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Expansion of CD4+CD28null T‐lymphocytes is common in chronic heart failure (CHF) patients. Its ability to produce high levels of proinflammatory cytokines is probably the key role of these cells in CHF. IL‐10 is a candidate for limiting CD4+CD28null T‐lymphocyte responses, whereas tumour necrosis factor (TNF) is the cytokine most closely involved in the loss of CD28 expression. Serum levels of TNF and IL‐10 were measured in 65 CHF patients (mean age, 65.2 ± 13.84 years). Patients with an IL‐10/TNF ratio ≥1 had significantly lower levels of CD4+CD28null T‐lymphocytes than those with a ratio <1. In vitro, IL‐10 reduced the frequency of proliferative CD4+CD28null T‐lymphocytes stimulated with anti‐CD3. Pre‐treatment with IL‐10 before anti‐CD3 stimulation was required for the cytokine to inhibit TNF production by CD4+CD28null T‐lymphocytes. In addition to the previously described effect of IL‐10 on HLA‐DR and ICAM‐1 expression, LFA‐3 protein and mRNA levels were reduced in the presence of the cytokine in monocytes. IL‐10 inhibition on CD4+CD28null T‐lymphocytes may be mediated by a reduction in HLA class II and LFA‐3 expression because blocking interactions with these costimulators has similar effects to those of IL‐10 treatment. Moreover, costimulation through CD2/LFA‐3 interaction is enough to induce proliferation and cytokine production in CD4+CD28null T‐lymphocytes. [ABSTRACT FROM AUTHOR]

Simple Summary: Current recommendations suggest setting two parallel cytogenetic cultures with 12-O-tetradecanoly-phorpol-13-acetate (TPA) and IL2+DSP30 as a mitogen to detect complex karyotypes (CKs) in chronic lymphocytic leukemia (CLL). However, studies comparing CK detection concordance between both methods in the same cohort are lacking. Herein, we evaluated the performance of two parallel cultures in a CLL cohort of 255 patients, specifically comparing CK detection (globally and in each individual patient). The CK detection rates and their prognostic impacts were similar for both mitogens. However, nearly one-third of CKs were only identified in one culture, mainly due to the detection of a normal karyotype or no metaphases in the other. In summary, the assessment of parallel cytogenetic cultures is the best strategy to detect CKs in CLL. Nonetheless, as IL2+DSP30 achieved the best performance, it should be prioritized above TPA if a single analysis is required to optimize cytogenetic assessment in routine practice. Current CLL guidelines recommend a two parallel cultures assessment using TPA and IL2+DSP30 mitogens for complex karyotype (CK) detection. Studies comparing both mitogens for CK identification in the same cohort are lacking. We analyzed the global performance, CK detection, and concordance in the complexity assessment of two cytogenetic cultures from 255 CLL patients. IL2+DSP30 identified more altered karyotypes than TPA (50 vs. 39%, p = 0.031). Moreover, in 71% of those abnormal by both, IL2+DSP30 identified more abnormalities and/or abnormal metaphases. CK detection was similar for TPA and IL2+DSP30 (10% vs. 11%). However, 11/33 CKs (33%) were discordant, mainly due to the detection of a normal karyotype or no metaphases in the other culture. Patients requiring treatment within 12 months after sampling (active CLL) displayed significantly more CKs than those showing a stable disease (55% vs. 12%, p < 0.001). Disease status did not impact cultures' concordance (κ index: 0.735 and 0.754 for stable and active). Although CK was associated with shorter time to first treatment (TTFT) using both methods, IL2+DSP30 displayed better accuracy than TPA for predicting TTFT (C-index: 0.605 vs. 0.580, respectively). In summary, the analysis of two parallel cultures is the best option to detect CKs in CLL. Nonetheless, IL2+DSP30 could be prioritized above TPA to optimize cytogenetic assessment in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Chromothripsis, a genomic event that generates massive chromosomal rearrangements, has been described in 1–3% of CLL patients and is associated with poor prognostic factors (e.g., TP53 abnormalities and genomic complexity). However, previous studies have not assessed its role in CLL patients with complex karyotypes. Herein, we aimed to describe the genetic characteristics of 33 CLL patients with high genomic complexity and chromothripsis. Moreover, we analyzed the clinical impact of chromothripsis, comparing these patients against a cohort of 129 patients with complex karyotypes not presenting this catastrophic event. Nine cases were also assessed via the novel cytogenomic methodology known as optical genome mapping. We confirmed that this phenomenon is heterogeneous and associated with a shorter time to first treatment. Nonetheless, our findings suggested that TP53 abnormalities, rather than chromothripsis itself, underlie the dismal outcome. Chromothripsis (cth) has been associated with a dismal outcome and poor prognosis factors in patients with chronic lymphocytic leukemia (CLL). Despite being correlated with high genome instability, previous studies have not assessed the role of cth in the context of genomic complexity. Herein, we analyzed a cohort of 33 CLL patients with cth and compared them against a cohort of 129 non-cth cases with complex karyotypes. Nine cth cases were analyzed using optical genome mapping (OGM). Patterns detected by genomic microarrays were compared and the prognostic value of cth was analyzed. Cth was distributed throughout the genome, with chromosomes 3, 6 and 13 being those most frequently affected. OGM detected 88.1% of the previously known copy number alterations and several additional cth-related rearrangements (median: 9, range: 3–26). Two patterns were identified: one with rearrangements clustered in the region with cth (3/9) and the other involving both chromothriptic and non-chromothriptic chromosomes (6/9). Cases with cth showed a shorter time to first treatment (TTFT) than non-cth patients (median TTFT: 2 m vs. 15 m; p = 0.013). However, when stratifying patients based on TP53 status, cth did not affect TTFT. Only TP53 maintained its significance in the multivariate analysis for TTFT, including cth and genome complexity defined by genomic microarrays (HR: 1.60; p = 0.029). Our findings suggest that TP53 abnormalities, rather than cth itself, underlie the poor prognosis observed in this subset. [ABSTRACT FROM AUTHOR]

Simple Summary: Genome complexity, detected by chromosome banding analysis or chromosomal microarray analysis, is a poor prognostic factor for chronic lymphocytic leukemia (CLL). Herein, we aimed to assess the performance of optical genome mapping (OGM) for the cytogenomic characterization of CLL patients, with a special focus on risk stratification based on genomic complexity. A cohort of 42 patients enriched in complex karyotypes was assessed by OGM, and the results were compared with those obtained from current methods. Moreover, clinical–biological characteristics and time to first treatment were analyzed according to the OGM-defined complexity. Globally, OGM identified 90% of the known alterations and provided novel structural information about these aberrations in 55% of patients. Regarding genomic complexity, OGM allowed us to identify a complex group (≥10 alterations) displaying enrichment of TP53 abnormalities and poorer evolution. Altogether, we confirmed that OGM is a valuable tool for the cytogenomic assessment and prognostic stratification of CLL patients. Novel treatments in chronic lymphocytic leukemia (CLL) have generated interest regarding the clinical impact of genomic complexity, currently assessed by chromosome banding analysis (CBA) and chromosomal microarray analysis (CMA). Optical genome mapping (OGM), a novel technique based on imaging of long DNA molecules labeled at specific sites, allows the identification of multiple cytogenetic abnormalities in a single test. We aimed to determine whether OGM is a suitable alternative to cytogenomic assessment in CLL, especially focused on genomic complexity. Cytogenomic OGM aberrations from 42 patients were compared with CBA, FISH, and CMA information. Clinical–biological characteristics and time to first treatment (TTFT) were analyzed according to the complexity detected by OGM. Globally, OGM identified 90.3% of the known alterations (279/309). Discordances were mainly found in (peri-)centromeric or telomeric regions or subclonal aberrations (<15–20%). OGM underscored additional abnormalities, providing novel structural information on known aberrations in 55% of patients. Regarding genomic complexity, the number of OGM abnormalities had better accuracy in predicting TTFT than current methods (C-index: 0.696, 0.602, 0.661 by OGM, CBA, and CMA, respectively). A cut-off of ≥10 alterations defined a complex OGM group (C-OGM, n = 12), which included 11/14 patients with ≥5 abnormalities by CBA/CMA and one patient with chromothripsis (Kappa index = 0.778; p < 0.001). Moreover, C-OGM displayed enrichment of TP53 abnormalities (58.3% vs. 3.3%, p < 0.001) and a significantly shorter TTFT (median: 2 vs. 43 months, p = 0.014). OGM is a robust technology for implementation in the routine management of CLL patients, although further studies are required to define standard genomic complexity criteria. [ABSTRACT FROM AUTHOR]

Understanding how older people respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical if we are to confront the coronavirus disease 2019 (COVID-19) pandemic and establish effective vaccination strategies. Immunosenescence reduces the ability to respond to neoantigens and may compromise the life of infected individuals. Here, we analyzed the immunological memory to SARS-CoV-2 in 102 recovered patients aged over 60 years several months after the infection had been resolved. Specific memory T lymphocytes against the virus were measured by interferon-γ (IFN-γ) and granzyme B release by ELISpot; memory B-lymphocyte responses were quantified by detection of anti-S IgG1 producer cells by ELISpot and anti-S and anti-N antibodies were determined by enzyme-linked immunosorbent assay (ELISA). Memory T lymphocytes were found in peripheral blood of most of the studied donors, more than 7 months after the infection in some of them. Fewer patients maintained memory B lymphocytes, but antibodies, mainly anti-S, were highly durable and positively correlated with T responses. More robust humoral responses were found in patients who had more severe symptoms and had been admitted to hospital. We concluded that specific immunity against SARS-CoV-2 is effectively preserved regardless of age, despite the great heterogeneity of their immune responses, and that memory T lymphocytes and anti-S IgG might be more durable than memory B cells and anti-N IgG. [ABSTRACT FROM AUTHOR]

The exquisite coupling between herpesvirus and human beings is the result of millions of years of relationship, coexistence, adaptation, and divergence. It is probably based on the ability to generate a latency that keeps viral activity at a very low level, thereby apparently minimising harm to its host. However, this evolutionary success disappears in immunosuppressed patients, especially in haematological patients. The relevance of infection and reactivation in haematological patients has been a matter of interest, although one fundamentally focused on reactivation in the post-allogeneic stem cell transplant (SCT) patient cohort. Newer transplant modalities have been progressively introduced in clinical settings, with successively more drugs being used to manipulate graft composition and functionality. In addition, new antiviral drugs are available to treat CMV infection. We review the immunological architecture that is key to a favourable outcome in this subset of patients. Less is known about the effects of herpesvirus in terms of mortality or disease progression in patients with other malignant haematological diseases who are treated with immuno-chemotherapy or new molecules, or in patients who receive autologous SCT. The absence of serious consequences in these groups has probably limited the motivation to deepen our knowledge of this aspect. However, the introduction of new therapeutic agents for haematological malignancies has led to a better understanding of how natural killer (NK) cells, CD4+ and CD8+ T lymphocytes, and B lymphocytes interact, and of the role of CMV infection in the context of recently introduced drugs such as Bruton tyrosine kinase (BTK) inhibitors, phosphoinosytol-3-kinase inhibitors, anti-BCL2 drugs, and even CAR-T cells. We analyse the immunological basis and recommendations regarding these scenarios. [ABSTRACT FROM AUTHOR]

High levels of inflammation play an important role in chronic heart failure (CHF). Patients with CHF have elevated levels of pro-inflammatory cytokines circulating systemically, mainly TNF and IL-6. However, there are almost no studies that relate these levels to the functional status of patients in CHF, much less to their CMV serostatus. In this study, patients with CHF (n=40; age=54.9 ± 6.3; New York Heart Association functional classification (NYHA, I-III) and healthy controls (n=40; age=53.5 ± 7.1) were analyzed. The serum concentrations of nine pro- and anti-inflammatory cytokines were measured by Luminex® xMap Technology and the basal level of mRNA expression of some immune molecules was quantified by TaqMan™ Array in CD4+ T-lymphocytes. The concentration of these cytokines in culture supernatants in response to anti-CD3 and LPS was also measured. The percentage of CD28null T-cells was determined, as well as the antibody titer against CMV. We found a higher concentration of all cytokines studied in CHF serum compared to healthy controls, as well as a direct correlation between functional status in CHF patients and levels of inflammatory cytokines. Moreover, the highest cytokine concentrations were found in patients with higher concentrations of lymphocytes lacking CD28 molecule. The cytokine production was much higher in CMV+ patients, and the production of these cytokines was found mainly in the T-lymphocytes of CMV+ patients in response to anti-CD3. Anti-CMV antibody levels were positively correlated with cytokine levels. The baseline expression of specific mRNA of the main molecules involved in the Th1 response, as well as molecules related to the CD4+CD28 null subset was higher in CMV+ patients. The cytokine concentrations are higher in CHF CMV+ patients and these concentrations are related to the production of antibodies against CMV. These high levels of cytokines are also associated with the more differentiated CD28null lymphocyte populations. All this, together with the dynamics of the pathology itself, makes CMV+ patients present a worse functional status and possibly a worse evolution of the pathology. [ABSTRACT FROM AUTHOR]

Diagnosis of hematolymphoid neoplasm (HLN) requires different technologies which are performed on a patient basis instead of per protocol. We hypothesize that integration of hematimetric and cytological analysis along with multiparametric flow cytometry (MFC) provides a framework to evaluate peripheral blood (PB) samples from Primary Care. Samples from patients with persistent (>3 months) lymphocytosis (>5 × 109/L) and/or monocytosis (>109/L) or the presence of atypical and/or blast cells upon the smear review were analyzed by MFC concurrent to cytological analysis. MFC studies were carried out following standardized procedures. In a 3-year period, smear review and MFC were performed simultaneously in 350 samples, demonstrating HLN in 194 cases (55.4%). In 156 cases, reactive cell populations were found. The combination of age, absolute lymphocyte count (ALC), hemoglobin and platelets provided the best correlation with MFC for the presence of a chronic lymphoproliferative disorder (CLPD) in lymphocytosis [area under the curve (AUC) 0.891, p < 0.05]. A model evaluating the probability of CLPD has been proposed and validated in an independent cohort. A strategy to perform MFC studies following standardized procedures has proven to be useful to evaluate samples from patients in Primary Care centers for HLN diagnosis or reactive conditions, providing a sensitive and rapid clinical orientation and avoiding unnecessary consultations in routine clinical practice. The probability for the presence of CLPD in PB can be calculated and help guide decision-making regarding further testing. [ABSTRACT FROM AUTHOR]

There are strong evidences that probiotics influence the immune status of the host, in a strain-specific manner, acting in the gastrointestinal tract. On the hypothesis that certain extracellular proteins and peptides from gut bacteria may mediate part of this immunomodulation and assuming they are able to diffuse through the mucus layer and interact with immune cells we have developed this work. Our study attempts to understand the immunomodulatory mechanisms of (i) Pext, the extracellular protein fraction of Lactobacillus acidophilus DSM20079T, (ii) HM14, a peptide encrypted in an extracellular glycoside hydrolase from Bifidobacterium longum NCIMB 8809 and (iii) Escherichia coli O111:B4 lipopolysaccharide (LPS), a well-known pro-inflammatory molecule, over human peripheral blood mononuclear cells (PBMCs). An untargeted LC-ESI-QTOF-MS metabolomics approach was applied to reveal intracellular changes in treated-PBMCs isolated from healthy donors. Differences in NADH arrest, NAD+ concentration reduction, as well as increases in palmitic acid and methanephrin were observed in HM14 and Pext treated-cells compared to those stimulated with LPS. This would support an anti-inflammatory molecular mechanism of action of such proteinaceous molecules. Moreover, this methodology has confirms the importance of metabolomics approaches to better understanding immune cell responses to gut bacterial-derived molecules. [ABSTRACT FROM AUTHOR]

Anti-CMV (cytomegalovirus) antibody titers are related to immune alterations and increased risk of mortality. To test whether they represent a marker of infection history, we analyzed the effect of viral reactivations on the production of specific antibodies in kidney transplant patients. We quantified CMV-DNAemia and antibody titers in 58 kidney transplant patients before transplantation and during a follow-up of 315 days (standard deviation, SD: 134.5 days). In order to calculate the intensity of the infection, we plotted the follow-up time of the infection on the x-axis and the number of DNA-CMV copies on the y-axis and calculated the area under the curve (CMV-AUC). The degree of T-lymphocyte differentiation was analyzed with flow cytometry, the cells were labelled with different monoclonal antibodies in order to distinguish their differentiation state, from naive T-cells to senescent T-cells. Peak viremia was significantly higher in patients experiencing a primary infection (VI) compared to patients experiencing viral reactivation (VR). Our data indicate that the overall CMV viral load over the course of a primary infection is significantly higher than in a reactivation of a previously established infection. Whereas patients who experienced an episode of CMV reactivation during the course of our observation showed increased levels of CMV-specific antibodies, patients who did not experience CMV reactivation (WVR) showed a drop in CMV antibody levels that corresponds to an overall drop in antibody levels, probably due to the continuing immunosuppression after the renal transplant. We found a positive correlation between the CMV viremia over the course of the infection or reactivation and the CMV-specific antibody titers in the examined patients. We also observed a positive correlation between anti-CMV titers and T-cell differentiation. In conclusion, our data show that anti-CMV antibody titers are related to the course of CMV infection in kidney transplant patients. [ABSTRACT FROM AUTHOR]

Scientific studies focused on the role of the human microbiome over human health have generated billions of gigabits of genetic information during the last decade. Nowadays integration of all this information in public databases and development of pipelines allowing us to biotechnologically exploit this information are urgently needed. Prediction of the potential bioactivity of the products encoded by the human gut microbiome, or metaproteome, is the first step for identifying proteins responsible for the molecular interaction between microorganisms and the immune system. We have recently published the Mechanism of Action of the Human Microbiome (MAHMI) database (http://www.mahmi.org), conceived as a resource compiling peptide sequences with a potential immunomodulatory activity. Fifteen out of the 300 hundred million peptides contained in the MAHMI database were synthesized. These peptides were identified as being encrypted in proteins produced by gut microbiota members, they do not contain cleavage points for the major intestinal endoproteases and displayed high probability to have immunomodulatory bioactivity. The bacterial peptides FR-16 and LR-17 encrypted in proteins from Bifidobacterium longum DJ010A and Bifidobacterium fragilis YCH46 respectively, showed the higher immune modulation capability over human peripheral blood mononuclear cells. Both peptides modulated the immune response toward increases in the Th17 and decreases in the Th1 cell response, together with an induction of IL-22 production. These results strongly suggest the combined use of bioinformatics and in vitro tools as a first stage in the screening of bioactive peptides encrypted in the human gut metaproteome. [ABSTRACT FROM AUTHOR]

Large genome-wide analysis studies (GWAS) and meta-analyses have dramatically increased our knowledge of the genetic risk factors of inflammatory bowel disease (IBD), identifying at least 163 loci. The endoplasmic reticulum aminopeptidase-2 (ERAP2) gene has been reported as a potential candidate gene for IBD. GWAS have also shown the potential associations between ERAP single nucleotide polymorphisms (SNP) loci and susceptibility to several autoimmune diseases, and ERAP1 and ERAP2 polymorphisms are related to HLA class I-associated diseases, including ankylosing spondylitis and Behçet’s disease. Interestingly, these associations were confined to individuals carrying HLA class I-risk alleles. The aim of this study was to investigate the association of ERAP1 and ERAP2 SNPs with IBD in a Spanish population, analysing their possible interaction with specific HLA-C alleles to IBD susceptibility. A total of 367 individuals were divided into 216 IBD cases and 151 controls. SNP genotyping was performed using TaqMan® genotyping assays, whereas HLA-C typing was analysed by sequence-specific oligonucleotide probing. Herein, we report an association of the ERAP1 SNP rs30187 with the HLA-C*07 allele. The existence of shared inflammatory pathways in immunologically related diseases together with the understanding of ERAP1 function may offer clues to novel treatment strategies. [ABSTRACT FROM AUTHOR]

Beyond midlife, the immune system shows aging features and its defensive capability becomes impaired, by a process known as immunosenescence that involves many changes in the innate and adaptive responses. Innate immunity seems to be better preserved globally, while the adaptive immune response exhibits profound age-dependent modifications. Elderly people display a decline in numbers of naïveT-cells in peripheral blood and lymphoid tissues, while, in contrast, their proportion of highly differentiated effector and memory T cells, such as the CD28null T-cells, increases markedly. Naïve and memory CD4C T-cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T-cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T-cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naïve CD4C T-cells throughout life, but although later than in CD8CT-cell compartment, these mechanisms ultimately fail with age. [ABSTRACT FROM AUTHOR]

Beyond midlife, the immune system shows aging features and its defensive capability becomes impaired, by a process known as immunosenescence that involves many changes in the innate and adaptive responses. Innate immunity seems to be better preserved globally, while the adaptive immune response exhibits profound age-dependent modifications. Elderly people display a decline in numbers of naïve T-cells in peripheral blood and lymphoid tissues, while, in contrast, their proportion of highly differentiated effector and memory T-cells, such as the CD28null T-cells, increases markedly. Naïve and memory CD4+ T-cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T-cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T-cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naïve CD4+ T-cells throughout life, but although later than in CD8+T-cell compartment, these mechanisms ultimately fail with age. [ABSTRACT FROM AUTHOR]

Summary One of the most prominent changes during T-cell aging in humans is the accumulation of CD28null T cells, mainly CD8+ and also CD4+ T cells. Enhancing the functional properties of these cells may be important as they provide an antigen-specific defense against chronic infections. Recent studies have shown that IL-15 does in fact play an appreciable role in CD4 memory T cells under physiological conditions. We found that treatment with IL-15 increased the frequency of elderly CD4+CD28null T cells by the preferential proliferation of these cells compared to CD4+CD28+ T cells. IL-15 induced an activated phenotype in CD4+CD28null T cells. Although the surface expression of IL-15R α-chain was not increased, the transcription factor STAT-5 was preferentially activated. IL-15 augmented the cytotoxic properties of CD4+CD28null T cells by increasing both the mRNA transcription and storage of granzyme B and perforin for the cytolytic effector functions. Moreover, pretreatment of CD4+CD28null T cells with IL-15 displayed a synergistic effect on the IFN-γ production in CMV-specific responses, which was not observed in CD4+CD28+ T cells. IL-15 could play a role enhancing the effector response of CD4+CD28null T cells against their specific chronic antigens. [ABSTRACT FROM AUTHOR]

Expanded CD4+CD28null T lymphocytes are found in the tissues and peripheral blood of patients with many autoimmune diseases, such as rheumatoid arthritis (RA). These highly differentiated cells present potent inflammatory activity and capability to induce tissue destruction, which has been suggested to predispose to the development of more aggressive disease. In fact, preferential migration to inflammatory sites has been proposed to be a contributing factor in the progression of autoimmune and cardiovascular diseases frequently found in these patients. The functional activity of CD4+CD28null T lymphocytes is largely dependent on interleukin 15 (IL-15), and this cytokine may also act as a selective attractor of these cells to local inflammatory infiltrates in damaged tissues. We have analysed, in RA patients, the migratory properties and transcriptional motility profile of CD4+CD28null T lymphocytes compared to their counterparts CD28+ T lymphocytes and the enhancing role of IL-15. Identification of the pathways involved in this process will allow us to design strategies directed to block effector functions that CD4+CD28null T lymphocytes have in the target tissue, which may represent therapeutic approaches in this immune disorder. [ABSTRACT FROM AUTHOR]

• Gut metaproteome is reservoir for encrypted immunomodulatory peptides. • These peptides can modulate the host immune response. • Some of these peptides, such as HM14, exert anti-inflammatory effects. This work supports the massive presence of potential immunomodulatory peptides in the human gut metaproteome. These peptides were identified through the MAHMI database as potentially anti-inflammatory, and sixteen of them synthesized for characterize their mechanism of action. From them, peptide HM14 was encrypted in an extracellular protein produced by Bifidobacterium longum , a common member of the human microbiota, and displayed the highest anti-inflammatory capability. Molecular mechanism of action of HM14 pointed to a specific interaction between this immunomodulatory peptide and antigen presenting cells, which resulted in a higher formation of iTreg cells. Moreover, HM14 was effective in decreasing pro-inflammatory parameters in PBMCs isolated from a cohort of Crohn's patients. Finally, non-targeted metabolomics confirmed the ability of HM14 to modulate the metabolic activity of PBMCs to fulfil its energy and biosynthetic requirements. Overall, our combined in silico /multiomics approach supports the human gut metaproteome as a source for immunomodulatory peptides. [ABSTRACT FROM AUTHOR]

Expansion of CD4 + CD28 null T-lymphocytes is common in chronic heart failure (CHF) patients. Its ability to produce high levels of proinflammatory cytokines is probably the key role of these cells in CHF. IL-10 is a candidate for limiting CD4 + CD28 null T-lymphocyte responses, whereas tumour necrosis factor (TNF) is the cytokine most closely involved in the loss of CD28 expression. Serum levels of TNF and IL-10 were measured in 65 CHF patients (mean age, 65.2 ± 13.84 years). Patients with an IL-10/TNF ratio ≥1 had significantly lower levels of CD4 + CD28 null T-lymphocytes than those with a ratio <1. In vitro, IL-10 reduced the frequency of proliferative CD4 + CD28 null T-lymphocytes stimulated with anti-CD3. Pre-treatment with IL-10 before anti-CD3 stimulation was required for the cytokine to inhibit TNF production by CD4 + CD28 null T-lymphocytes. In addition to the previously described effect of IL-10 on HLA-DR and ICAM-1 expression, LFA-3 protein and mRNA levels were reduced in the presence of the cytokine in monocytes. IL-10 inhibition on CD4 + CD28 null T-lymphocytes may be mediated by a reduction in HLA class II and LFA-3 expression because blocking interactions with these costimulators has similar effects to those of IL-10 treatment. Moreover, costimulation through CD2/LFA-3 interaction is enough to induce proliferation and cytokine production in CD4 + CD28 null T-lymphocytes., (© 2024 John Wiley & Sons Ltd.)

T lymphocytes, from their first encounter with their specific antigen as naïve cell until the last stages of their differentiation, in a replicative state of senescence, go through a series of phases. In several of these stages, T lymphocytes are subjected to exponential growth in successive encounters with the same antigen. This entire process occurs throughout the life of a human individual and, earlier, in patients with chronic infections/pathologies through inflammatory mediators, first acutely and later in a chronic form. This process plays a fundamental role in amplifying the activating signals on T lymphocytes and directing their clonal proliferation. The mechanisms that control cell growth are high levels of telomerase activity and maintenance of telomeric length that are far superior to other cell types, as well as metabolic adaptation and redox control. Large numbers of highly differentiated memory cells are accumulated in the immunological niches where they will contribute in a significant way to increase the levels of inflammatory mediators that will perpetuate the new state at the systemic level. These levels of inflammation greatly influence the process of T lymphocyte differentiation from naïve T lymphocyte, even before, until the arrival of exhaustion or cell death. The changes observed during lymphocyte differentiation are correlated with changes in cellular metabolism and these in turn are influenced by the inflammatory state of the environment where the cell is located. Reactive oxygen species (ROS) exert a dual action in the population of T lymphocytes. Exposure to high levels of ROS decreases the capacity of activation and T lymphocyte proliferation; however, intermediate levels of oxidation are necessary for the lymphocyte activation, differentiation, and effector functions. In conclusion, we can affirm that the inflammatory levels in the environment greatly influence the differentiation and activity of T lymphocyte populations. However, little is known about the mechanisms involved in these processes. The elucidation of these mechanisms would be of great help in the advance of improvements in pathologies with a large inflammatory base such as rheumatoid arthritis, intestinal inflammatory diseases, several infectious diseases and even, cancerous processes.

HIV-infected individuals suffer from accelerated immunologic aging. One of the most prominent changes during T lymphocyte aging is the accumulation of CD28(null) T lymphocytes, mainly CD8(+) but also CD4(+) T lymphocytes. Enhancing the functional properties of these cells may be important because they provide antigen-specific defense against chronic infections. The objective of this study was to compare the responses of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes from HIV-infected patients to the immunomodulatory effects of cytokines IL-15 and IL-21. We quantified the frequencies of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes in peripheral blood from 110 consecutive, HIV-infected patients and 25 healthy controls. Patients showed increased frequencies of CD4(+)CD28(null) and CD8(+)CD28(null). Both subsets were positively correlated to each other and showed an inverse correlation with the absolute counts of CD4(+) T lymphocytes. Higher frequencies of HIV-specific and CMV-specific cells were found in CD28(null) than in CD28(+) T lymphocytes. Activation of STAT5 by IL-15 and STAT3 by IL-21 was higher in CD28(null) compared with CD28(+) T lymphocytes. Proliferation, expression of CD69, and IFN-γ production in CD28(null) T lymphocytes were increased after treatment with IL-15, and IL-21 potentiated most of those effects. Nevertheless, IL-21 alone reduced IFN-γ production in response to anti-CD3 stimulation but increased CD28 expression, even counteracting the inhibitory effect of IL-15. Intracytoplasmic stores of granzyme B and perforin were increased by IL-15, whereas IL-21 and simultaneous treatment with the 2 cytokines also significantly enhanced degranulation in CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes. IL-15 and IL-21 could have a role in enhancing the effector response of CD28(null) T lymphocytes against their specific chronic antigens in HIV-infected patients., (© Society for Leukocyte Biology.)