Conversely, IL-4, IL, corticosteroids and catecholamines directly inhibit newly activated Th0 cells from differentiating into Th1 cells. Cytokines, hormones, and microbial antigens stimulate the innate immune system to produce either IL or IL-4 in the local microenvironment around a newly activated T cell. IL induces Th0 polarization to the Th1 phenotype and inhibits polarization to the Th2 phenotype, whereas IL-4 acts reciprocally.
Naive Th0 cells exposed to IL-4 differentiate into Th2 cells. Exposure of naive Th0 cells to IL inhibits polarization to Th2 cells; however, if both IL-4 and IL are present at the time of naive T cell activation, the effects of the IL-4 will dominate, and a type 2 response will ensue.
Sadick and Locksley et al. Mosmann's group Krishnan et al. Such pregnant mice mounted futile type 2 responses and were unable to control Leishmania infections. The evolutionary benefit of suppression of inflammation by the pregnant state was made obvious in a second study by the same group; induction of a type 1 response to Leishmania in infected pregnant mice caused fetal resorption and uterine scarring [ ].
IL must be present during the initial infection in order for protective type 1 responses to develop, but once a population of Th1 cells is established, IL is not required for the cells to mediate protection [ ]. The dispensability of IL after establishment of type 1 responses was strongly supported by a study in which mature Th1 cells adoptively transferred into severe combined immunodeficiency SCID mice were able to protect the mice from Leishmania infection without addition of recombinant IL [ ].
As Th1 cells do not actually secrete IL IL is secreted only by antigen-presenting cells , IL cannot have been necessary for the protective effect of the Th1 cells against infection. Conversely, it has been possible to reverse the phenotype of populations of ex vivo T cells taken from animals with established infection [ , ].
These studies raised an interesting question: if populations of ex vivo T cells taken from mice with established infections can be reverted in vitro, why can't the phenotype of the overall immune response be reversed in vivo? A likely answer was provided by Nabors et al. These investigators administered IL with or without a chemotherapy agent to mice with Leishmania infections.
Only the combination of IL and the antimicrobial agent was able to reverse the established nonhealing type 2 response in vivo, allowing a healing type 1 response to develop. The implication is that decreasing the antigenic burden of the infected animals was crucial to disinhibiting the animals' type 1 immunity.
This is consistent with the notion that high infectious inoculations stimulate type 2 immunity, whereas lower inoculations allow protective type 1 inflammation to develop. These results indicate that antimicrobial chemotherapy is a powerful tool for inducing healing type 1 responses in hosts whose normal type 1 immunity is suppressed by overwhelming antigenic burden.
Bacterial infections. As well, ex vivo spleen cells taken from mice with acute E. Thereafter, a gradual switch in profiles was noted, such that by several months after infection the level of type 1 cytokines was decreased.
This is consistent with the notion that the immune system uses type 1 responses for protection against acute infection and switches to type 2 responses when the danger is passed in order to reestablish homeostasis and protect the host from autoinflammatory destruction. Such knockout mice quickly developed more intensely polarized type 1 responses than their wild-type littermates, so that by 48—72 h after infection, their microbial tissue burden was fold lower than that of the wild-type mice [ ].
This is consistent with in vitro data suggesting that intracellular pathogens with innately antigenic fractions induce early IL release from leukocytes, whereas large extracellular pathogens induce frustrated phagocytosis, thereby eliciting a type 2 response.
Type 1 responses are also protective against other bacteria, such as Pseudomonas, Yersinia , and Klebsiella [ — ]. Mycobacterial infections. Type 1 immunity has also been shown to be protective against mycobacteria.
Mice inherently resistant to Mycobacterium leprae produced IL early on at the site of infection [ , ], but mice susceptible to M. When IL was administered to mice with established M. Orme et al. This is in concordance with the recurrent theme that type 1 cytokines are expressed during the protective phase of an immune response, and a switch is made to expression of type 2 cytokines during the resolution phase.
Fungal infections. Adding to the notion that high microbial burden suppresses type 1 immunity, normally susceptible mice infected with sublethal inocula of Candida developed type 1 immunity instead of their usual type 2 immune response [ ]. This reversal of immunologic phenotype was due to diminished induction of IL-4 secretion by the lower inoculum. Furthermore, lowering fungal burden in infected mice by treatment with either amphotericin B or fluconazole induced a healing type 1 immune response, an effect potentiated by blockade of IL-4 [ , ].
Therefore, it is the balance of IL and IL-4 induced early after infection that determines the eventual phenotype adopted by the adaptive immune response. High microbial burden tips the balance in favor of IL-4, suppressing cell-mediated immunity and polarizing the immune response toward a type 2 phenotype.
Antimicrobial chemotherapy is an effective intervention to favor type 1 immunity by lowering microbial burden. In addition, strains of mice prone to type 1 responses, although innately resistant to most bacteria, are inherently susceptible to helminthic infections [ ].
Therefore, unlike every disease model so far discussed, it is type 2 immunity rather than type 1 immunity that protects mammals from helminths [ — ]. Type 2 responses correlate with diminished worm burden, whereas type 1 responses allow chronic infection and scarring to develop [ ].
Mast cell activation has been shown to be a key component of type 2 immunity to various helminths, including Trichinella and Nippostrongylus [ — ]. IL-9 is important in mast cell activation, which increases gastrointestinal peristalsis that successfully expels parasites from the gut [ ]. Indeed, transgenic mice overexpressing IL-9 were highly resistant to trichinella infection [ ], and blockade of IL-9 worsened infection in mice normally resistant to trichuris infection [ ].
Conversely, blocking IL-4 or administering IL in normally resistant mice led to the development of futile type 1 responses, which allowed chronic infection to develop [ — ]. Although the above studies provide convincing evidence that type 2 immunity is protective against helminths, recent revisionist thinking has challenged this notion [ ].
Although conceding that type 2 immunity is the natural mammalian response to helminths, the revisionist theory states that type 2 immunity occurs because helminths deviate the host immune response to a nonprotective posture, enabling the worms to successfully infect the host.
The evidence in support of this notion derives from studies in which serum IgE and IL-4 levels have failed to correlate with host protection against helminths [ — ]. In fact, IL-4 knockout mice are perfectly resistant to Nippostrongylus infection, indicating that IL-4 is not required for protection against this helminth in mice [ ].
The notion that type 2 immunity is a maladaptive response to helminthic infection was directly challenged by an elegant study by Bancroft et al. Wild-type mice mounted strong type 2 responses that successfully cleared the helminth. IL-4 knockout mice failed to mount type 2 responses; they produced no IL-4 and had markedly diminished IL-5 and IL levels, which resulted in a huge increase in worm burden.
It is interesting that in contrast to IL-4 knockout mice, production of IL-4 and IL-5 by the IL knockout mice was only mildly diminished in comparison with that in wild-type animals, indicating that they still mounted type 2 responses.
Nevertheless, despite their apparent type 2 response, the IL knockout mice suffered from twice the worm burden than that in the IL-4 knockout mice. Thus a type 2 immune response is protective against Trichuris only if IL is present. Left Y- axis , Ex vivo cytokine production by peripheral blood mononuclear cells; right Y- axis , tissue worm burden number of worms cultured from cecum and colon.
An overwhelming majority of data indicate that type 2 immunity is the key to mammalian protection against infection by helminths. IL-4 is important for induction of type 2 immunity, but IL-5, IL-9, and IL are the key effector cytokines in type 2-mediated protection.
IL-5 and IL-9 act via eosinophil and mast cell stimulation. Although it has been suggested that IL acts via secondary induction of TNF [ ], its definitive mechanism remains obscure. The findings of studies of immunity in patients infected with Leishmania parallel the data generated in animal models.
Biopsies of lesions from patients suffering from destructive mucocutaneous American leishmaniasis demonstrated a marked increase in the level of IL-4 mRNA, which is consistent with a failed type 2 host immune response. Analogous to murine data on infectious burden, expression of IL was found to be higher in patients with active Leishmania donovani infections than in patients who had been cured of disease [ ].
Conversely, ex vivo cytokine production by lymphocytes taken from patients with severe visceral leishmaniasis was dominated by the type 2 cytokines IL-4 and IL [ ]. Thus type 1 immunity is the key to protection against Leishmania infections in humans, and a high infectious burden suppresses the human immune system from mounting type 1 responses. Similarly, Lactobacillus, S. Case reports concerning patients with identified genetic defects in cytokine or cytokine receptor genes are illustrative of the role of cytokines in host defense against infection.
The dichotomy between patients with lepromatous leprosy, which is the disseminated, severe form of the disease, and those with tuberculoid leprosy, which is local disease controlled by the immune system, parallels in vivo cytokine production [ ].
Lepromatous leprosy develops in patients who mount type 2 immune responses to the organism, whereas tuberculoid leprosy is synonymous with a successful type 1 immune response to M. Furthermore, lesion-biopsy specimens from patients with tuberculoid leprosy contained Th1 cells expressing fold higher levels of IL mRNA than in lepromatous patients [ ]. Conversely, biopsy specimens from lepromatous patients contained high levels of IL-4 and IL There is also a dichotomy between a high humoral response and a high DTH response among patients infected with Mycobacterium tuberculosis [ , ].
In addition, infected patients produced higher levels of IL-4 [ , ]. These data are consistent with the notion that active M. As in mice, immunity to mycobacteria in humans evolves over time figure 5 [ ]. By a week after inoculation, the production of Th1 cytokines reached a plateau and there was a sudden burst in IL-4 production. By days 10—12 after vaccination, there was a remarkable suppression of type 1 cytokine activity and a rise in IL-5 and IL production.
This elegant study provided powerful confirmatory evidence that type 1 immunity is directly induced by mycobacteria and that the immune system naturally switches over time to a type 2 immune response in order to reestablish homeostasis after the battle is won.
Change in cytokine pattern over time following BCG vaccination in humans. Ex vivo peripheral blood mononuclear cells PBMCs were analyzed by fluorescence-activated cell-sorting FACS for intracellular cytokine production on sequential days following administration of BCG vaccine to healthy volunteers.
Cells from such patients produced an altered profile of cytokines, more reminiscent of a type 2 profile, when stimulated in vitro with Candida antigens [ ]. Since IL-4 inhibits human phagocytes from killing Candida [ ], this switch to a type 2 profile can explain the inherent susceptibility of such patients to candidal infections. Such patients suffer from an inability to generate a respiratory burst in phagocytic cells and therefore commonly develop invasive pyogenic and fungal infections, often caused by Aspergillus [ ].
Because of the loss of IL-2 secretion, T cells from HIV-positive patients are typically unable to proliferate when stimulated by common antigens. Analyses of the impact of highly active antiretroviral therapy on immune reconstitution in patients with AIDS have been recently published [ , ].
This paralleled a recovery in T cell counts. Similar results have been found in studies of children treated with highly active antiretroviral therapy [ ]. Therefore, clinicians may be able to reverse the immune dysregulation in patients with AIDS by affecting viral suppression. This switch in receptor usage during disease progression parallels the frequency with which Th1 and Th2 cells are found in vivo.
Thus part of the pathogenesis of AIDS is a selective loss of Th1 cells, which then forces the virus to adapt to infect Th2 cells in order to persist in the host.
Although suppression of IL production by phagocytes is one mechanism by which HIV acts to suppress type 1 immunity, in vivo studies have demonstrated an additional effect.
Hormonal abnormalities, such as a loss of serum testosterone derivatives, are commonly seen in patients with AIDS and result in lean-muscle-mass wasting [ — ]. Conversely, loss of CD4 cells and AIDS progression were inversely correlated with serum cortisol levels [ , , ].
This is the perfect recipe for systemic suppression of type 1 responses and stimulation of type 2 responses. These studies provide the theoretical underpinning for the hypothesis that HIV induces a gradual paralysis of type 1 immunity, allowing expansion of Th2 cells at the expense of naive T cells and Th1 cells.
This theory was confirmed by clinical observations in several key studies. Therefore, HIV-positive children suffer from dysregulated immunity in which type 2 responses overwhelm type 1 responses, and the rate of loss of type 1 immunity parallels the loss of T helper cells.
Ex vivo cytokine production by peripheral blood mononuclear cells and serum IgE levels in 58 vertically infected children with HIV infection or AIDS, compared to that in 35 serorevertant HIV-negative control subjects figure reproduced with permission from [ , ].
HIV is unique among the disorders so far discussed in that several interventional cytokine trials involving humans have been performed. Kovacs et al. There was no difference in the viral load between the 2 groups at the end of the year.
Thus the difference in T helper cell counts at the end of the year was unrelated to the degree of viral suppression. Rather, the exogenous IL-2 restored the immune system's ability to produce more peripheral T cells, a finding confirmed by more recent clinical trials [ — ].
Like Kovacs et al. Like the total T cell population, the numbers of naive T cells also doubled in the ILtreated patients, whereas there was no change in the number of naive T helper cells in the group treated with antiretrovirals alone.
Therefore, IL-2 not only enables activation of and expansion of the number of Th1 effector cells but also promotes survival of naive Th0 cells in patients with AIDS.
In addition, Khatri et al. The final proof of a shift from type 1 to type 2 immunity in patients with AIDS derives from an elegant study by Norbiato et al. These investigators studied 10 patients with AIDS who developed Addisonian symptoms and were found to be glucocorticoid-resistant, as determined by low-affinity binding of their glucocorticoid receptors to dexamethasone.
Conversely, although patients with AIDS who had normal steroid receptors had urinary cortisol levels somewhat lower than those of the steroid-resistant patients with AIDS, the cortisol completely suppressed endogenous IL-2 production in these patients figure 7. A comparison of serum IgE levels in the cortisol-resistant and normal-receptor patients with AIDS closes the argument. Clearly, these patients with AIDS were suffering from an overwhelming excess of type 2 immunity.
Thus in vitro and in vivo data indicate that HIV, beyond simply killing T cells, disrupts normal homeostasis of type 1 and type 2 immunity. Abnormally high levels of glucocorticoids and suppressed levels of DHEA, along with direct viral suppression of IL production, create a host environment that suppresses differentiation of type 1 effector cells and stimulates development of type 2 immune responses that are ineffective at controlling a broad range of pathogens.
As repeatedly discussed, the immune system restores homeostasis by switching a type 1 response into a type 2 response once an infection has been cleared. Recent data from Gett and Hodgkin shed new light on the mechanism of this switch [ ]. These investigators developed a sophisticated experimental system to determine how many cell divisions a given T cell had undergone after activation.
They simultaneously measured in vitro cytokine production by the lymphocytes, allowing correlations to be drawn between cell division number and cytokine production figure 8. Cytokine secretion as a function of T cell division. In vitro-activated murine T lymphocytes were stained with an intracellular fluorescent dye whose intensity decreases with each cell division. FACS was used to sort lymphocytes into populations of equivalent cell-division number.
The cultures were restimulated with anti-CD3 antibody, and cytokines in the supernatants were analyzed by ELISA, allowing cytokine production to be matched to T cell division number figure reproduced with permission from [ ].
Immediately after activation of naive T cells, only IL-2 was produced. IL-4 secretion began at division 6, accompanied by the gradual waning of IL-2 secretion. Finally, at cell division 8, there was a sharp burst in production of IL Unfortunately, the limit of the technology is about 8 cell divisions. Thus there is a molecular genetic basis for the clinical phenomenon of switching from a type 1 to a type 2 response over time during infection.
T cells appear to gradually lose the ability to secrete pro-inflammatory cytokines as they mature after multiple cell divisions. Clinicians traditionally measure vaccine-induced protective immunity by following antibody titers. Furthermore, passive immunization, or administration of exogenous antibody, mediates protection against a variety of infections. Thus, although the model outlined above indicates that type 1 responses are the keys to protection against most infections, paradoxical observations suggest that vaccines and passive immunization rely on type 2 immunity to mediate protection.
The first concept is that type 1 immunity does not actively suppress antibody responses. Although titers are lower in dominant type 1 responses than in type 2 responses, Th1 cells are quite capable of inducing antibody production by B cells [ 13 ]. Thus antibody production is consistent with either a type 1 or type 2 response, depending on the subtypes of antibody present. Thus, by serving as opsonins, antibody induced during a type 1 immune response synergistically increases the effectiveness of cell-mediated immunity.
The second concept is that type 2 immunity, in addition to inducing antibody, actively suppresses cell-mediated immunity. Thus administration of exogenous antibody is not equivalent to induction of a type 2 immune response. Rather, passive immunization with exogenous antibody garners the immunologic benefit of a humoral response without the added deficit of suppressing cell-mediated immunity. Instead, passive immunization synergizes with type 1 immunity by providing extra opsonins to assist activated phagocytes.
Passive immunization therefore does not fit into either the type 1 or type 2 description of endogenous immunity. This is logical, since passive immunization is obviously not a normal, physiological component of mammalian immune systems. Although antibody titers are used clinically to determine the efficacy of vaccines, this correlation of high titers with protective immunity cannot be reliably interpreted as an indication that vaccines work via induction of type 2 immunity.
Indeed, Parish demonstrated 2 zones of humoral and cell-mediated equivalency in his seminal article [ 3 ]. Indeed, antibody induced by vaccines may be of the IgG1 or IgG3 isotype, consistent with a type 1 immune profile [ ]. When such studies have been undertaken, a dominance of type 1 immunity has been found to be elicited by vaccines [ , ]. Type 1 outcomes generate both cell-mediated and humoral responses that act synergistically, whereas type 2 outcomes generate humoral responses but actively suppress cell-mediated responses.
In animal models, vaccines inducing type 1 immunity have been proven highly effective at preventing infections, whereas vaccines inducing type 2 immunity increase susceptibility to infection [ , , , , — ].
Type 1 immunity is the default response to all infections by normal inocula of intracellular or phagocytosable microbes occurring in nonimmunosuppressed hosts. Type 1 immune responses clear such pathogens, thereby diminishing further antigenic stimulation for type 1 immunity. In addition, T lymphocytes naturally switch from production of type 1 cytokines to production of type 2 cytokines as they progress through multiple cell divisions. Therefore, over time a type 1 immune response will tend to convert into a type 2 response, allowing homeostasis to be reestablished.
However, with persistent antigenic stimulation—for example, if the type 1 immune response is never able to completely clear the infection—continual stimulation of T cells can induce chronic type 1 responses, leading to host tissue destruction. Conversely, type 2 immunity is the default response to infections by large, extracellular pathogens that cannot be phagocytosed, such as helminths. Type 2 immunity naturally develops over time from type 1 immune responses. However, in patients who have excess sympathetic stimulation before infection, have excess glucocorticoids or high estrogen or progestin levels, are ILdeficient because of cyclosporine or FK, or are inoculated by an overwhelming microbial burden, the usual type 1 response is suppressed and a type 2 response occurs instead.
Clinical factors that induce glucocorticoid or sympathetic responses will tend to make patients susceptible to infections that would normally be dealt with by type 1 immune responses. Malnutrition has been shown to suppress serum DHEA levels and directly induce high systemic levels of glucocorticoids and catecholamines [ — ], as has the presence of malignancy, even independently of malnutrition [ ].
Indeed, patients with malignancies are prone to type 2 immunity at the expense of type 1 responses [ , ]. Furthermore, the clinical conditions of congestive heart failure [ — ], chronic obstructive pulmonary disease [ ], and hepatic cirrhosis [ ] are all associated with hypersympathetic stimulation and high circulating catecholamine levels, conditions suppressive to type 1 immunity.
Finally, severe systemic stresses induced by traumatic injury [ , ], extensive surgery [ , ], and the use of total parenteral nutrition [ ] have been shown to suppress type 1 immunity and favor type 2 immunity.
The implications for clinicians from these data are three. First, the paradigm of type 1 and type 2 immunity provides a pathophysiological explanation for why patients with the above systemic ailments are prone to severe infections. Second, the model suggests new potential weapons in the clinical battle for host defense. Third, the model explains an important and previously unknown effect of antimicrobial chemotherapy: lowering antigenic burden by treating with antibiotics disinhibits protective type 1 immunity.
Early studies on the use of IL-2 and IL in humans revealed their potential for severe systemic adverse effects [ , ]. Despite the initial setbacks in patients with cancer, the use of newer schedules of dosing of IL-2 and IL have demonstrated impressive effects in patients with infectious diseases. In addition, IL has demonstrated antiviral effects with minimal toxicity in patients with chronic hepatitis [ , ]. Conversely, the anti-inflammatory effects of IL in humans [ — ] have led to its use in hyperinflammatory states ranging from psoriasis [ ] to organ transplantation immunosuppression [ ] to Crohn's disease [ ], with promising results.
Blockade of cytokine effects has also been attempted. Specifically, inhaled recombinant IL-4 receptor has shown promise as an anti-asthmatic agent, serving to soak up IL-4 in the airways [ ].
However, exogenous administration of cytokines is a systemic intervention, whereas the immune system normally regulates itself on the basis of the cytokine milieu present at local microenvironments. Polarized Th1 and Th2 cells not only exhibit different functional properties, but also show the preferential expression of some activation markers and distinct transcription factors.
Several mechanisms may influence the Th cell differentiation, which include the cytokine profile of "natural immunity" evoked by different offending agents, the nature of the peptide ligand, as well as the activity of some costimulatory molecules and microenvironmentally secreted hormones, in the context of the individual genetic background.
In addition to playing different roles in protection, polarized Th1-type and Th2-type responses are also responsible for different types of immunopathological reactions. Although the differentiation of T cells is affected by antigen concentration or co-stimulatory molecules, cytokines are the most effective regulators of Th cell differentiation.
In addition, the effects of extracellular microenvironment and transcription factors have also played a major role. Signaling Pathway in Th Cell Differentiation. Although Th1 and Th2 are differentiated from common precursor cells, there are certain differences between them:. Th1 and Th2 cells play an important role in immunity. Th1 cells stimulate cellular immune response, participate in the inhibition of macrophage activation and stimulate B cells to produce IgM , IgG1. Th2 stimulates humoral immune response, promotes B cell proliferation and induces antibody production IL It can also induce the differentiation and proliferation of mast cells IL-3, IL-4 , and the differentiation and proliferation of eosinophilic leukocytes IL Overexpression of Th2 can lead to inappropriate immune responses, leading to diseases such as allergies and asthma.
Overexpression of Th1 or Th17 can lead to autoimmune diseases such as rheumatoid arthritis and multiple sclerosis [3] [4]. Figure 1 Cytokines and transcription factors involved in the differentiation of Th1 and Th2.
The differentiation of Th1 and Th2 cells is regulated by many factors, and cytokines play the most important role. In general, IL is the most important cytokine that initiates Thl cell differentiation. IL is a newly discovered cytokine.
Its activity is affected by the IL receptor signal. T1 was initially selected and expressed on Th2 cells as a serum and tumor protein-inducible gene, belonging to the IL-1R family.
SOCS proteins inhibit signaling in certain signaling pathways. In addition to cytokines, many transcription factors are involved in the differentiation of Th1 cells and Th2 cells. NFAT is phosphorylated by calcineurin and transported into the nucleus. C-maf is a transcription factor that is specifically expressed in Th2 cells. Activation of C-maf induces IL-4 expression and promotes Th2 differentiation. The researchers found that C-maf also promotes Th2 differentiation via an ILindependent pathway.
T-bet also known as T-box 21 is a newly discovered Th1-specific transcription factor [13]. T-bet also binds to an IL-4 silencer region and inhibits IL-4 expression [16].
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