The paradigm of Th1 and Th2 cytokines: its relevance to autoimmunity and allergy

In the past few years, considerable evidence has accumulated to suggest the existence of functionally polarized responses by the CD4+ T helper (Th)--and the CD8+ T cytotoxic (Tc)-cell subsets that depend on the cytokines they produce. The Th1 and Th2 cellular immune response provide a useful model for explaining not only the different types of protection, but also the pathogenic mechanisms of several immunopathological disorders. The factors responsible for the polarization of specific immune response into a predominant Th1 or Th2 profile have been extensively investigated in mice and humans. Evidence has accumulated from animal models to suggest that Th1-type lymphokines are involved in the genesis of organ-specific autoimmune diseases, such as experimental autoimmune uveitis, experimental allergic encephalomyelitis, or insulin-dependent diabetes mellitus. Accordingly, data so far available in human diseases favor a prevalent Th1 lymphokine profile in target organs of patients with organ-specific autoimmunity. By contrast, Th2-cell predominance was found in the skin of patients with chronic graft-versus host disease, progressive systemic sclerosis, systemic lupus erythematosus, and allergic diseases. The Th1/Th2 concept suggests that modulation of relative contribution of Th1- or Th2-type cytokines regulate the balance between protection and immunopathology, as well as the development and/or the severity of some immunologic disorders. In this review, we have discussed the paradigm of Th1 and Th2 cytokines in relation to autoimmunity and allergy.     

Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases

CD4⁺ T cells play a key role in regulating immune system function. When these regulatory processes go awry, organ-specific autoimmune diseases may develop. Here, Roland Liblau, Steven Singer and Hugh McDevitt explore the thesis that a particular subset of CD4⁺ T cells, namely T helper 1 (Th1) cells, contributes to the pathogenesis of organ-specifc autoimmune diseases, while another subset, Th2 cells, prevents them.     

Interplay Between Effector Th17 and Regulatory T Cells

Introduction  Over two decades ago, T helper cells were classified into its functional subsets. Soon after the classical observation of Mosmann et al., immunologists agreed to accept the Th1/Th2 paradigm of the T helper subsets. Each subset is not only characterized by its specific cytokines pattern and effector functions but also by their properties to counter regulate each other’s functions. This classification helped to understand the complex principles of T helper cell biology and allowed us to comprehend different immune reactions in context of Th1 and Th2 subsets. Discussion  Although Th1 subsets thought to be the crucial player for most of the organ-specific autoimmune diseases like multiple sclerosis and type-1 diabetes but the loss of Th1 dominant cytokine, IFN-γ did not prevent the development of autoimmunity which raised the possibility of involvement of other Th subsets, different from Th1 cells in the induction of autoimmunity. Conclusion  Recently, a new subset of Th cells that predominantly produce IL-17 and induce autoimmunity has been discovered, and it is believed that this subset may be the major cell type involved in orchestrating tissue inflammation and autoimmunity. Recent data propose that the differentiation factors of Th17 cells reveal a link with induction of Foxp3⁺ regulatory T cells. Here, we review the interplay between Th17 and Foxp3⁺ T-reg cells and Tr1 cells during autoimmune inflammatory reaction.     

Role of Th1 and Th17 cells in organ-specific autoimmunity

CD4(+) IFN-gamma-producing Th1 cells have long been associated with the pathogenesis of many organ-specific autoimmune diseases; however, the observation of disease in mice deficient in molecules involved in Th1 cell differentiation raised the possibility that other effector T cells were responsible for inducing autoimmunity. Recently, a new CD4(+) effector T cell subset that produces IL-17 (Th17) has emerged. The fact that Th17 cells are highly auto-pathogenic has fueled a debate as to what role, if any, Th1 cells play in the induction of tissue inflammation and autoimmune disease. This review will discuss the respective roles of the Th1 and Th17 subsets in organ-specific autoimmunity.     

PKCε promotes human Th17 differentiation: Implications in the pathophysiology of psoriasis

PKCε is implicated in T cell activation and proliferation and is overexpressed in CD4⁺‐T cells from patients with autoimmune Hashimoto's thyroiditis. Although this might induce the suspicion that PKCε takes part in autoimmunity, its role in the molecular pathophysiology of immune‐mediated disorders is still largely unknown. We studied PKCε expression in circulating CD4⁺‐T cells from patients with psoriasis, a skin disorder characterized by an increased amount of Th17 cells, a CD4⁺ subset that is critical in the development of autoimmunity. Although the mechanisms that underlie Th17 differentiation in humans are still unclear, we here show that: (i) PKCε is overexpressed in CD4⁺‐T cells from psoriatic patients, and its expression positively correlates with the severity of the disease, being reduced by effective phototherapy; (ii) PKCε interacts with Stat3 during Th17 differentiation and its overexpression results in an enhanced expression of Stat3 and pStat3(Ser727); iii) conversely, when PKCε is forcibly downregulated, CD4⁺‐T cells show lower levels of pStat3(Ser727) expression and defective in vitro expansion into the Th17‐lineage. These data provide a novel insight into the molecular mechanisms of Th17 cell polarization that is known to play a crucial role in autoimmunity, pinpointing PKCε as a potential target in Th17‐mediated diseases.     

CD4 T-cell subsets in autoimmunity

The discovery that functionally heterogeneous CD4⁺ T-cell subsets secrete different cytokines offers an explanation for the ability of certain T cells to mediate a predominant cell-mediated immune response versus a humoral response often accompanied by allergic manifestations. Th1 cells, important for cell-mediated immunity by their production of IL-2, IFN-γ and lymphotoxin, have been implicated in the immunopathology of certain organ-specific autoimmune diseases whereas a role as regulators has been suggested for IL-4 and IL-10 producing Th2 cells. Recent findings, however, beg re-evaluation of the direct role of Th2 cells in the induction or maintenance of tolerance, whereas evidence for the role of a distinct subset of regulatory T cells producing TGF-β to suppress cell-mediated immunopathology is compelling.     

Th17 and regulatory T lymphocytes in primary biliary cirrhosis and systemic sclerosis as models of autoimmune fibrotic diseases

Fibrotic autoimmune diseases are characterized by an inflammatory process in which fibrogenic cytokines, such as TGFβ and IL6, have a major role. Interestingly, these cytokines are also involved in the generation and function of both an effector T lymphocyte subpopulation, the Th17 cells, and the regulatory T lymphocytes (Treg). These evidences raised the hypothesis that an unbalanced equilibrium induced by the overproduction of the fibrogenic cytokines may have pathogenic relevance in fibrotic autoimmune diseases.On this basis, this review analyzes the available data concerning Th17 and Treg generation and function in two representative fibrotic autoimmune diseases, primary biliary cirrhosis (PBC) and systemic sclerosis (SSc), as models for organ-specific and systemic diseases, respectively.With regard to the Th17 cells, their expansion was found to be a common feature associated with a relative contraction of Th1 immune responses. Concerning to the regulatory T cell compartment, quantitative and qualitative alterations were observed in both diseases. However, while PBC patients showed defects only in the CD8 + Treg subset, SSc patients demonstrated abnormalities regarding to both the CD4 + CD25 + and the CD8 + Treg subpopulations. Hence, the CD8 + Treg subset seems to be the most involved in the pathogenic cascade leading to fibrotic disease onset and maintenance.Collectively, the reviewed data support the concept that altered homeostasis between effector and regulatory T cell circuits is present in fibrotic autoimmune diseases and that the major factors responsible for such disequilibrium are Th17 cells in the effector arm and CD8 + Treg in the regulatory arm.     

Lack of Th2 cytokine increase during spontaneous remission of experimental allergic encephalomyelitis

The mechanisms underlying spontaneous remission of autoimmune diseases are presently unknown, though regulatory T cells are believed to play a major role in this process. We tested the hypothesis that Th2 and/or other T cell regulatory cytokines cause the spontaneous remission of experimental allergic encephalomyelitis (EAE), a model of Th1-mediated autoimmunity. We analyzed the cytokine profile of lymph node and central nervous system-infiltrating cells in individual SJL mice at different stages of proteolipid protein (PLP) 139 – 151 peptide-induced EAE. We found that IFN-γ slowly fades away after clinical recovery, whereas IL-4, IL-10 and transforming growth factor-β remain low or undetectable. Our peptide-results therefore suggest that regulatory T cells producing anti-inflammatory cytokines are not involved in spontaneous remission of EAE and challenge the view that the Th1/Th2 balance has a key role in EAE regulation.     

Th9 cells and IL-9 in autoimmune disorders: Pathogenesis and therapeutic potentials

Naïve CD4⁺ T cells are pleiotropically divided into various T helper (Th) cell subsets, according to their pivotal roles in the regulation of immune responses. The differentiation of Th9 cells, an interleukin (IL)-9 producing subset, can be impacted by specific environmental cues, co-stimulation with transforming growth factor β (TGF-β) and IL-4, and other regulatory factors. Although IL-9 has been recognized as a classical Th2-related cytokine, recent studies have indicated that IL-9-producing cells contribute to a group of autoimmune disorders including systemic lupus erythematosus (SLE), multiple sclerosis (MS), inflammatory bowel diseases (IBD), rheumatoid arthritis (RA) and psoriasis. Studies of Th9 cells in autoimmune diseases, although in their infancy, are expected to be of growing interest in the study of potential mechanisms of cytokine regulatory pathways and autoimmune pathogenesis. Several in vitro and in vivo pre-clinical trials have been conducted to explore potential therapeutic strategies by targeting the IL-9 pathway. Specifically, anti-IL-9 monoclonal antibodies (mAbs) and IL-9 inhibitors may potentially be used for the clinical treatment of allergic diseases, autoimmune diseases or cancers. Here, we review recent research on Th9 cells and IL-9 pertaining to cell differentiation, biological characteristics and pivotal cellular inter-relationships implicated in the development of various diseases.     

IL-13-producing Th1 and Th17 cells characterize adaptive responses to both self and foreign antigens

In helper T cells, IL‐13 is traditionally considered a Th2‐type cytokine that is coexpressed with IL‐4. Using mouse models of immunization and autoimmunity, we demonstrate that IL‐13 is frequently uncoupled from IL‐4, and that it can be produced by both IFN‐γ⁺ Th1 cells and IL‐17⁺ Th17 cells. We report that these IL‐13‐producing Th1 and Th17 cells are distinct from classical IL‐4⁺ Th2 cells and that they are relatively common, appearing in the context of both protective and pathogenic T‐cell responses. We also demonstrate that IL‐13 and Th2‐type cytokines can have important consequences in Th1‐ and Th17‐dominated settings, such as lymphopenia‐induced autoimmune disease, where they can be either pro‐ or anti‐inflammatory, depending on whether they act on innate or adaptive immune cells. Taken together, our studies indicate that IL‐13 production is more widespread than previously appreciated and that blocking this cytokine may have therapeutic benefits even in settings where traditional IL‐4‐driven Th2‐type responses are not evident.     

Manipulation of the Th1/Th2 balance in autoimmune disease

Many autoimmune diseases are caused by autopathogenic Th1 cells. Because in vitro Th1 and Th2 cells cross-regulate each other, it is likely that the induction of self-antigen-specific Th2 cells can prevent autoimmune disease. In the past year, investigators have further defined the role of Th1 and Th2 cytokines in the induction and regulation of autoimmunity. Furthermore, the role of MHC—antigen—T-cell avidity (strength of signal) in inducing such protective immune responses has been elucidated.     

Immunosteroid as a regulator for Th1/Th2 balance: Its possible role in autoimmune diseases

Immune balance controlled by Th1 and Th2 cells is critical for the protection of host from pathogenic invasion while its imbalance becomes the cause of various immune disorders including autoimmune diseases. Cytokines, such as IL-12 and IL-4, are critical factor to drive the differentiation of naïve CD4⁺ T cells to Th1 or Th2 cells. In addition to cytokines, steroid hormones have been demonstrated to affect on the control of Th1/Th2 balance and the onset of autoimmune diseases. Here, we will propose a new concept that immunosteroid, which is designated as a steroid produced by immunoregulatory cells, also play a critical role for regulation of Th1/Th2 balance. First example of immunosteroid is Th2-dependently produced progesterone. Th2 cells, but not Th1 cells expressed P450scc and 20α-HSD and produced progesterone from 22R-hydroxycholesterol in cooperation with 3β-HSD-expressing mouse fibroblasts. Th2-dependently produced progesterone induced apoptotic cell death of Th1 cells and inhibited the differentiation of Th1 cells. While Th2 cells were escaped from toxic effect of progesterone by metabolizing it to non-toxic 20α-hydroxyprogesterone with 20α-HSD. Second example of immunosteroid is dendritic cell (DC)-dependently produced 1α,25-dihydroxyvitamin D3 [1,25(OH)₂D] secosteroid hormone, which has been demonstrated to inhibit autoimmune diseases. We found that 25-hydroxyvitamin D3 1α-hydroxylase, which metabolize 25-hydroxyvitamin D3 (inactive form) to 1,25(OH)₂D was expressed in Th2-cytokine induced bone marrow-derived DC2 but not Th1-cytokine induced DC1. Moreover, 1,25(OH)₂D was significantly inhibited DC1-induced type1 immunity.

Thus, we initially demonstrated the critical role of immunosteroids in the control of Th1/Th2 balance influencing on the onset of autoimmune diseases. Therefore, it will be an important issue to investigate the possible role of immunosteroids for the regulation of autoimmune diseases.     

Contribution of survivin to the immune system,allergies and autoimmune diseases

In addition to malignancies, survivin (a member of the apoptosis inhibitor family) has been implicated in the pathogenesis of inflammatory disorders, including autoimmune and allergic diseases. Survivin is constantly expressed in the proliferating hematopoietic progenitor cells, and it is re-expressed in the mature cells of the innate and adaptive immunity, upon activation. Survivin enhances the expression of co-stimulatory molecules and MHC class II molecules in dendritic cells, and promotes the lifespan of macrophages, neutrophils, and eosinophils, while suppressing natural killer (NK) cell activity. Survivin has been implicated in T cell maturation, T cell expansion, effector CD4⁺ T cell differentiation, maintenance of memory CD4⁺ T and CD8⁺ T cells, as well as antibody production. Upregulated expression of survivin was indicated in the T cells as well as various samples collected from allergic patients. Survivin can contribute to the pathogenesis of allergic diseases via the promotion of the Th2 polarization, promoting IL-4 expression, compromising activation-induced cell death (AICD) in Th2 cells, and preventing apoptosis of eosinophils, as well as, amplification of eosinophilia. Moreover, survivin can interfere with clonal deletion of autoreactive T and B cells, as well as suppress Treg cell development and activity supporting the development of autoimmune diseases. This review discusses the role of survivin in immunity, allergy and autoimmunity as well as provides evidence that survivin may be considered as a novel therapeutic target for the treatment of allergic and autoimmune diseases.     

T cell epitopes of Per a 10 modulate local-systemic immune responses and airway inflammation by augmenting Th1 and T regulatory cell functions in murine model

Peptide immunotherapy (PIT) represents a safe and efficacious therapeutic modality for allergic diseases. Present study evaluates immunotherapeutic potential of T cell peptides of major cockroach allergen, Per a 10 in murine model of airway allergy. Treatment with peptides T-P8 and T-P10 demonstrated maximal resolution of pathophysiological features such as reduced recruitment of inflammatory cells to airways, lowered specific IgE, induction of IgG2a antibodies in serum, immune deviation towards Th1 cytokine milieu, suppression of Th2 cytokines in BALF and splenocyte culture supernatant and resolution of lung inflammation. A significant increase in CD4⁺Foxp3⁺ cells in spleen indicate towards induction of T regulatory cell mediated peripheral tolerance characterized by shift in cytokine milieu from Th2 to T regulatory cytokines. PIT modulates regulation of immune responses at both local and systemic levels, contributes towards holistic improvement in allergic features in mice and thus demonstrate potential for safe, specific and efficacious treatment for cockroach allergy.     

Letter from the Editor

The potential role of B-1 cells (i.e the CD5⁺ B cell and “sister” B cell subsets) in autoimmunity is controversial. CD5⁺ B cells have been shown to secrete antibodies of similar specificity as those found in many systemic autoimmune diseases; in addition, increases in CD5⁺ B cell frequency have been reported in patients suffering from rheumatoid arthritis, Sjögren's syndrome, myasthenia gravis, insulin-dependent diabetes mellitus and Hashimoto's thyroiditis. Whether these increases are due to expansion of B-1 lineage cells in the human or due to activation-induced expression of CD5 by conventional B cells is unclear. In the present study, we used three murine models of systemic autoimmunity: murine acquired immunodeficiency syndrome (MAIDS), chronic graft-versus-host disease (cGvHD), and collagen-induced arthritis (CIA) to determine whether increases in B-1 cell frequency are universally seen in models of autoimmunity which are mechanistically distinct. In contrast to the aforementioned human systemic autoimmune diseases which exhibit an increase in CD5⁺ B cell frequency, the percentage of CD5⁺ B cells declined in all three murine models of systemic autoimmune disease. Even though there was a decrease in the frequency of CD5⁺ B cells there was no change in the actual number of CD5⁺ B cells. Thus, the apparent decline in CD5⁺ B cell frequency was due to increases in either T cells, conventional FcR⁺ B cells, or both. The only actual decline in a B cell subset was the loss of IgM⁺, Fc±R^dull cells in both the spleen and peritoneal cavity of mice undergoing a chronic graft-versus-host reaction. Therefore, our data suggests that expansion of the B-1 subset does not occur as a general feature of murine systemic autoimmune disease. These observations, consistent with previous studies of Ig gene usage in autoreactive antibodies, support the view that expansion and differentiation of the CD5⁺ B cell subset is not a central event leading to autoantibody production.     

Annexin-A1 restricts Th17 cells and attenuates the severity of autoimmune disease

Annexin-A1 (Anx-A1) is an endogenous anti-inflammatory molecule and while described as a repressor of innate immune responses, the role of Anx-A1 in adaptive immunity, and in particular in T helper (Th) cell responses, remains controversial. We have used a T-cell mediated mouse model of retinal autoimmune disease to unravel the role of Anx-A1 in the development of autoreactive Th cell responses and pathology. RBP_1–20-immunized C57BL/6 Anx-A1^−/− mice exhibit significantly enhanced retinal inflammation and pathology as a result of an uncontrolled proliferation and activation of Th17 cells. This is associated with a limited capacity to induce SOCS3, resulting in un-restricted phosphorylation of STAT3. RBP_1–20-specific CD4⁺ cells from immunized Anx-A1^−/− animals generated high levels of Th17 cells-associated cytokines. Following disease induction, daily systemic administration of human recombinant Anx-A1 (hrAnx-A1), during the afferent phase of disease, restrained autoreactive CD4⁺ cell proliferation, reduced expression of pro-inflammatory cytokines IL-17, IFN-γ and IL-6 and attenuated autoimmune retinal inflammatory disease. Furthermore, in man, Anx-A1 serum levels when measured in active uveitis patient sera were low and associated with the detection of IgM and IgG anti-Anx-A1 antibodies when compared to healthy individuals. This data supports Anx-A1 as an early and critical regulator of Th17 cell driven autoimmune diseases such as uveitis.     

Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4+ T‐cell subsets in multiple sclerosis patients

Excessive levels of proinflammatory cytokines in the CNS are associated with reduced serotonin (5‐HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5‐HT to modulate the T‐cell behavior of patients with MS, a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5‐HT attenuated, in vitro, T‐cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5‐HT reduced IFN‐γ and IL‐17 release by CD8⁺ T cells. By contrast, 5‐HT increased IL‐10 production by CD4⁺ T cells from MS patients. A more accurate analysis of these IL‐10‐secreting CD4⁺ T cells revealed that 5‐HT favors the expansion of FoxP3⁺CD39⁺ regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T‐cell subset. The effect of 5‐HT in upregulating CD39⁺ Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5‐HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS.     

The role of T cells in pemphigus vulgaris and bullous pemphigoid

Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are autoantibody-mediated diseases clinically characterized by blisters and erosions of skin and/or mucous membranes. Immune imbalance and antibody generation are the key pathologies of autoimmune bullous diseases. Recently, a large number of studies have shown that T cell subsets, which are critical players in autoimmunity, exhibit a range of abnormalities and drive immunopathogenesis and skin inflammation in PV and BP. T helper (Th)1 cells mediate pro-inflammatory or immune responses through IFN-γ and Th2-derived cytokines, such as IL-4, can promote B cell proliferation, antibody production and immunoglobulin class-switching. Th17 cells promote inflammatory response and skin damage, while regulatory T cells suppress autoreactive CD4⁺ T cell activation and help control inflammation. T follicular helper cells cross-talk with B cells and facilitate autoantibody production. In this review, we discuss the immune features of PV and BP, with a focus on the aberrations in T cell subsets, such as Th1 cells, Th2 cells, Th17 cells, regulatory T cells, T follicular helper cells, CD8⁺ T cells, γδ T cells and resident memory T cells in the pathogenesis of PV and BP. Improved understanding of biological and immunological functions of T cell subsets in patients with autoimmune skin disorders will offer unique opportunities for the recognition of treatment targets for these complex diseases.