Inappropriately sustained inflammation is a hallmark of chronic ischemic heart failure (HF); however, the pathophysiological role of T lymphocytes is unclear.
Permanent coronary ligation was ...performed in adult C57BL/6 mice. When compared with sham-operated mice, mice with HF (8 weeks after ligation) exhibited the following features: (1) significant (
<0.05) expansion of circulating CD3
CD8
cytotoxic and CD3
CD4
helper (Th) T lymphocytes, together with increased Th1, Th2, Th17, and regulatory T-cell (Treg) CD4
subsets; (2) significant expansion of CD8
and CD4
T cells in failing myocardium, with increased Th1, Th2, Th17, and Treg CD4
subsets, marked reduction of the Th1/Th2 ratio, augmentation of the Th17/Treg ratio, and upregulation of Th2 cytokines; and (3) significantly increased Th1, Th2, Th17 cells, and Tregs, in the spleen and mediastinal lymph nodes, with expansion of splenic antigen-experienced effector and memory CD4
T cells. Antibody-mediated CD4
T-cell depletion in HF mice (starting 4 weeks after ligation) reduced cardiac infiltration of CD4
T cells and prevented progressive left ventricular dilatation and hypertrophy, whereas adoptive transfer of splenic CD4
T cells (and, to a lesser extent, cardiac CD3
T cells) from donor mice with HF induced long-term left ventricular dysfunction, fibrosis, and hypertrophy in naive recipient mice.
CD4
T lymphocytes are globally expanded and activated in chronic ischemic HF, with Th2 (versus Th1) and Th17 (versus Treg) predominance in failing hearts, and with expansion of memory T cells in the spleen. Cardiac and splenic T cells in HF are primed to induce cardiac injury and remodeling, and retain this memory on adoptive transfer.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in ...children (MIS-C) associated with COVID-19, presenting 4–6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.
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•Hyperinflammation in MIS-C differs from that of acute COVID-19•T cell subsets discriminate Kawasaki disease patients from MIS-C•IL-17A drives Kawasaki but not MIS-C hyperinflammation•Global profiling reveals candidate autoantibodies with pathogenic potential
A systems immunology approach describes how multisystem inflammatory syndrome in children (MIS-C) is distinct from Kawasaki disease as well as the cytokine storm associated with severe COVID-19 in terms of its molecular and immune profiles.
Recent years have seen a marked increase in our understanding of innate lymphoid cells (ILCs). ILCs can be classified into different groups based on their similarity to T cell subsets in terms of ...their expression of key transcription factors and cytokine production. Various immunological functions of ILCs have been described, and increasing numbers of studies have implicated these cells in inflammatory disorders. Here, we detail the roles of ILCs in inflammatory diseases; we cover type 2 inflammatory diseases (such as asthma, chronic rhinosinusitis and atopic dermatitis), as well as inflammatory bowel diseases, psoriasis and other systemic or organ-specific inflammatory and autoimmune diseases. Future directions in the field are discussed, together with potential avenues of treatment.
We have discovered a distinct mature B-cell subset that accumulates with age, which we have termed age-associated B cells. These cells comprise up to 30% of mature B cells by 22 months. Despite ...sharing some features with other mature B-cell subsets, they are refractory to BCR and CD40 stimulation. Instead, they respond to TLR9 or TLR7 stimulation and divide maximally on combined BCR and TLR ligation, leading to Ig production and preferential secretion of IL-10 and IL-4. Although similar to follicular B cells in both B-lymphocyte stimulator (BLyS) receptor expression and BLyS binding capacity, these cells do not rely on BLyS for survival. They are neither cycling nor the result of intrinsically altered B lymphopoiesis in aged BM, but instead appear to be generated from mature B cells that exhaustively expand during the individual's lifetime. Finally, they present Ag effectively and favor polarization to a TH17 profile. Together, these findings reveal that while the magnitude of the mature primary B-cell niche is maintained with age, it is increasingly occupied by cells refractory to BCR-driven activation yet responsive to innate receptor stimulation.
•The immune status is significantly different between severe and non-severe COVID-19.•The decrease of T lymphocyte correlated with the course of patients with COVID-19.•The level of T lymphocyte is ...an indicator for severity and prognosis of COVID-19.
To explore the clinical course and its dynamic features of immune status in COVID-19 patients and find predictors correlated with severity and prognosis of COVID-19.
The electronic medical records of 204 patients with COVID-19 pneumonia confirmed by nucleic acid testing were retrospectively collected and analyzed.
All patients were divided into severe (69) and non-severe group (135). Lymphocyte subsets count, including CD3+ T cell, CD4+ T cell, CD8+ T cell, B cell (CD19+) and NK cell (CD16+ 56+), were significantly lower in severe group (P＜0.001). The dynamic levels of T lymphocyte in severe group were significantly lower from disease onset, but in the improved subgroup the value of T lymphocyte began to increase after about 15-day treatment and finally returned to the normal level. The cut-off value of the counts of CD3+ (576), CD4+ (391) and CD8+ (214) T cell were calculated and indicated significantly high sensitivity and specificity for severity of COVID-19.
Our results shown that the decrease of CD3+, CD4+ and CD8+ T lymphocyte correlated with the course of patients with COVID-19 pneumonia, especially in severe cases. The level of T lymphocyte could be used as an indicator for prediction of severity and prognosis of patients with COVID-19 pneumonia. The application of glucocorticoid should be cautious in severe cases.
Females are more susceptible than males to many autoimmune diseases. The processes causing this phenomenon are incompletely understood. Here, we demonstrate that aged female mice acquire a previously ...uncharacterized population of B cells that we call age-associated B cells (ABCs) and that these cells express integrin αX chain (CD11c). This unexpected population also appears in young lupus-prone mice. On stimulation, CD11c+ B cells, both from autoimmune-prone and healthy strains of mice, secrete autoantibodies, and depletion of these cells in vivo leads to reduction of autoreactive antibodies, suggesting that the cells might have a direct role in the development of autoimmunity. We have explored factors that contribute to appearance of ABCs and demonstrated that signaling through Toll-like receptor 7 is crucial for development of this B cell population. We were able to detect a similar population of B cells in the peripheral blood of some elderly women with autoimmune disease, suggesting that there may be parallels between the creation of ABC-like cells between mice and humans.
The difficulty in predicting the consequences of interactions between different cytokine networks has increased with the expansion of the T helper (Th) cell universe and the discovery of numerous B ...lymphocyte-derived cytokines. Consequently, it is now difficult to conceptualize a straightforward view of the contribution of these disturbances to the pathogenesis of primary Sjögren's syndrome (SS). Th1 cells, which produce interferon-γ and IL-2, and Th17 cells, which make IL-17 and TNF-α, have been cast in the leading roles of the play. However, the complex role of T-cell subsets in SS is accentuated by the reciprocal effects of Th17 cells and regulatory T cells found in salivary glands of SS patients. Furthermore, B lymphocyte polarization into type-1 B effector (Be1) and Be2 cells and B-cell modulating factors of the TNF family, most notably the B-cell-activating factor (BAFF), and their prominent role in SS are additional complicating factors. Whereas Th17 cells orchestrate autoreactive germinal centers, local BAFF would repress the generation of Th17 cells. Such new insights into interconnected cytokines in primary SS may lead to new treatments for these patients.
T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells ...are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8
tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8
TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8
TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8
TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8
T cells might be an important component of improving the response to checkpoint blockade.
Adaptive immune responses to Ags released by dying cells play a critical role in the development of autoimmunity, allograft rejection, and spontaneous as well as therapy-induced tumor rejection. ...Although cell death in these situations is considered sterile, various reports have implicated type I IFNs as drivers of the ensuing adaptive immune response to cell-associated Ags. However, the mechanisms that underpin this type I IFN production are poorly defined. In this article, we show that dendritic cells (DCs) can uptake and sense nuclear DNA-associated entities released by dying cells to induce type I IFN. Remarkably, this molecular pathway requires STING, but not TLR or NLR function, and results in the activation of IRF3 in a TBK1-dependent manner. DCs are shown to depend on STING function in vivo to efficiently prime IFN-dependent CD8(+) T cell responses to tumor Ags. Furthermore, loss of STING activity in DCs impairs the generation of follicular Th cells and plasma cells, as well as anti-nuclear Abs, in an inducible model of systemic lupus erythematosus. These findings suggest that the STING pathway could be manipulated to enable the rational design of immunotherapies that enhance or diminish antitumor and autoimmune responses, respectively.
Despite advances that have improved survival after allogeneic hematopoietic stem cell transplantation (HCT), chronic graft-versus-host disease (GVHD) remains a leading cause of late morbidity and ...mortality after transplant. Current treatment options show limited efficacy in steroid-refractory disease, and there exists a paucity of robust data to guide management decisions. Lack of United States Food and Drug Administration (FDA)- or European Medicines Agency (EMA)-approved agents in GVHD underscore the importance of developing novel therapies. Better understanding of the biology of chronic GVHD has provided novel targets for treatment, and structured guidelines in diagnosis and in clinical trial design have provided a common language and pathways for research in this area. These, combined with the surge of drug development in Oncology and Immunology, are factors that have contributed to the accelerating field of drug development and clinical research in chronic GVHD. In these exciting times, it is possible to foresee long awaited advances in the treatment of this devastating complication of HCT. This review will summarize the ongoing clinical development for novel therapies in chronic GVHD.
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