IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells

The development of T helper (T_H)17 and regulatory T (T_reg) cells is reciprocally regulated by cytokines. Transforming growth factor (TGF)-β alone induces FoxP3⁺ T_reg cells, but together with IL-6 or IL-21 induces T_H17 cells. Here we demonstrate that IL-9 is a key molecule that affects differentiation of T_H17 cells and T_reg function. IL-9 predominantly produced by T_H17 cells, synergizes with TGF-β1 to differentiate naïve CD4⁺ T cells into T_H17 cells, while IL-9 secretion by T_H17 cells is regulated by IL-23. Interestingly, IL-9 enhances the suppressive functions of FoxP3⁺ CD4⁺ T_reg cells in vitro, and absence of IL-9 signaling weakens the suppressive activity of nT_regs in vivo, leading to an increase in effector cells and worsening of experimental autoimmune encephalomyelitis. The mechanism of IL-9 effects on T_H17 and T_regs is through activation of STAT3 and STAT5 signaling. Our findings highlight a role of IL-9 as a regulator of pathogenic versus protective mechanisms of immune responses.     

Les lymphocytes TH17 : différenciation, phénotype, fonctions, et implications en pathologie et thérapeutique humaine

Differentiation of naive CD4⁺ T helper (T_H) cells is a major step of the adaptative immune response. When activated by pathogens in a specific cytokine environment, CD4⁺ T cells differentiate into different subsets of T_H cells with specific effector functions. T_H1 lymphocytes orchestrate cellular immune response by producing interferon-γ and stimulating cytotoxic cells whereas T_H2 cells orchestrate humoral immune response by producing interleukin-4 (IL-4), IL-5 and IL-10, leading to immunoglobulin production. Conversely, regulatory T cells (Treg) are capable of inhibiting immune response. Recently discovered, T_H17 cells are characterized by their ability to produce IL-17 and play an important role in anti-infectious and inflammatory immune responses. This review focuses on present knowledge about T_H17 cells: their induction, phenotype, functions, implications in host defense and human disease, and their potential to represent possible therapeutic targets.     

A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice

Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor γ chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T_H17) and follicular CD4 T helper cells (T_FH), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T_H17 cells and was not limited to conventional CXCR5⁺ T_FH but instead was produced broadly by ICOS⁺ CD4⁺ splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.     

Brief Report: Transient and durable T cell reactivity after COVID-19

This study analyzed whole blood samples (n = 56) retrieved from 30 patients at 1 to 21 (median 9) mo after verified COVID-19 to determine the polarity and duration of antigen-specific T cell reactivity against severe acute respiratory syndrome coronavirus 2–derived antigens. Multimeric peptides spanning the entire nucleocapsid protein triggered strikingly synchronous formation of interleukin (IL)-4, IL-12, IL-13, and IL-17 ex vivo until ∼70 d after confirmed infection, whereafter this reactivity was no longer inducible. In contrast, levels of nucleocapsid-induced IL-2 and interferon-γ remained stable and highly correlated at 3 to 21 mo after infection. Similar cytokine dynamics were observed in unvaccinated, convalescent patients using whole-blood samples stimulated with peptides spanning the N-terminal portion of the spike 1 protein. These results unravel two phases of T cell reactivity following natural COVID-19: an early, synchronous response indicating transient presence of multipolar, antigen-specific T helper (T_H) cells followed by an equally synchronous and durable T_H1-like reactivity reflecting long-lasting T cell memory.     

IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms

Parasitic helminths are a major cause of chronic human disease, affecting more than 3 billion people worldwide. Host protection against most parasitic helminths relies upon Type 2 cytokine production, but the mechanisms that regulate interleukin (IL) 4 and 13 production from CD4⁺ T helper 2 cells (T_H2) and innate lymphoid type 2 cells (ILC2s) remain incompletely understood. The epithelial cell-derived cytokines IL-25 and IL-33 promote Type 2 responses, but the extent of functional redundancy between these cytokines is unclear and whether Type 2 memory relies upon either IL-25 or IL-33 is unknown. Herein, we demonstrate a pivotal role for IL-33 in driving primary and anamnestic immunity against the rodent hookworm Nippostrongylus brasiliensis. IL-33–deficient mice have a selective defect in ILC2–derived IL-13 during both primary and secondary challenge infections but generate stronger canonical CD4⁺ T helper 2 cells responses (IL-4, IgE, mast cells, and basophils) than WT controls. Lack of IL-13 production in IL-33–deficient mice impairs resistin-like molecule beta (RELMβ) expression and eosinophil recruitment, which are two mechanisms that eliminate N. brasiliensis parasites from infected hosts. Thus, IL-33 is requisite for IL-13 but not IL-4–driven Type 2 responses during hookworm infection.     

No effect of antifungal compounds on functional properties of human antifungal T‐helper type 1 cells

Despite the availability of new antifungal compounds, invasive fungal disease is associated with a high mortality in hematopoietic stem cell transplant (HSCT) recipients. A growing body of evidence suggests that T lymphocytes from the T‐helper type 1 (T_H1) play an important role in the antifungal host defense, and preliminary data indicate a potential benefit of infusing donor‐derived antifungal T_H1 cells to HSCT patients suffering from invasive fungal disease. Unfortunately, it is unclear to date whether the function of these cells is affected by concomitantly administered antifungal agents. We therefore analyzed the effects of various concentrations of commonly used antifungal compounds such as amphotericin B, caspofungin, fluconazole, voriconazole, and posaconazole on the functional properties of cultivated human antifungal T_H1 cells. None of the antifungal compounds tested significantly influenced the secretion of interferon‐γ and tumor necrosis factor‐α, and only posaconazole at high concentrations slightly decreased proliferation of antifungal T_H1 cells. Our data indicate that the antifungal agents tested do not significantly affect the functional properties of antifungal T_H1 cells and can therefore be concomitantly administered.     

Clinical Consequences of Targeting IL-17 and TH17 in Autoimmune and Allergic Disorders

The T_H17 lineage of T cells and its canonical cytokine IL-17 have been the focus of many recent studies in autoimmune, allergic, and infectious disease. In this review, we will briefly discuss the current knowledge about the role of these cells and IL-17 in a spectrum of disorders. It is clear that IL-17 plays pathogenic roles in certain conditions while the same pathway is critically important to immunity in others. Targeting of T_H17 cells or IL-17 therapeutically may impart many benefits, but this approach is not without potentially serious implications regarding host defense. These issues will be discussed herein as we evaluate pharmacological approaches targeting this pathway that are just beginning to be fully tested in human disease.     

Th9与支气管哮喘

支气管哮喘(简称哮喘)是一种由多种细胞如淋巴细胞、嗜酸粒细胞、肥大细胞等及其细胞组分参与的气道慢性炎症疾患,Th2细胞被认为是哮喘发病机制中的主要效应细胞.长期以来,白介素9(IL-9)都被认为是Th2类细胞因子,在变应性疾病,尤其是过敏性哮喘、变应性鼻炎等发病机制中起着重要的作用.近年来研究发现,机体内可能存在着一群...     

Characterization of the HCMV-Specific CD4 T Cell Responses that Are Associated with Protective Immunity

Most humans become infected with human cytomegalovirus (HCMV). Typically, the immune system controls the infection, but the virus persists and can reactivate in states of immunodeficiency. While substantial information is available on the contribution of CD8 T cells and antibodies to anti-HCMV immunity, studies of the T_H1, T_H2, and T_H17 subsets have been limited by the low frequency of HCMV-specific CD4 T cells in peripheral blood mononuclear cell (PBMC). Using the enzyme-linked Immunospot^® assay (ELISPOT) that excels in low frequency measurements, we have established these in a sizable cohort of healthy HCMV controllers. Cytokine recall responses were seen in all seropositive donors. Specifically, interferon (IFN)-γ and/or interleukin (IL)-17 were seen in isolation or with IL-4 in all test subjects. IL-4 recall did not occur in isolation. While the ratios of T_H1, T_H2, and T_H17 cells exhibited substantial variations between different individuals these ratios and the frequencies were relatively stable when tested in samples drawn up to five years apart. IFN-γ and IL-2 co-expressing polyfunctional cells were seen in most subjects. Around half of the HCMV-specific CD4 cells were in a reversible state of exhaustion. The data provided here established the T_H1, T_H2, and T_H17 characteristic of the CD4 cells that convey immune protection for successful immune surveillance against which reactivity can be compared when the immune surveillance of HCMV fails.     

Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase

The T-cell costimulatory receptors, CD28 and the inducible costimulator (ICOS), are required for the generation of follicular B helper T cells (T_FH) and germinal center (GC) reaction. A common signal transducer used by CD28 and ICOS is the phosphoinositide 3-kinase (PI3K). Although it is known that CD28-mediated PI3K activation is dispensable for GC reaction, the role of ICOS-driven PI3K signaling has not been defined. We show here that knock-in mice that selectively lost the ability to activate PI3K through ICOS had severe defects in T_FH generation, GC reaction, antibody class switch, and antibody affinity maturation. In preactivated CD4⁺ T cells, ICOS delivered a potent PI3K signal that was critical for the induction of the key T_FH cytokines, IL-21 and IL-4. Under the same settings, CD28 was unable to activate PI3K but supported a robust secondary expansion of T cells. Thus, our results demonstrate a nonredundant function of ICOS-PI3K pathway in the generation of T_FH and suggest that CD28 and ICOS play differential roles during a multistep process of T_FH differentiation.     

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4+ T cells through IL-12 and TGF-β1

The differentiation of naive CD4⁺ T cells into distinct lineages plays critical roles in mediating adaptive immunity or maintaining immune tolerance. In addition to being a first line of defense, the innate immune system also actively instructs adaptive immunity through antigen presentation and immunoregulatory cytokine production. Here we found that sirtuin 1 (SIRT1), a type III histone deacetylase, plays an essential role in mediating proinflammatory signaling in dendritic cells (DCs), consequentially modulating the balance of proinflammatory T helper type 1 (T_H1) cells and antiinflammatory Foxp3⁺ regulatory T cells (T_reg cells). Genetic deletion of SIRT1 in DCs restrained the generation of T_reg cells while driving T_H1 development, resulting in an enhanced T-cell–mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1α)-dependent pathway, orchestrating the reciprocal T_H1 and T_reg lineage commitment through DC-derived IL-12 and TGF-β1. Our studies implicates a DC-based SIRT1–HIF1α metabolic checkpoint in controlling T-cell lineage specification.CD4⁺ T cells are essential components of the adaptive immune system that regulate immune responses against foreign antigen. Upon antigen recognition, naive CD4⁺ T cells undergo activation and expansion, and, depending on inflammatory contexts and cytokine milieus, differentiate into functional and phenotypic T helper (T_H) subsets characterized by distinct cytokine production profile and function (1–3). T_H1 cells produce IFN-γ and elicit cellular immunity in responding to intracellular pathogens; T_H2 cells produce IL-4 and IL-5 and promote humoral immunity in responding to extracellular bacteria and helminthes; and T_H17 cells produce IL-17 and mediate antifungal defense and inflammation (4, 5). Additionally, regulatory T cells, often known as “induced regulatory T cells” (iT_reg cells), which act in synergy with naturally occurring T_reg cells (nT_reg cells), produce IL-10 and TGF-β1 and dampen immune responses elicited from T_H1, T_H2, and T_H17 (6–9).Dendritic cells (DCs), an essential component in the innate immune system, play a critical role in initiating front-line primary immune responses and directing subsequent pathogen-specific adaptive immune responses (2). In addition to presenting antigens and modulating cell surface costimulatory molecules, DC-derived cytokines and chemokines can result in either a proinflammatory or antiinflammatory environment, engaging distinct T-cell differentiation programs on naive CD4⁺ T cells (1, 10–16). For example, DC-producing IL-12 can support T_H1 development, whereas DC-producing IL-10 or TGF-β1 can support T_reg development. Recent studies from us and others have shown that innate signaling in DCs mediated by G protein-coupled receptor S1P1, the mitogen-activated kinases (MAPKs), and Wnt–β-catenin plays important roles in stimulating adaptive immune responses through directing native CD4⁺ T-cell differentiation (17–20). However, other critical signaling components in DCs that may play a role in shaping T-cell lineage engagement remain to be identified.SIRT1 is a mammalian homolog of the yeast NAD⁺-dependent protein deacetylase Sirt2, and plays a role in a variety of essential biological processes, including cell cycle progression, apoptosis, cell survival, gene silencing, heterochromatin formation, tumorigenesis, metabolism, and development (21, 22). SIRT1 has also been implicated in regulating immune responses. In T cells, SIRT1 is required to maintain T-cell tolerance (23, 24) and also play a role in inhibiting the function of T_reg cells in allograft survival (25). In myeloid cells, SIRT1 limits the inflammatory process by inhibiting the expression of proinflammatory cytokines (26, 27), while promoting DC maturation and T_H2 response in airway allergy (28). However, whether SIRT1 is involved in bridging the innate immune signal to adaptive immune response remains unexplored.Here, we found that SIRT1 plays a critical role in determining the T-cell lineage fate by directing DC-derived cytokine production, which links innate and adaptive immune modulation. Largely through a HIF1α–dependent signaling pathway, SIRT1 is required for the reciprocal production of IL-12 and TGF-β1 production in DCs as well as the expression of IL-12Rβ2 and TGF-βR2 in responding T cells, resulting in a differential lineage engagement of T_H1 and iT_reg in the microbial-induced inflammation.     

Challenges and Prospects of Adoptive Immunotherapy in Prevention and Treatment of Opportunistic Mycoses in Hematologic Transplant Recipients

Invasive fungal infections remain a serious and life-threatening complication in patients undergoing hematopoietic stem cell transplantation. Since it became clear that lymphocytes, in particular lymphocytes from the T helper 1 (T_H1) subset, play a critical secondary defense against fungal pathogens, the adoptive transfer of functionally active antifungal T_H1 cells might be an attractive option to restore adaptive antifungal immune effector mechanisms. Major advances have been made in the generation and characterization of antifungal T cells, which are active against medical important fungi such as Aspergillus spp and Candida spp. However, given the paucity of large homogenous patient populations, major challenges remain in evaluating the clinical usefulness of adoptive antifungal immunotherapy, which should be performed in international collaborative trials.     

The role of autologous helper and suppressor T cells in the regulation of human granulopoiesis

Helper and suppressor T cells play a physiological role in immunoregulation and possibly in other biological systems. Previous studies have suggested that unfractionated T cells influence human blood cell formation in vitro. Subpopulations of such cells (T_M and T_G cells) were prepared by immune ox erythrocyte resetting techniques. Co-cultures were established in semi-solid agar with autologous null lymphocytes as a source of granulocyte—macrophage progenitor cells (CFU-GM). T_M (helper) cells produced an increase and T_G (suppressor) cells a decrease in the expression of CFU-GM as reflected in the number of GM colonies generated by comparison with cultures of null lymphocytes alone. These data point to a contribution from T lymphocyte subpopulations to the physiological regulation of human granulopoiesis.     

Autoimmunity as a model for aging: insight into their similar mechanisms

The age-related decline of immunologic function is generally associated with an increase in susceptibility to infections and in incidence of autoimmune phenomena and malignancies in elderly individuals. We found that circulating B lymphocytes from elderly individuals contained reduced numbers of genuine resting B cells and increased numbers of B cells that spontaneously secrete immunoglobulins, suggesting polyclonal B cell activationin vivo in elderly individuals. It is well known that the prevalence rate of rheumatoid factors and antinuclear antibodies in circulation correlates well with aging. It has also been reported that MRL +/+ mice, a counterpart of MRLlpr/lpr mice, that spontaneously produce antinuclear autoantibodies are predisposed to hypermaturity and accelerated aging. Recently, it was also reported that autoreactive T cells are prevalent in the aged mice and that T helper (T_h) 1 cytokine production such as interferon (IFN)-γ and interleukin (IL)-2 was significantly decreased, whereas T_h2 cytokines production including IL-4 and IL-6 was unchanged or up-regulated in the elderly humans. This imbalance of T_h1/T_h2 may be important for both aged individuals and patients with autoimmune diseases. In addition, these changes associated with aging may be partly due to the alteration of neuro-endocrine systems. Although autoimmunity is considered to be physiological phenomenon and requires additional factor(s) for the development of autoimmune diseases, it should be emphasized that alterations of the immune system with aging resemble autoimmunity and autoimmune diseases.     

Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells

In primary humoral responses, B-cell lymphoma 6 (Bcl6) is a master regulator of follicular helper T (T_FH) cell differentiation; however, its activation mechanisms and role in memory responses remain unclear. Here we demonstrate that survival of CXCR5⁺ T_FH memory cells, and thus subsequent recall antibody response, require Bcl6 expression. Furthermore, we show that, upon rechallenge with soluble antigen Bcl6 in memory T_FH cells is rapidly induced in a dendritic cell-independent manner and that peptide:class II complexes (pMHC) on cognate memory B cells significantly contribute to this induction. Given the previous evidence that antigen-specific B cells residing in the follicles acquire antigens within minutes of injection, our results suggest that memory B cells present antigens to the cognate T_FH memory cells, thereby contributing to rapid Bcl6 reexpression and differentiation of the T_FH memory cells during humoral memory responses.The development of high-affinity B-cell memory is essential in most effective vaccines that are in use today. Because most protein antigens require T-cell help to induce B-cell responses, understanding the mechanisms by which memory T and B cells are generated and maintained, as well as how their swift activation is executed, is of fundamental importance for vaccine development.In primary immune responses, it is widely accepted that among several differentiated helper T-cell subsets follicular helper CD4 T cells (T_FH cells) are the major subset to deliver help to B cells (1). T_FH cells express CXC-chemokine receptor 5 (CXCR5), the chemokine receptor for the B-cell homing chemokine CXCL13. Surface expression of CXCR5 enables T_FH cells to migrate into B-cell follicles, where they provide help to B cells to form germinal centers. In addition, T_FH cells are needed for the crucial affinity-maturation process of B cells in germinal centers, whereby Ag-specific B cells undergo repeated rounds of somatic hypermutation and positive selection by T_FH cells to rapidly evolve high-affinity somatically mutated B-cell receptors. B-cell lymphoma 6 (Bcl6) has recently been identified as a T_FH lineage regulator (2–4); it is highly expressed by T_FH cells and is required for their development. According to the current view, during a primary response Bcl6 expression by T cells is induced by priming with dendritic cells (5–7) and ICOS is a key coreceptor molecule for induction of Bcl6 (5, 8). The initial Bcl6 induction and subsequent CXCR5 expression allow CD4 T cells to migrate toward the T–B border, where T_FH cells interact with antigen-specific B cells. According to this model, cognate B cells are not required for the induction of Bcl6 but support the expansion of T_FH cells (9).Although the importance of Bcl6 and its expression kinetics in naïve T-cell differentiation have been well elucidated, its role and activation mechanisms in T_FH memory cells still remain obscure. Hence, in this paper we first focus upon the roles of Bcl6, demonstrating its importance for maintenance of T_FH memory cells. Then, we show that Bcl6 in memory T_FH cells was rapidly induced upon rechallenge with soluble antigen and that this response was mainly mediated through antigen presentation by the cognate memory B cells. Given the good association between Bcl6 with IL-21 expression in differentiated memory T_FH cells, our results suggest that memory B cells are the primary antigen-presenting cells (APCs) to induce the rapid differentiation of memory T_FH cells toward effector cells, further accelerating memory B-cell responses during recall.     

Dendritic cells—the link between innate and adaptive immunity in allergy

Conclusions During the past years, a large number of studies have provided compelling evidence that dendritic cells are the principal APCs involved in the polarization of T helper cell responses, not only in the T_H1 but also in the T_H2 direction. Although in vitro studies have improved our understanding of the various factors that effect dendritic cell function, we are only beginning to comprehend the complex interactions of environmental and local factors that modulate dendritic cells under natural allergen exposure conditions. Identification and characterization of factors relevant for the T_H2-promoting capacity of dendritic cells in vivo will advance our understanding of the pathogenesis of allergic diseases and possibly provide novel targets for therapeutic or preventive intervention.