A study using an APC that was deficient for both B7. In addition, blockade of B7-CD28 interaction in vivo reduced the Th2 responses in both Leishmania and nematode infection models [ 30 ]. The molecular mechanisms by which CD28 mediates Th2 differentiation is not very clear. In support of this, Viola et al [ 31 ] observed that CD28 cosimulation resulted in reorganization of membrane lipid microdomains and sustained tyrosine phosphorylation.
Consistent with this, we showed [ 25 ] that CD28 enhanced nuclear accumulation of nuclear factor of activated T cells NFATc , a transcription factor required for Th2 differentiation. CTLA-4 plays an inhibitory costimulatory role in regulating T-cell response. Mice that are deficient in CTLA-4 display polyclonal T-cell activation and lymphoproliferative disorder that resulted in neonatal lethality [ 32 ].
It is also expressed by activated T cells. ICOS costimulation enhances T-cell proliferation and cytokine production. To add further complexity, two more B7 homologs were recently reported. CD40 ligand CD , which is expressed by activated T cells, is crucial for T-cell-mediated immune response [ 39 ]. OX40, which is also expressed by activated T cells, plays an important role in Th1-type immune responses. On the other hand, mice deficient in OX40 ligand exhibited impaired delayed hypersensitivity [ 43 ].
In comparison with the IL p35 promoter, the IL p40 promoter and the transcription factors that bind to it are better characterized. By the use of gene disruptions in mice, interferon responsive factor IRF -1 and interferon consensus sequence binding protein another member of the IRF-1 family have been shown to be required for IL p40 expression [ 53 , 54 , 55 , 56 ].
IL is secreted mainly by APCs upon innate immune recognition of pathogen-associated molecular patterns, including lipopolysaccharide. Lipopolysaccharide has recently been determined to function through Toll-like receptors [ 57 ].
How signals from these receptors activate IL transcription machinery is not yet completely understood. Our laboratory has recently found that p38 mitogen-activated protein Kinase MAPK pathway, activated by lipopolysaccharide or CD40, plays a crucial role in IL regulation [ 58 ]. Macrophages isolated from mice deficient in the p38 kinase, MAPK kinase MKK 3, have a profound defect in IL p35 and p40 transcription when stimulated by lipopolysaccharide.
In a mouse macrophage cell line, activation of the p38 pathway activates IL p40 promoter activity. IL receptor expression by T cells is regulated during Th differentiation, which may impact on their responsiveness to IL and resultant lineage determination. IL-4 inhibits its expression, which may lead to cells to become unresponsive to IL and differentiate into the Th2 subsets. IL-4 is a cytokine that is not only produced by differentiating and differentiated Th2 cells, but also is the key factor driving Th2 differentiation.
The source of the initial IL-4 that primed the Th2-type response in vivo has been debated for some years. Natural killer T cells produce IL-4 very rapidly upon TCR engagement and were therefore thought to be the regulatory cell for Th2 reaction. Mice that are deficient for CD1, and thus for natural killer T cells, have normal Th2 responses, however, which suggests that IL-4 may come from other sources [ 60 , 61 ].
They found that most clones were expressed in a monoallelic manner and that the allelic pattern was transmitted as a stable epigenetic trait.
In another study, Riviere et al [ 63 ] generated a mouse strain in which one allele of the IL-4 gene was replaced by human CD2 by gene targeting.
Using this model, they convincingly showed that most Th2 cells expressed only the functional IL-4 allele or the targeted allele. Estimation of the frequency of monoallelic versus biallelic expression in this model also suggests a stochastic process in the activation of each individual allele, in which each cytokine gene can be turned on probabilistically to generate diverse profiles of cytokine expression and effector population.
The IL-4 gene is located on chromosome 11 in a locus containing the gene for the other Th2 cytokines IL-5 and IL, which suggests a mechanism to coordinate the expression of these genes. Two groups have identified several deoxyribonuclease I-hypersensitivity sites in IL-4 and IL gene loci that are associated with Th2 differentiation [ 65 , 66 ], which may indicate a chromatin remodeling process during Th2 commitment that makes the loci more accessible to the transcription machinery.
In addition, IL-4 locus remodeling is accompanied by demethylation and was shown to require both antigen receptor and IL-4 cytokine signaling [ 66 ]. The bp proximal promoter of the IL-4 gene has been extensively studied, and it confers Th2 specificity in transgenic mice despite a substantially lower expression level than the endogenous gene [ 69 ].
The first four NFATs are cytoplasmic and translocated into the nucleus only after dephosphorylation in their serine-proline rich and serine rich regions by calcineurin phosphatase [ 72 ]; NFAT5 is constitutively nuclear [ 73 ].
In fact, NFAT-AP1 composite sequences exist in promoters of numerous cytokine and immune effector genes, and have been shown to be critical for regulation of these genes. Precisely why this is so is still a puzzle. Using the representation difference analysis approach, we found GATA-3 to be selectively expressed in the Th2 pathway [ 82 ].
During the past 2 years, GATA-3 has been shown by several studies to be the critical regulatory transcription factor involved in Th2 differentiation. This result was confirmed by a more recent study [ 85 ], in which expression of a dominant-negative mutant of GATA-3 in mice in a T-cell-specific manner reduced the expression of all of the Th2 cytokines IL-4, IL-5, and IL, and diminished airway hypersensitivity in vivo.
In another study, Ouyang et al [ 87 ], using a similar approach, found that GATA-3 expression could rescue Th2 development in Stat6-deficient cells, resulting in Th2 cytokine expression and the establishment of Th2-specific deoxyribonuclease I hypersensitive sites in the IL-4 locus. These experiments show that GATA-3 is the master Th2 regulatory factor, and is both necessary and sufficient to generate Th2 responses. How GATA-3 works is still not understood, however.
The proximal promoter of IL-4 gene lacks a strongly functional GATAbinding site, so we believe that its major role is likely to be as a Th2-specific enhancer s or perhaps as a locus control region eg in the IL-4, IL-5, and IL regions.
It binds to a site in the proximal IL-4 promoter. USA 88 , — Del Prete, G. Human IL is produced by both type 1 helper Th1 and type 2 helper Th2 T cell clones and inhibits their antigen-specific proliferation and cytokine production.
Hawrylowicz, C. Potential role of interleukinsecreting regulatory T cells in allergy and asthma. Nature Rev. Levings, M. Gerosa, F. Ejrnaes, M. Resolution of a chronic viral infection after interleukin receptor blockade.
Brooks, D. Interleukin determines viral clearance or persistence in vivo. Hsu, D. Science , — Pohl-Koppe, A. Jankovic, D. Immunity 16 , — Shaw, M. Anderson, C. Belkaid, Y.
Suffia, I. Interleukin production by effector T cells: Th1 cells show self control. Zheng, W. Cell 89 , — Zhu, J. Nature Immunol. Shoemaker, J. Mowen, K. Signaling pathways in Th2 development. Windhagen, A. Meyaard, L. Wang, Z. Regulation of IL gene expression in Th2 cells by Jun proteins. Jones, E. STAT6 dimer nuclear translocation and further initiation of transcription and expression of IL-4 and other genes [20]. CaN plays a role in T cell activation, differentiation and proliferation by activating the nuclear factor of activated T cell NFAT [21].
After the translocation of the activated NFAT nucleus, it combines with transcription factors such as AP-1 family proteins and other activation factors to form a complex to jointly regulate the expression of cytokines. The Hedgehog signaling pathway is also somewhat related to T cell differentiation. We found that the key Th2 cytokine IL-4 is a novel transcriptional target of Hh signaling in T cells, providing a mechanism for the role of Hh in Th differentiation [22].
Annual Review of Immunology, , 12 12 : Role of Th1 and Th17 cells in organ-specific autoimmunity [J]. Journal of Autoimmunity, , 31 3 : Journal of Molecular Cell Biology, , 1 1 : Annual Review of Immunology, , 18 1 : The Journal of Immunology, , 3 : Annual Review of Immunology, , 16 1 : Lineage commitment in the immune system: the T helper lymphocyte grows up [J].
Genes Dev, , 14 14 : Deletion of a conserved IL-4 silencer impairs T helper type 1-mediated immunity [J]. Nature Immunology, , 5 12 : Cytokines induce the development of functionally heterogeneous T helper cell subsets [J].
Immunity, , 8 3 : Those T cells that survive thymic selection leave the thymus and form the peripheral T-cell repertoire Fig. Schematic representation of T cell development. T cells originate from the common lymphoid progenitor cells in the bone marrow. They migrate as immature precursor T cells via the bloodstream into the thymus, which they populate as thymocytes.
The thymocytes go through a series of maturation steps including distinct changes in the expression of cell surface receptors, such as the CD3 signaling complex not shown and the coreceptors CD4 and CD8, and the rearrangement of their antigen receptor T cell receptor , TCR genes.
Peripheral T cells are characterized by the expression of an array of distinctive surface receptors [ 1 — 3 ]. The cytoplasmic domains of CD4 and CD8 are constitutively associated with the src-family tyrosine kinase p56 lck , which phosphorylates particular recognition motifs within the CD3 complex denoted immunoreceptor tyrosine-based activation motifs , thereby promoting T-cell activation.
MHC molecules are membrane glycoproteins that are encoded by several closely linked, highly polymorphic genes. Differentiation of T cells is characterized by a number of phenotypic and functional alterations, such as changes in their migratory capacities, modification to their lifespan, and secretion of effector cytokines e. Memory cells respond more rapidly to antigen challenge and have a diverse array of effector functions. Engagement of the TCR induces activation of signaling cascades that result in changes in the transcriptional program of the T cell.
Extensive work has demonstrated that the 44 kDa glycoprotein CD28 is the major co-stimulatory molecule involved in T-cell activation [ 7 ]. Thus, memory T cells do not depend on the interaction with professional APCs for activation, provided their specific antigen can be presented in the context of the appropriate MHC molecules by nonprofessional APCs. Therefore, T cell clonality at the site of inflammation may reflect enrichment for memory T cells specific for foreign antigens rather than proliferation of autoreactive T cells specific for self-antigen.
Whereas B Q mice lacking CD4 are less susceptible to collagen-induced arthritis CIA , but not completely resistant, the CD8 deficiency has no significant impact on the disease [ 22 ]. It has become clear in recent years that the mechanisms resulting in the destruction of tissue and the loss of organ function during the course of an autoimmune disease are essentially the same as in protective immunity against invasive micro-organisms.
Moreover, appropriate T-cell directed therapies have clearly conferred clinical benefit in RA Table 2 [ 27 — 29 ]. Th1 cells develop preferentially during infections with intracellular bacteria. They activate macrophages to produce reactive oxygen intermediates and nitric oxide, stimulate their phagocytic functions, and enhance their ability for antigen presentation by upregulating MHC class II molecules. Moreover, Th1 cells promote the induction of complement fixing, opsonizing antibodies and of antibodies involved in antibody-dependent cell cytotoxicity e.
IgG 1 in humans and IgG 2a in mice. Consequently, Th1 cells are involved in cell-mediated immunity. Immune responses driven by Th1 cells are exemplified by the delayed-type hypersensitivity reaction [ 32 , 33 ].
Th2 cells predominate after infestations with gastrointestinal nematodes and helminths. They produce the anti-inflammatory cytokines IL-4 and IL-5, and provide potent help for B-cell activation and Ig class switching to IgE and subtypes of IgG that do not fix complement e.
IgG 2 in humans and IgG 1 in the mouse. Th2 cells mediate allergic immune responses and have been associated with downmodulation of macrophage activation, which is conferred largely by the anti-inflammatory effects of IL-4 [ 32 , 33 ]. Upon activation with specific antigen, CD4 T cells proliferate and differentiate into either the Th1 or the Th2 subset. Th1 cells promote cellular immunity and are involved in the development of autoimmune diseases; Th2 cells mediate humoral immunity and are involved in allergic immune responses.
The different functional T-cell subsets do not derive from different pre-committed lineages but rather develop from the same uncommitted precursor cell under the influence of environmental and genetic factors [ 34 ]. Differentiation of the appropriate T-cell subset is of crucial importance to the host in mounting protective immunity against exogenous micro-organisms.
However, it is apparent that immune responses driven preferentially by activated T-cell subsets are also involved in the development of pathologic immune disorders.
Whereas atopic diseases result from Th2-dominated responses to environmental allergens, Th1-mediated immunity is involved in the generation of several organ-specific experimental autoimmune diseases in animals, such as experimental allergic encephalomyelitis, insulin-dependent diabetes mellitus, and CIA [ 33 ].
Although dichotomizing complex diseases such as RA in terms of Th1 or Th2 patterns may be an over-simplification, evidence is accumulating that suggests that human autoimmune diseases, such as RA, might also be driven by preferentially activated Th1 cells without sufficient Th2 cell development to downregulate inflammation.
Various epidemiologic and clinical observations suggest a pathogenic Th1 drive in rheumatoid inflammation. For several decades, clinical observations have highlighted the ameliorating effect of pregnancy on the course of RA [ 35 ]. In fact, the effect of pregnancy on RA activity is greater than the effect of some of the newer therapeutic agents.
Although the mechanisms underlying this phenomenon remain unclear, a marked decrease in Th1-mediated immunity during pregnancy has been firmly established. For example, pregnant women have a higher incidence of infections than do nonpregnant females, in particular infections with intracellular pathogens.
The characteristic Th1 immune reaction, delayed-type hypersensitivity, is diminished during pregnancy. Most recently, a placental derived protein placental protein 14 could be identified that inhibited Th1 immune responses and synergized with IL-4 to promote Th2 immunity by inhibiting the downmodulation of the Th2 specific transcription factor GATA-3 [ 36 ].
Together, the data suggest that pregnancy induces a shift from Th1 to Th2 immune responses, thereby increasing anti-inflammatory cytokines, which may contribute to the gestational amelioration of RA. At that time, pregnancy-associated alterations in Th subset activation can no longer be found [ 35 ], suggesting that the beneficial Th2 shift has resolved and has allowed the Th1-dominated autoimmune inflammation to recur. Patients with RA have a decreased prevalence of allergic diseases [ 37 ].
Moreover, those patients with RA who, for example, have hay fever have less severe disease than do control patients with RA without hay fever [ 37 ].
Because allergy is the prototype Th2 disease and activated Th2 cells are able to inhibit the generation and the function of Th1 effectors, these studies support the contention that the occurrence of a Th2-mediated immune response might be beneficial in RA by inhibiting Th1 driven immunity.
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