNAs were analyzed in whole blood (GSE84844) and salivary gland (GSE40611) of patients with pSS. In total, 15 hub genes were identified, among which ICOS was indicated to serve a role in the most pivotal immunity pathways. pSS was markedly associated with inflammatory pathways. Results from the present study found that ICOS was upregulated in the salivary gland, whole blood and saliva of patients with pSS. Salivary weight was negatively correlated with the levels of ICOS in the saliva of patients with pSS. The expression of AQP5 was markedly lower in patients with pSS. The expression of AQP5 was negatively associated with ICOS. Compared with that of healthy individuals, the expression of ICOS and inflammatory factors was higher and the expression of AQP5 was lower in pSS patients as assessed by western blotting. These data demonstrated that ICOS may affect AQP5 expression by promoting inflammation in the salivary glands of patients with pSS.

The transcription factor Zfp281 sustains CD4+ T lymphocyte activation through directly repressing Ctla-4 transcription.

The expression of coinhibitory receptors, such as CTLA-4, on effector T cells is a key mechanism for the negative regulation of T-cell activation. However, the transcriptional regulation of CTLA-4 is not well understood. Zfp281, a C2H2 zinc finger protein, is a negative regulator of pluripotency maintenance of embryonic stem cells. Nevertheless, the function of Zfp281 in differentiated cells has not been studied. We generated Zfp281 conditional knockout mice in which the function of the Zfp281 gene was conditionally disrupted by the Cd4Cre transgene to study its impact on T cell function. Zfp281 had no effect on T-cell development, but CD4+ T cell activation and cytokine production were impaired due to diminished T-cell receptor signaling. Furthermore, Zfp281 deficiency inhibited in vivo T cell responses to Listeria monocytogenes infection. Using genome-wide expression profiling assays, we determined that Zfp281 repressed Ctla-4 expression by directly binding to GC-rich sites in its promoter, which inhibited the negative feedback of T cell activation. In line with this result, CTLA-4 blockade and shRNA knockdown partly rescued the reduced cytokine production caused by Zfp281 deficiency. These findings indicate that Zfp281 sustains CD4+ T lymphocyte activation by directly repressing Ctla-4 transcription.

Cxxc Finger Protein 1 Positively Regulates GM-CSF-Derived Macrophage Phagocytosis Through Csf2rα-Mediated Signaling.

Macrophages have a defensive function against bacteria through phagocytosis and the secretion of cytokines. Histone modifications play an essential role in macrophage functions. Here, we report that Cxxc finger protein 1 (CFP1), a key component of the SETD1 histone methyltransferase complex, promoted the phagocytic and bactericidal activity of GM-CSF-derived macrophages. CFP1-deficient mice were more susceptible to bacterial infection due to the decreased expression of Csf2rα, a subunit of the GM-CSF receptor essential for inflammation and alveolar macrophage development, through the loss of H3K4 modifications in the promoter of the Csf2rα gene. In addition, the lung tissues of CFP1-deficient mice exhibited spontaneous inflammatory symptoms, including both the infiltration of inflammatory cells and the accumulation of surfactant phospholipids and proteins. Furthermore, we showed that Csf2rα and PU.1 can partially rescue the defects in phagocytosis and in the intracellular killing of bacteria. Collectively, our data highlight the importance of CFP1 in the phagocytic and bactericidal activity of macrophages.

Transformation of amorphous calcium carbonate to rod-like single crystal calcite via "copying" collagen template.

Collagen Langmuir films were prepared by spreading the solution of collagen over deionized water, CaCl2 solution and Ca(HCO3)2 solution. Resultant collagen Langmuir monolayers were then compressed to a lateral pressure of 10 mN/m and held there for different duration, allowing the crystallization of CaCO3. The effect of crystallization time on the phase composition and microstructure of CaCO3 was investigated. It was found that amorphous calcium carbonate (ACC) was obtained at a crystallization time of 6 h. The amorphous CaCO3 was transformed to rod-like single crystal calcite crystals at an extended crystallization time of 12 h and 24 h, via "copying" the symmetry and dimensionalities of collagen fibers. Resultant calcite crystallites were well oriented along the longitudinal axis of collagen fibers. The ordered surface structure of collagen fibers and electrostatic interactions played key roles in tuning the oriented nucleation and growth of the calcite crystallites. The mineralized collagen possessing both desired mechanical properties of collagen fiber and good biocompatibility of calcium carbonate may be assembled into an ideal biomaterial for bone implants.