Peripheral Lymphocyte Changes Associate With the Progression of Necrotizing Enterocolitis in Infants.

INTRODUCTION: Immune factors are important antecedents in the pathophysiology of necrotizing enterocolitis (NEC). However, studies on the peripheral blood lymphocyte subsets changes in NEC patients among different Bell stages and in patients requiring surgery are scarce. METHODS: 34 infants with NEC and 33 age-matched controls were included. Peripheral blood was collected within 48 h after NEC diagnosis. Peripheral blood B and T lymphocytes subsets were detected by 12-color flow cytometry. Cell ratios were calculated, and their relationship to disease severity and their roles as indicators for surgery were assessed. RESULTS: NEC patients showed elevated percentages of unSwB cells (CD27+IgD+ unswitched memory/activated B cells)/B cells, SwB cells (CD27+IgD-switched memory B cells)/B cells, CD8+ T (CD3+CD8+ T cells)/T cells, Tem (CD45RA-CCR7-effector memory T cells)/CD4+ T cells, Tem/CD8+ T cells and decreased Bn (CD27-IgD+ naïve B cells)/B cells, CD4+T (CD3+CD4+ T cells)/T cells, CD45RA+ CCR7+ naïve T cells (CD45RA+CCR7+ naïve T cells)/CD8+T cells. Compared to NEC patients at BELL stage I + II, patients at BELL stage III showed increased percentages of SwB cells/B cells, antibody secreting cell (ASC, CD3-CD20-CD27high CD38high ASCs)/B cells and Tem/CD4+ T cells, and decreased percentages of CD45RA+CCR7+ naïve T cells/CD4+ T cells. The Receiver Operating Characteristic Curve analysis showed that the sensitivity of ASC/B cells ratio (0.52%) is 86.67% and the specificity of Tem/CD4+T ratio (5.22%) is 100%, indicating that NEC patients required surgery. CONCLUSIONS: The severity of NEC exhibits codirectional changes with the maturation of B and T lymphocytes, especially CD4+ T cells. The increased ASC/B and Tem/CD4+ T cells could serve as potential indicators for NEC patients requiring surgery.

CD38 and extracellular NAD+ regulate the development and maintenance of Hp vaccine-induced CD4+ TRM in the gastric epithelium.

Tissue-resident memory T cells (TRM) can be induced by infection and vaccination, and play a key role in maintaining long-term protective immunity against mucosal pathogens. Our studies explored the key factors and mechanisms affecting the differentiation, maturation, and stable residence of gastric epithelial CD4+ TRM induced by Helicobacter pylori (Hp) vaccine and optimized Hp vaccination to promote the generation and residence of TRM.CD38 regulated mitochondrial activity and enhanced TGF-ß signal transduction to promote the differentiation and residence of gastric epithelial CD4+ TRM by mediating the expression of CD105. Extracellular nucleotides influenced the long-term maintenance of TRM in gastric epithelium by P2RX7. Vitamin D3 and Gram-positive enhancer matrix particles (GEMs)as immune adjuvants combined with Hp vaccination promoted the production of CD69+CD103+CD4+ TRM.

[Challenges and strategies for improving efficacy in CAR-T therapy].

CAR-T cell therapy targeting CD19 and BCMA for relapsed or refractory hematopoietic tumors has been adopted in routine practice and has shown dramatic results. However, half of patients who achieve remission with CAR-T therapy eventually relapse, and thus efforts to improve the efficacy of CAR-T therapy are gaining momentum. Notably, studies have described innovative technologies that enable control of cell kinetics after infusion, which is not possible with conventional CAR-T therapies. In this article, we review the challenges of CAR-T cell therapy and the development of new technologies.

Nano-Pulse Treatment Overcomes the Immunosuppressive Tumor Microenvironment to Elicit In Situ Vaccination Protection against Breast Cancer.

We previously reported that nano-pulse treatment (NPT), a pulsed power technology, resulted in 4T1-luc mammary tumor elimination and a strong in situ vaccination, thereby completely protecting tumor-free animals against a second live tumor challenge. The mechanism whereby NPT mounts effective antitumor immune responses in the 4T1 breast cancer predominantly immunosuppressive tumor microenvironment (TME) remains unanswered. In this study, orthotopic 4T1 mouse breast tumors were treated with NPT (100 ns, 50 kV/cm, 1000 pulses, 3 Hz). Blood, spleen, draining lymph nodes, and tumors were harvested at 4-h, 8-h, 1-day, 3-day, 7-day, and 3-month post-treatment intervals for the analysis of frequencies, death, and functional markers of various immune cells in addition to the suppressor function of regulatory T cells (Tregs). NPT was verified to elicit strong in situ vaccination (ISV) against breast cancer and promote both acute and long-term T cell memory. NPT abolished immunosuppressive dominance systemically and in the TME by substantially reducing Tregs, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). NPT induced apoptosis in Tregs and TAMs. It also functionally diminished the Treg suppression capacity, explained by the downregulation of activation markers, particularly 4-1BB and TGFß, and a phenotypic shift from predominantly activated (CD44+CD62L-) to naïve (CD44-CD62L+) Tregs. Importantly, NPT selectively induced apoptosis in activated Tregs and spared effector CD4+ and CD8+ T cells. These changes were followed by a concomitant rise in CD8+CD103+ tissue-resident memory T cells and TAM M1 polarization. These findings indicate that NPT effectively switches the TME and secondary lymphatic systems from an immunosuppressive to an immunostimulatory state, allowing cytotoxic T cell function and immune memory formation to eliminate cancer cells and account for the NPT in situ vaccination.

The Multifaceted Role of Tissue-Resident Memory T Cells.

Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (TRM) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating TRM cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of TRM cell heterogeneity and function across tissues and disease states. We discuss mechanisms of TRM cell-mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how TRM cell responses might be durably boosted or dampened for therapeutic gain.

Regulatory and memory T lymphocytes infiltrating prostate tumors predict long term clinical outcomes.

Introduction: The localization, density but mostly the phenotype of tumor infiltrating lymphocytes (TIL) provide important information on the initial interaction between the host immune system and the tumor. Our objective was to assess the prognostic significance of T (CD3+), T regulatory (Treg) (FoxP3+) and T memory (Tmem) (CD45RO+) infiltrating lymphocytes and of genes associated with TIL in prostate cancer (PCa). Methods: Immunohistochemistry (IHC) was used to assess the infiltration of CD3+, FoxP3+ and CD45RO+ cells in the tumor area, tumor margin and adjacent normal-like epithelium of a series of 98 PCa samples with long clinical follow-up. Expression of a panel of 31 TIL-associated genes was analyzed by Taqman Low-Density Array (TLDA) technology in another series of 50 tumors with long clinical follow-up. Kaplan-Meier and Cox proportional hazards regression analyses were performed to determine association of these markers with biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa. Results: TIL subtypes were present at different densities in the tumor, tumor margin and adjacent normal-like epithelium, but their density and phenotype in the tumor area were the most predictive of clinical outcomes. In multivariate analyses, a high density of Treg (high FoxP3+/CD3+ cell ratio) predicted a higher risk for need of definitive ADT (HR=7.69, p=0.001) and lethal PCa (HR=4.37, p=0.04). Conversely, a high density of Tmem (high CD45RO+/CD3+ cell ratio) predicted a reduced risk of lethal PCa (HR=0.06, p=0.04). TLDA analyses showed that a high expression of FoxP3 was associated with a higher risk of lethal PCa (HR=5.26, p=0.02). Expression of CTLA-4, PD-1, TIM-3 and LAG-3 were correlated with that of FoxP3. Amongst these, only a high expression of TIM-3 was associated with a significant higher risk for definitive ADT in univariate Cox regression analysis (HR=3.11, p=0.01). Conclusion: These results show that the proportion of Treg and Tmem found within the tumor area is a strong and independent predictor of late systemic progression of PCa. Our results also suggest that inhibition of TIM-3 might be a potential approach to counter the immunosuppressive functions of Treg in order to improve the anti-tumor immune response against PCa.

Secukinumab and Dead Sea Climatotherapy Impact Resolved Psoriasis Skin Differently Potentially Affecting Disease Memory.

Secukinumab and Dead Sea treatment result in clear skin for many psoriasis patients, through distinct mechanisms. However, recurrence in the same areas after treatments suggests the existence of a molecular scar. We aimed to compare the molecular and genetic differences in psoriasis patients who achieved complete response from secukinumab and Dead Sea climatotherapy treatments. We performed quantitative immunohistochemical and transcriptomic analysis, in addition to digital spatial profiling of skin punch biopsies. Histologically, both treatments resulted in a normalization of the lesional skin to a level resembling nonlesional skin. Interestingly, the transcriptome was not normalized by either treatments. We revealed 479 differentially expressed genes between secukinumab and Dead Sea climatotherapy at the end of treatment, with a psoriasis panel identifying SERPINB4, SERPINB13, IL36G, IL36RN, and AKR1B10 as upregulated in Dead Sea climatotherapy compared with secukinumab. Using digital spatial profiling, pan-RAS was observed to be differentially expressed in the microenvironment surrounding CD103+ cells, and IDO1 was differentially expressed in the dermis when comparing the two treatments. The differences observed between secukinumab and Dead Sea climatotherapy suggest the presence of a molecular scar, which may stem from mechanistically different pathways and potentially contribute to disease recurrence. This may be important for determining treatment response duration and disease memory.

High percentage of bone marrow CD8+ tissue-resident-like memory T cells predicts inferior survival in patients with acute myeloid leukemia.

Tissue-resident memory T (TRM) cells infiltrating solid tumors could influence tumor progression and the response to immune therapies. However, the proportion and prognostic value of TRM cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) are unclear. In this study, we used flow cytometry to assay the phenotype of 49 BM samples from patients newly diagnosed with AML (ND-AML). We found that the BM CD8+ effector memory (TEM) cells highly expressed CD69 (CD8+ TRM-like T cells), and their percentage was significantly increased in patients with ND-AML compared with that in healthy individuals (HI). The high percentage of CD8+ TRM-like subset was associated with poor overall survival in our ND-AML cohort. The Kaplan-Meier Plotter database verified a significantly reduced survival rate among patients with high expression of CD8+ TRM-like T cell characteristic genes (CD8A, CD69, and TOX), especially the M4 and M5 subtypes. Phenotypic analysis revealed that the BM CD8+ TRM-like subpopulation exhibited exhausted T cell characteristics, but its high expression of CD27 and CD28 and low expression of CD57 suggested its high proliferative potential. The single-cell proteogenomic dataset confirmed the existence of TRM-like CD8+ T cells in the BM of patients with AML and verified the high expression of immune checkpoints and costimulatory molecules. In conclusion, we found that the accumulation of BM CD8+ TRM-like cells could be an immune-related survival prediction marker for patients with AML.

Islet-Resident Memory T Cells Orchestrate the Immunopathogenesis of Type 1 Diabetes through the FABP4-CXCL10 Axis.

Type 1 diabetes (T1D) is a chronic disease characterized by self-destruction of insulin-producing pancreatic ß cells by cytotoxic T cell activity. However, the pathogenic mechanism of T cell infiltration remains obscure. Recently, tissue-resident memory T (TRM) cells have been shown to contribute to cytotoxic T cell recruitment. TRM cells are found present in human pancreas and are suggested to modulate immune homeostasis. Here, the role of TRM cells in the development of T1D is investigated. The presence of TRM cells in pancreatic islets is observed in non-obese diabetic (NOD) mice before T1D onset. Mechanistically, elevated fatty acid-binding protein 4 (FABP4) potentiates the survival and alarming function of TRM cells by promoting fatty acid utilization and C-X-C motif chemokine 10 (CXCL10) secretion, respectively. In NOD mice, genetic deletion of FABP4 or depletion of TRM cells using CD69 neutralizing antibodies resulted in a similar reduction of pancreatic cytotoxic T cell recruitment, a delay in diabetic incidence, and a suppression of CXCL10 production. Thus, targeting FABP4 may represent a promising therapeutic strategy for T1D.

Cellular and humoral immunogenicity against SARS-CoV-2 vaccination or infection is associated with the memory phenotype of T- and B-lymphocytes in adult allogeneic hematopoietic cell transplant recipients.

We conducted a cross-sectional study to evaluate cellular and humoral immunogenicity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination or infection and examine how lymphocyte subpopulations in peripheral blood correlate with cellular and humoral immunogenicity in adult allogeneic hematopoietic cell transplantation (HCT) recipients. The median period from SARS-CoV-2 vaccination or infection to sample collection was 110.5 days (range, 6-345 days). The median SARS-CoV-2 spike-specific antibody level was 1761 binding antibody units (BAU)/ml (range, 0 to > 11,360 BAU/ml). Enzyme-linked immunosorbent spot (ELISpot) assay of T cells stimulated with SARS-CoV-2 spike antigens showed that interferon-gamma (IFN-γ)-, interleukin-2 (IL-2)-, and IFN-γ + IL-2-producing T cells were present in 68.9%, 62.0%, and 56.8% of patients, respectively. The antibody level was significantly correlated with frequency of IL-2-producing T cells (P = 0.001) and IFN-γ + IL-2-producing T cells (P = 0.006) but not IFN-γ-producing T cells (P = 0.970). Absolute counts of CD8+ and CD4+ central memory T cells were higher in both IL-2- and IFN-γ + IL-2-producing cellular responders compared with non-responders. These data suggest that cellular and humoral immunogenicity against SARS-CoV-2 vaccination or infection is associated with the memory phenotype of T cells and B cells in adult allogeneic HCT recipients.

Tissue-Resident Memory T Cells in Gastrointestinal Cancers: Prognostic Significance and Therapeutic Implications.

Gastrointestinal cancers, which include a variety of esophageal and colorectal malignancies, present a global health challenge and require effective treatment strategies. In the evolving field of cancer immunotherapy, tissue-resident memory T cells (Trm cells) have emerged as important players in the immune response within nonlymphoid tissues. In this review, we summarize the characteristics and functions of Trm cells and discuss their profound implications for patient outcomes in gastrointestinal cancers. Positioned strategically in peripheral tissues, Trm cells have functions beyond immune surveillance, affecting tumor progression, prognosis, and response to immunotherapy. Studies indicate that Trm cells are prognostic markers and correlate positively with enhanced survival. Their presence in the tumor microenvironment has sparked interest in their therapeutic potential, particularly with respect to immune checkpoint inhibitors, which may improve cancer treatment. Understanding how Trm cells work will not only help to prevent cancer spread through effective treatment but will also contribute to disease prevention at early stages as well as vaccine development. The role of Trm cells goes beyond just cancer, and they have potential applications in infectious and autoimmune diseases. This review provides a thorough analysis of Trm cells in gastrointestinal cancers, which may lead to personalized and effective cancer therapies.

Patients taking benralizumab, dupilumab, or mepolizumab have lower postvaccination SARS-CoV-2 immunity.

BACKGROUND: Biologic therapies inhibiting the IL-4 or IL-5 pathways are very effective in the treatment of asthma and other related conditions. However, the cytokines IL-4 and IL-5 also play a role in the generation of adaptive immune responses. Although these biologics do not cause overt immunosuppression, their effect in primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization has not been studied completely. OBJECTIVE: Our aim was to evaluate the antibody and cellular immunity after SARS-CoV-2 mRNA vaccination in patients on biologics (PoBs). METHODS: Patients with severe asthma or atopic dermatitis who were taking benralizumab, dupilumab, or mepolizumab and had received the initial dose of the 2-dose adult SARS-CoV-2 mRNA vaccine were enrolled in a prospective, observational study. As our control group, we used a cohort of immunologically healthy subjects (with no significant immunosuppression) who were not taking biologics (NBs). We used a multiplexed immunoassay to measure antibody levels, neutralization assays to assess antibody function, and flow cytometry to quantitate Spike-specific lymphocytes. RESULTS: We analyzed blood from 57 patients in the PoB group and 46 control subjects from the NB group. The patients in the PoB group had lower levels of SARS-CoV-2 antibodies, pseudovirus neutralization, live virus neutralization, and frequencies of Spike-specific B and CD8 T cells at 6 months after vaccination. In subgroup analyses, patients with asthma who were taking biologics had significantly lower pseudovirus neutralization than did subjects with asthma who were not taking biologics. CONCLUSION: The patients in the PoB group had reduced SARS-CoV-2-specific antibody titers, neutralizing activity, and virus-specific B- and CD8 T-cell counts. These results have implications when considering development of a more individualized immunization strategy in patients who receive biologic medications blocking IL-4 or IL-5 pathways.

Elevated memory T-cell conversion in a preclinical mouse model of hemophilia A.

One of the major challenges in the choice of the best therapeutic approach for the treatment of patients affected by hemophilia A (HA) is the definition of criteria predicting the formation of factor VIII (FVIII) neutralizing antibodies, called inhibitors. Both genetic and environmental elements influencing the immune response toward FVIII have been identified but still not all the factors causing the pathological rejection of FVIII have been identified. Since there is a connection between coagulation and inflammation, here we assessed the role played by the FVIII deficiency in shaping the humoral and cellular response toward an antigen other than FVIII itself. To this aim, we challenged both HA and wild-type (WT) mice with either FVIII or ovalbumin (OVA) and followed antigen-specific antibody level, immune cell population frequency and phenotype up to 9 weeks after the last antigen booster. The activation threshold was evaluated in vitro by stimulating the murine T cells with a decreasing dose of α-CD3. The humoral response to FVIII was similar between the two groups while both the in vivo and in vitro experiments highlighted an antigen-independent sensitivity of HA compared with WT T cells causing an increase in memory T-cell conversion and proliferation capability.

Immunological insights into hypertension: unraveling triggers and potential therapeutic avenues.

Hypertension remains the leading cause of morbidity and mortality worldwide. Despite its prevalence, the development of novel antihypertensive therapies has only recently accelerated, with novel agents not yet commercialized, leaving a substantial proportion of individuals resistant to existing treatments. The intricate pathophysiology of hypertension is now understood to involve chronic low-grade inflammation, which places the immune system in the spotlight as a potential target for new therapeutics. This review explores the factors that initiate and sustain an immune response in hypertension, offering insights into potential targets for new treatments. Several factors contribute to immune activation in hypertension, including diet and damage-associated molecular pattern (DAMP) generation. Diets rich in fat or sodium can promote inflammation by inducing intestinal barrier dysfunction and triggering salt-sensitive receptors in T cells and dendritic cells. DAMPs, such as extracellular adenosine triphosphate and heat-shock protein 70, are released during episodes of increased blood pressure, contributing to immune cell activation and inflammation. Unconventional innate-like γδ T cells contribute to initiating and maintaining an immune response through their potential involvement in antigen presentation and regulating cytokine-mediated responses. Immunologic memory, sustained through the formation of effector memory T cells after exposure to hypertensive insults, likely contributes to maintaining an immune response in hypertension. When exposed to hypertensive insults, these memory cells are rapidly activated and contribute to elevated blood pressure and end-organ damage. Evidence from human hypertension, although limited, supports the relevance of distinct immune pathways in hypertension, and highlights the potential of targeted immune interventions in human hypertension. Diet and acute bouts of high blood pressure result in the release of dietary triggers, neoantigens, and damage-associated molecular patterns (DAMPs), which promote immune system activation. Elements such as lipopolysaccharides (LPS), sodium, heat-shock protein (HSP)70, extracellular adenosine triphosphate (eATP), and growth arrest-specific 6 (GAS6) promote activation of innate immune cells such as dendritic cells (DCs) and monocytes (Mo) through their respective receptors (toll-like receptor [TLR]4, amiloride-sensitive epithelial sodium channel [ENaC], TLR2/4, P2X7 receptor [P2RX7], and Axl) leading to costimulatory molecule expression and interleukin (IL)-1ß and IL-23 production. The neoantigens HSP70 and isolevuglandins (IsoLGs) are presented to T cells by DCs and possibly γδ T cells, triggering T cell activation, IL-17 and interferon (IFN)-γ production, and the formation of T effector memory (TEM) cells in the kidney, perivascular adipose tissue, bone marrow, and spleen. Exposure of TEM cells to their cognate antigen or previous activating stimuli causes these cells rapid expansion and activation. Cumulatively, this inflammatory state contributes to hypertension and end-organ damage. The figure was created using images from smart.servier.com and is licensed under a Creative Commons Attribution 4.0 license (CC BY 4.0).

Alterations in CD4+ T-cell Subsets in Living Donor Liver Transplantation Associated With Graft Rejection.

Background and objectives: Regulatory T-cells (Tregs) play a key role in immune homeostasis after organ transplantation. However, the role of CD4+ T cell subsets in early acute rejection is still not well understood. Therefore, our aim was to determine changes in CD4+ T-cell subsets in living donor liver transplantation (LDLT). Methods: LDLT patients were assessed for T-cell subsets, Tregs frequencies and their functionality by flow-cytometry at peri- and post-transplant in the span of 1 year. Results: 33 patients were followed up and 11 (33%) patients have developed early acute cellular rejection (ACR). At peri-transplant time point, MFI of Foxp3+ Tregs was significantly increased compared to HC (P = 0.04). However, CD4+CD25+Foxp3+/CD127- Tregs numbers and IL-10, IL-17 and TGF-ß secreting functional Tregs were significantly decreased at 3 months compared to peri-transplant (P = 0.003). But in patients with rejection, CD4+CD25+FOXP3+ and CD4+CD25+CD127- Tregs were significantly decreased at day 3 compared to no rejection group (P = 0.048). Patients with rejection also showed significantly decreased numbers of IL-17 and TGF-ß secreting CD4+CD25+FOXP3+ Tregs at peri-transplant time (P = 0.04, P = 0.03) compared to no rejection. Further, rejection group showed decreased terminally differentiated effector memory (TEMRA) at peri-transplant and day 7 (P = 0.048 and P = 0.01). Additionally, CD4+ central memory (CM) was decreased at peri-transplant (P = 0.05), 1 month (P = 0.04), and 3 to 6 month (P = 0.02). Interpretation and conclusion: Tregs frequencies were significantly decreased in peri-TX in rejection patients. Further, decreased frequencies of CD4+ TEMRA and CD4+ CM at day 7 and 1 month were associated with rejection.

Heterogeneity and plasticity of tissue-resident memory T cells in skin diseases and homeostasis: a review.

Skin tissue-resident memory T (Trm) cells are produced by antigenic stimulation and remain in the skin for a long time without entering the peripheral circulation. In the healthy state Trm cells can play a patrolling and surveillance role, but in the disease state Trm cells differentiate into various phenotypes associated with different diseases, exhibit different localizations, and consequently have local protective or pathogenic roles, such as disease recurrence in vitiligo and maintenance of immune homeostasis in melanoma. The most common surface marker of Trm cells is CD69/CD103. However, the plasticity of tissue-resident memory T cells after colonization remains somewhat uncertain. This ambiguity is largely due to the variation in the functionality and ultimate destination of Trm cells produced from memory cells differentiated from diverse precursors. Notably, the presence of Trm cells is not stationary across numerous non-lymphoid tissues, most notably in the skin. These cells may reenter the blood and distant tissue sites during the recall response, revealing the recycling and migration potential of the Trm cell progeny. This review focuses on the origin and function of skin Trm cells, and provides new insights into the role of skin Trm cells in the treatment of autoimmune skin diseases, infectious skin diseases, and tumors.

Fiber rich food suppressed airway inflammation, GATA3 + Th2 cells, and FcεRIα+ eosinophils in asthma.

Background: Allergic Asthma is a disease presenting various endotypes and no current therapies act curative but alleviate disease symptoms. Dietary interventions are gaining increasing importance in regulating immune responses. Furthermore, short chain fatty acids (SFCA), as the main products of dietary fiber's fermentation by the gut bacteria, ameliorate the pathogenesis and disease burden of different illnesses including asthma. Nevertheless, the connection and crosstalk between the gut and lung is poorly understood. Objective: In this work, the role of high fiber diet on the development of allergic asthma at baseline and after exacerbation of disease induced by respiratory viruses was investigated. Methods: Hereby, SCFA in serum of asthmatic and non-asthmatic pre-school children before and after airway disease symptoms were analyzed. Moreover, the effect of high fiber diet in vivo in a murine model of house dust mite extract (HDM) induced allergic asthma and in the end in isolated lung and spleen cells infected ex vivo with Rhinovirus was analyzed. Results: In this study, a decrease of the SCFA 3-Hydroxybutyric acid in serum of asthmatic children after symptomatic episodes at convalescent visit as compared to asthmatic and control children at baseline visit was observed. In experimental asthma, in mice fed with high fiber diet, a reduced lung GATA3 + Th2 type mediated inflammation, mucus production and collagen deposition and expression of Fc epsilon receptor Ia (FcεRIa) in eosinophils was observed. By contrast, the CD8+ memory effector T cells were induced in the lungs of asthmatic mice fed with high fiber diet. Then, total lung cells from these asthmatic mice fed with either standard food or with fiber rich food were infected with RV ex vivo. Here, RV1b mRNA was found significantly reduced in the lung cells derived from fiber rich food fed mice as compared to those derived from standard food fed asthmatic mice. Looking for the mechanism, an increase in CD8+ T cells in RV infected spleen cells derived from fiber rich fed asthmatic mice, was observed. Conclusion: Convalescent preschool asthmatic children after a symptomatic episode have less serum ß-Hydroxybutyric acid as compared to control and asthmatic children at baseline visit. Fiber rich diet associated with anti-inflammatory effects as well as anti-allergic effects by decreasing Type 2 and IgE mediated immune responses and inducing CD8+ memory effector T cells in a murine model of allergic asthma. Finally, ex vivo infection with Rhinovirus (RV) of total lung cells from asthmatic mice fed with fiber rich food led to a decreased RV load as compared to mice fed with standard food. Moreover, spleen cells derived from asthmatic mice fed with fiber rich food induced CD8+ T cells after ex vivo infection with RV. Clinical implications: Dietary interventions with increased content in natural fibers like pectins would ameliorate asthma exacerbations. Moreover, respiratory infection in asthma downregulated SCFA in the gut contributing to asthma exacerbations.

Comparison of T cell maturation profiles in the 1st and 5th wave of COVID-19 in the Polish population.

BACKGROUND: The coronavirus pandemic has become the most critical global health threat of this century and the greatest challenge to the human population. The search for simple and quick diagnostic methods enabling the identification of patients infected with the SARS-CoV-2 virus may be a valuable method to track infection. OBJECTIVES: The aim of the study was the clinical and immunological characterization of patients by assessing the degrees of maturity of T lymphocytes from the 1st and 5th waves of coronavirus disease 2019 (COVID-19) in comparison to a healthy control group (HC). MATERIAL AND METHODS: We determined leukocyte and T lymphocyte subpopulations (recent thymic emigrant (RTE), naïve, effector, central memory and effector memory) in patients from the 1st COVID-19 wave (n = 23), the 5th COVID-19 wave (n = 38) and HC (n=20) using a panel of monoclonal antibodies using multiparameter flow cytometry. RESULTS: We observed a lower median proportion of lymphocytes and NK cells, and elevated percentage and number of neutrophils in patients from the 5th wave compared to the 1st. We found a reduced percentage of CD4+ effector memory cells in the 1st wave group compared to the 5th wave (14.1 vs 23.2, p < 0.05), and a higher percentage of RTE and naïve CD8+ cells in the 1st wave compared to the 5th wave (p < 0.05). The effector memory CD8+ cells were highest in the 5th wave compared to both 1st wave and HC patients (respectively, 35.1 vs 18.1 vs 19.3%, p < 0.05). The 5th wave group showed significantly more differences compared to HC. CONCLUSIONS: Our results showed a clear increase of effector cells with a simultaneous decrease in virgin T cells in the 5th COVID-19 infection. Monitoring lymphocyte subsets during infection allows assessment of the patient's immune status and of readiness of lymphocytes to respond to the immune response, and may be necessary to improve clinical outcomes.

Crohn's disease treatment and memory T-cell subset changes: insights from a case series.

Background: Crohn's disease (CD) is a chronic inflammatory bowel disease with significant morbidity, affecting millions worldwide. The intricacies of immune responses in CD, especially post-treatment, remain a vital area of exploration. While memory T (Tm)-cell subsets play a pivotal role in adaptive immunity, their specific function in patients with CD after treatment is not well-understood. This study aims to investigate the effect and function of Tm-cell subsets in these patients, addressing a crucial knowledge gap in the context of CD therapeutics. Methods: A total of eight patients diagnosed with CD were selected based on predefined inclusion criteria. All patients were treated with either anti-inflammatory agents, immunosuppressive drugs, or a combination of both. For comparison, healthy donors were enrolled based on exclusion of autoimmune or inflammatory diseases. Peripheral blood mononuclear cells (PBMCs) and lymphocytes were isolated from blood and lymph node tissue respectively. The phenotype and cytokine production of T lymphocytes from both CD patients and healthy donors were analyzed using flow cytometry. Statistical comparisons of the outcomes between CD patients and healthy donors were made using Mann-Whitney test (two-tailed) and Student t-test. Results: Post-treatment CD patients exhibited an altered T cell distribution with a notable increase in CD8+ T cells in PBMCs (P=0.0005), and altered frequencies of CD4+ and CD8+ T cells in mesenteric lymph nodes (MLNs). Tm cells showed decreased interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production, with significant alterations in the frequency of IFN-γ-producing CD8+ stem cell-like Tm (Tscm) cells in lesions of the MLNs from patients with CD (CD-M-Lys) compared to healthy MLNs from patients with CD (N-M-Lys) (P=0.0152). Differences in tissue-resident Tm (Trm)-cell subset frequencies were observed between the MLNs and small intestinal mucosa in CD patients. Conclusions: The treatments with anti-inflammatory agents and/or immunosuppressive drugs have a significant effect on the frequency and function of Tm-cell subsets. Clinically, these findings suggest a potential therapeutic avenue in modulating Tm-cell responses, which might be particularly beneficial for conditions where immune response modulation is crucial. Further clinical studies are warranted to explore the full therapeutic implications of these findings.

Innate phase production of IFN-γ by memory and effector T cells expressing early activation marker CD69 during infection with Cryptococcus deneoformans in the lungs.

Cryptococcus deneoformans is a yeast-type fungus that causes fatal meningoencephalitis in immunocompromised patients and evades phagocytic cell elimination through an escape mechanism. Memory T (Tm) cells play a central role in preventing the reactivation of this fungal pathogen. Among these cells, tissue-resident memory T (TRM) cells quickly respond to locally invaded pathogens. This study analyzes the kinetics of effector T (Teff) cells and Tm cells in the lungs after cryptococcal infection. Emphasis is placed on the kinetics and cytokine expression of TRM cells in the early phase of infection. CD4+ Tm cells exhibited a rapid increase by day 3, peaked at day 7, and then either maintained their levels or exhibited a slight decrease until day 56. In contrast, CD8+ Tm cells reached their peak on day 3 and thereafter decreased up to day 56 post-infection. These Tm cells were predominantly composed of CD69+ TRM cells and CD69+ CD103+ TRM cells. Disruption of the CARD9 gene resulted in reduced accumulation of these TRM cells and diminished interferon (IFN) -γ expression in TRM cells. TRM cells were derived from T cells with T cell receptors non-specific to ovalbumin in OT-II mice during cryptococcal infection. In addition, TRM cells exhibited varied behavior in different tissues. These results underscore the importance of T cells, which produce IFN-γ in the lungs during the early stage of infection, in providing early protection against cryptococcal infection through CARD9 signaling.