Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity

Inhibitors of cAMP-specific phosphodiesterase (PDE) 4 have been shown to inhibit inflammatory mediator release and T cell proliferation, and are considered candidate therapies for T(h)1-mediated diseases. However, little is known about how PDE4 inhibitors influence dendritic cells (DC), the cells responsible for the priming of naive T(h) cells. Therefore, we investigated the PDE profile of monocyte-derived DC, and whether PDE4 inhibitors modulate DC cytokine production and T cell-polarizing capacity. We mainly found cAMP-specific PDE4 enzymatic activity in both immature and mature DC. In contrast to monocytes that mainly express PDE4B, we found that PDE4A is the predominant PDE4 subtype present in DC. Immature DC showed reduced ability to produce IL-12p70 and tumor necrosis factor (TNF)-alpha upon lipopolysaccharide or CD40 ligand (CD40L) stimulation in the presence of PDE4 inhibitors, whereas cytokine production upon CD40L stimulation of fully mature DC in the presence of PDE4 inhibitors was not affected. Exposure to PDE4 inhibitors for 2 days during DC maturation did not influence T cell-stimulatory capacity or acquisition of a mature phenotype, but increased the expression of the chemokine receptor CXCR4. Furthermore, DC matured in the presence of PDE4 inhibitors showed reduced capacity to produce IL-12p70 and TNF-alpha upon subsequent CD40L stimulation. Using these PDE4 inhibitor-matured DC to stimulate naive T cells resulted in a reduction of IFN-gamma-producing (T(h)1) cells. These findings indicate that PDE4 inhibitors can affect T cell responses by acting at the DC level and may increase our understanding of the therapeutic implication of PDE4 inhibitors for T(h)1-mediated disorders.     

Autoimmunity to a pathogenic retinal antigen begins as a balanced cytokine response that polarizes towards type 1 in a disease-susceptible and towards type 2 in a disease-resistant genotype.

Susceptible, but not resistant, strains of rodents immunized for induction of experimental autoimmune uveitis (EAU) with the uveitogenic protein interphotoreceptor retinoid-binding protein (IRBP) exhibit a type 1 response at the time of disease expression. Here we investigate the evolution of this response using the prototypic EAU-susceptible and EAU-resistant mouse strains, B10.A and BALB/c. Disease severity and IRBP-specific responses (proliferation, cytokines and antibody isotypes) were evaluated 7, 14 and 21 days after uveitogenic immunization. B10.A mice initially exhibited an IgG1-dominated antibody response, and their lymph node cells produced IL-4 and IL-5 in addition to IFN-gamma. On day 14 and 21, however, the IgG2a isotype became predominant, and the primed lymph node cells produced mainly IFN-gamma and IL-12. B10.A mice developed EAU before day 14. BALB/c mice initially produced IL-12 and IFN-gamma in addition to IL-5, IL-4 and IL-10. At later time points IL-12 and IFN-gamma production diminished, and IL-4, IL-5 and IL-10 increased. An IgG1-dominated antibody response was maintained throughout. BALB/c mice failed to develop EAU even at day 21. Thus, both susceptible and resistant genotypes initially mount a balanced, type 0-like cytokine response to a uveitogenic challenge, that subsequently polarizes towards type 1 in the susceptible strain and towards type 2 in the resistant strain.     

Altered expression of vasoactive intestinal peptide receptors in T lymphocytes and aberrant Th1 immunity in multiple sclerosis

Vasoactive intestinal peptide (VIP) has a unique property of regulating T(h)1 and T(h)2 immunity of CD4+ T cells. In this study, we demonstrated, for the first time, that differential expression of VIP receptors and a compensatory mechanism directly affect the responsiveness of CD4+ T cells and their T(h)1 and T(h)2 properties to VIP. The expression of VIP receptor-1 (VPAC1) and VPAC2 in CD4+ T cells changed reciprocally in the context of the activation state. In activated CD4+ T cells of healthy individuals, markedly decreased VPAC1 expression was compensated for by increased expression of VPAC2 induced by T cell activation. In contrast, there was altered expression of VPAC2 in activated CD4+ T cells derived from multiple sclerosis (MS) patients, which rendered CD4+ T cells less responsive to VIP and skewed the system to a predominantly in a T(h)1 direction. Detailed characterization with agonist peptides of VIP showed that residues Met and Ser at positions 17 and 25 of VIP were critical to its regulatory properties through interaction with VAPC2. Furthermore, altered levels of VPAC2 expression in T cells of MS patients were not associated with single-nucleotide polymorphism in the encoding region of the VPAC2 gene but with gene regulation as characterized by a distinct DNA footprinting pattern in the promoter region of the VPAC2 gene in MS as compared with controls. This study has provided new evidence for an intrinsic mechanism associated with an aberrant, pro-inflammatory state of CD4+ T cells in MS.     

Development of an assay to measure in vivo cytokine production in the mouse.

The short in vivo lifespan of many cytokines can make measurement of in vivo cytokine production difficult. A method was developed to measure in vivo IL-4 and IFN-gamma production that eliminates this problem. Mice are injected with a biotin-labeled neutralizing IgG anti-IL-4 or anti-IFN-gamma mAb and bled 2-24 h later. Secreted cytokine is captured by the biotin-labeled mAb to produce a complex that has a relatively long in vivo half-life and consequently accumulates in serum. Serum concentrations of the complex are determined by ELISA, using wells coated with an antibody to a second epitope on the same cytokine to capture the complex. This technique is specific and increases sensitivity of detection of secreted IL-4 at least 1000-fold. The amount of cytokine measured is directly proportional to the amount produced and relatively independent of the site of cytokine production. Furthermore, because mice are injected with small quantities of biotin-labeled anti-cytokine mAb, which sample, rather than neutralize, all secreted cytokines, cytokine-dependent responses are not inhibited. The in vivo half-lives of the cytokine-anti-cytokine mAb complexes are sufficiently short to allow cytokine production to be measured every 2-3 days in the same mice. Thus, use of this assay provides a practical and relatively simple and inexpensive way to measure ongoing in vivo cytokine production. Furthermore, the techniques that have been developed to measure in vivo production of IL-4 and IFN-gamma can be applied to in vivo measurement of other molecules that have a short in vivo lifespan, including other cytokines.     

Critical role of CD81 in cognate T-B cell interactions leading to Th2 responses

We previously demonstrated that CD81-/- mice fail to develop Th2-biased immune responses and allergen-induced airway hyper-reactivity. Because CD81 is expressed on both activated T and on B cells, we examined the role of CD81 expression by each cell type. We established an in vitro system by backcrossing the CD81 deletion to TCR transgenic (Tg) mice and to BCR Tg mice. Here we demonstrate that CD81 expression by T cells is critical for their induction of IL-4 synthesis by B cells. CD81-/- TCR Tg T cells were impaired in IL-4 production compared to CD81+/+ TCR Tg T cells, whereas CD81-/- and CD81+/+ BCR Tg B cells induced equivalent amounts of IL-4 in CD81+/+ TCR Tg T cells. CD81-/- TCR Tg T cells expressed reduced levels of ICOS, GATA-3, STAT6 and phosphorylated STAT6 when activated by antigen-presenting B cells. Taken together, these results indicate that CD81 expression by T cells greatly enhances cognate T-B cell interactions and greatly augments intracellular activation pathways leading to Th2 polarization.     

Specific decrease of Th1-like activity in mice with plasma cell tumors

Previously we examined the ability of the host's immune responsesto regulate Ig production in an IgE-secreting murine plasmacell tumor (B53). In the present study we have examined thereverse phenomenon, in that we have investigated the effectsof this and other plasma cell tumors on the immune responsesof their hosts. We found that splenocytes from plasma cell tumor-bearingmice demonstrate decreased proliferation in response to polyclonalstimulation by either Con A or a combination of PMA and calciumionophore (A23187 [GenBank] ). Fractionation of the splenocytes demonstratedthat this reduction in proliferation was confined to CD4⁺T cellsand that the proliferation of CD8⁺ T cells was unaffected. Inorder to determine whether the down-modulatory effects of thetumor were confined to a particular CD4⁺helper T cell subset,we examined the production of cytokines representing the T_h1subset (IL-2 and IFN-) and the T_h2 subset (IL-4 and IL-10) fromstimulated splenocytes and from stimulated enriched splenicT cells. We found that both stimulated splenocytes and T cellsfrom plasma cell tumor-bearing mice produced lower levels ofthe T_h1 cytokines IL-2 and IFN- compared with normal cultures,demonstrating that T_h1-like responses are inhibitsed in thehosts of these tumors. However, no alterations in the productionof the T_h2 cytokines IL-4 and IL-10 were observed in these stimulatedsplenocyte or T cell cultures from the tumor-bearing mice. Thus,our data demonstrate that plasma cell tumors induce a decreasein the immune responsiveness of their hosts, and this decreaseis restricted specifically to T_h1-like activity, with the T_h2-likeactivity and CD8⁺T cell proliferative responses remaining intact.     

Anergy in vivo: down-regulation of antigen-specific CD4+ Th1 but not Th2 cytokine responses

Efficient immunologic tolerance, defined as antlgen-speclflcunresponslveness, can be peripherally induced by the l.v. Injectionof syngenelc splenocytes coupled with antigen using ethylenecarbodilmlde (ECDI). We have previously reported that unresponslvenessinduced via l.v. Injection of syngenelc splenocytes coupledwith intact, UV-lnactlvated Theiler's murine encephalomyelitisvirus (TMEV-SP) resulted in ‘split tolerance’. Bothvtrus-speclflc delayed-type hypersensltlvlty and lgG2a levelswere inhibited, whereas lgG1 levels were increased when comparedwith sham tolerized controls. In the present report we demonstratethat tolerance induced by l.v. Injection of TMEV-coupled splenocytesresulted in antigen-specific inhibition of T cell proliferation,as well as IL-2 and IFN- production in response to both wholeTMEV and the immunodomlnant viral epitope. Additionally, toleranceinduction resulted in abrogation of T_h1 -derived [IL-2, IFN-and LT/tumor necrosis factor-ß (TNF-ß)]cytokine mRNA expression in response to In vitro stimulationwith UV-inactlvated TMEV as determined by reverse transcrlptasepolymerase chain reaction. In contrast, expression of T_h2-derived(IL-4, IL-6 and IL-10) cytokine mRNA was not affected in tolerizedmice. Tolerance functioned directly at the level of CD4⁺ T_h1cells at both the induction and effector limbs as depletionof CD8⁺ T cells both prior to in vivo tolerizatlon or in vitroculture had no effect on inhibition of T_h1-specific responses.The mechanism of In vivo tolerance induction appeared to beanergy of CD4⁺ T_h1 cells since IL-2, IFN- and LT/TNF-ßmRNA expression as well as virus-specific prollferatlve responsescould be restored by addition of rlL-2 to In vitro culturesof tolerant, CD4⁺ T_h1 populations. These results suggest thatin vivo ‘split tolerance’ Induced by l.v. Injectionof ECDI-flxed, antigen-coupled splenocytes involves anergy ofTMEV-speclflc, CD4⁺ T_h1 lymphocytes and concomitant primingof T_h2 cells. The induction of antlgen-speclflc, in vivo anergyhas important implications in the design of therapeutic strategiesfor immunopathologic diseases mediated by T_h1 lymphocytes, especiallyT cell-mediated autoimmune disorders.     

Marking IL-4-producing cells by knock-in of the IL-4 gene

IL-4 is a cytokine which can be expressed by a number of cell types including Th2 cells, mast cells and a population of CD4+ NK1.1+ NK T cells. Although phenotypic markers exist for identifying each of these cell types, there is at present no known cell surface marker common to all IL-4-producing cells. Using gene targeting in embryonic stem cells, we have modified the IL-4 locus by knock-in of a transmembrane domain to generate mice that express a membrane-bound form of IL-4 (mIL-4). Flow cytometry using an IL-4-specific mAb allowed the detection of IL-secreting Th2 cells, mast cells and NK T cells from mIL-4 mice. Furthermore, the analysis of immune responses in mIL-4 mice following immunization with anti-CD3 and anti-IgD has allowed us to identify distinct subpopulations of IL-4-producing NK T cells. Thus, the expression of IL-4 in a membrane-bound form provides a novel method for the identification and characterization of IL-4-producing cells.     

Differential ability of Th1 and Th2 T cells to express Fas ligand and to undergo activation-induced cell death

Stimulation of previously activated T cells through the antigenreceptor can result in the apoptotic death of the respondingcell, a process referred to as activation-induced cell death(AICD). This process appears to involve Fas (CD95) and tts ligand(Fas-L). The distribution of Fas and Fas-L on various T cellsubsets has not been extensively characterized. We have thereforeanalyzed cells committed to a T_h1- or T_h2-type differentiationpattern for the expression and function of Fas-L. Using botha sensitive bloassay and flow cytometry, we demonstrate thatcloned T_h1 cells express high levels of Fas-L, whereas clonedT_h cells express only low levels. The expression of Fas-L byT_h1 and T_h2 cells correlates with the relative abilities ofthese two cell types to undergo AICD. Whereas AICD is readilyobserved in cultures of cloned T_h1, but not T_h2 cells, T_h2 cellsare capable of undergoing apoptosls in the presence of T_h1 cellsexpressing Fas-L The ability of T cells to undergo AICD appearsto be unrelated to the presence of various cytokines. Thus,the Fas/Fas-L pathway appears to be critical for the inductionof AICD and this pathway is differentially regulated in cellscommitted to either T_h1 or T_h2 differentiation.     

Lack of correlation between chemokine receptor and T(h)1/T(h)2 cytokine expression by individual memory T cells

Chemokine and chemokine receptor interactions may have important roles in leukocyte migration to specific immune reaction sites. Recently, it has been reported that CXC chemokine receptor (CXCR) 3 and CC chemokine receptor (CCR) 5 were preferentially expressed on T(h)1 cells, and CCR3 and CCR4 were preferentially expressed on T(h)2 cells. To investigate chemokine receptor expression by T(h) subsets in vivo, we analyzed cytokine (IL-2, IL-4 and IFN-gamma) and chemokine receptor (CXCR3, CXCR4, CCR3, CCR4 and CCR5) mRNA expression by individual peripheral CD4(+) memory T cells after short-term stimulation, employing a single-cell RT-PCR method. This ex vivo analysis shows that the frequencies of cells expressing chemokine receptor mRNA were not significantly different between T(h)1 and T(h)2 cells in normal peripheral blood. To assess a potential role of in vivo stimulation, we also analyzed unstimulated rheumatoid arthritis synovial CD4(+) memory T cells. CXCR3, CXCR4, CCR3 and CCR5 expression was detected by individual synovial T cells, but the frequencies of chemokine receptor mRNA were not clearly different between T(h)1 and non-T(h)1 cells defined by expression of IFN-gamma or lymphotoxin-alpha mRNA in all RA patients. These data suggest that chemokine receptor expression does not identify individual memory T cells producing T(h)-defining cytokines and therefore chemokine receptor expression cannot be a marker for T(h)1 or T(h)2 cells in vivo.     

A pivotal role of IL-12 in Th1-dependent mouse liver injury

Intravenous injection of Proplonibacterium acnes and llpopolysaccharide(LPS) with a 7 day interval caused CD4⁺ T cell-dependent severeliver injury in the C57BL/6 (H-2^b) mouse strain. In contrast,BALB/c (H-2^d mice were resistant to P. acnes and LPS-inducedliver injury. The different susceptibilities of the two mousestrains to liver injury appeared to be closely correlated withtheir different abilities to produce IFN- after P. acnea priming.Namely, the sensitive C57BL/6 mouse strain produced a significantlevel of IFN- 7–10 days after P. acnes injection, whereasno significant amount of serum IFN- was detected in the resistantBALB/c mouse strain. The important role of IFN- in liver injurywas demonstrated from the finding that In vivo administrationof anti-IFN- mAb abrogated P. acnes and LPS-induced liver injuryin C57BL/6 mice. Moreover, it was demonstrated that In vivoadministration of recombinant IL-12, a key cytokine for theinduction of IFN-, into mice induced P. acnes and LPS-inducedliver injury in the resistant BALB/c mouse strain. Conversely,In vivo administration of anti-IL-12 mAb blocked the developmentof liver injury in the sensitive C57BL/6 mouse strain. Moreover,it was demonstrated that the failure of the induction of liverinjury in BALB/c mice appeared to be derived from the lack ofexpression of IL-12 at the local site of liver in P. acnes-prlmedmice. These results strongly indicated that endogenous IL-12,which stimulates T^h 1-dominant cellular immunity and IFN- production,may be an essential cytokine on the course of T cell-dependentliver injury.     

Mechanisms of cytokine synergy essential for vaccine protection against viral challenge.

The ability of cytokines to steer CD4(+) T(h) cell responses toward a T(h)1 or T(h)2 phenotype and enhance the magnitude of both CD8(+) cytotoxic T lymphocytes (CTL) and antibody responses has clearly been demonstrated by our lab and others, but the influence of cytokines on protective immune responses is much less clear. Here we show an essential role for CD4(+) T(h)1 helper cell induction and IFN-gamma production in protection from viral challenge with a recombinant vaccinia virus expressing HIV-1MN viral envelope glycoprotein gp160. Complete protection from viral challenge is achieved only when the triple combination of exogenous cytokines granulocyte macrophage colony stimulating factor (GM-CSF), IL-12 and tumor necrosis factor (TNF)-alpha are co-administered with the peptide vaccine. In vivo depletion of CD4(+) cells or immunization of IFN-gamma-deficient mice abrogates protection. GM-CSF, IL-12 and TNF-alpha also synergize for the enhanced induction of CTL; however, adoptive transfer of a CD8(+) CTL line afforded only partial protection in this viral challenge model. As a possible mechanism of in vivo protection we show that GM-CSF increases the percentage and activity of antigen-presenting dendritic cells in draining lymph nodes where the immune response is initiated. We further demonstrate synergy between IL-12 and the proinflammatory cytokine TNF-alpha in driving IFN-gamma production. Thus, a combination of IL-12 and TNF-alpha is essential for the optimal development of T(h)1 responses and help for CTL induction in BALB/c mice, and is complemented by a third cytokine, GM-CSF, which enhances antigen presentation.     

A regulatory role for suppressor of cytokine signaling-1 in T(h) polarization in vivo

Suppressor of cytokine signaling (SOCS)-1 is an inhibitory molecule for JAK, and its deficiency in mice leads to lymphocyte-dependent multi-organ disease and perinatal death. Crossing of SOCS-1(-/-) mice on an IFN-gamma(-/-), STAT1(-/-) and STAT6(-/-) background revealed that the fatal disease of SOCS-1(-/-) mice is also dependent on IFN-gamma/STAT1 and IL-4/STAT6 signaling pathways. Since IFN-gamma and IL-4 are representative T(h)1 and T(h)2 cytokines respectively, here we investigated the role of SOCS-1 in T(h) differentiation. Freshly isolated SOCS-1(-/-) CD4(+) T cells stimulated with anti-CD3 rapidly produced larger amounts of IFN-gamma and IL-4 than control cells, suggesting that these mutant T cells had already differentiated into T(h)1 and T(h)2 cells in vivo. In addition, SOCS-1(+/-) CD4(+) T cells cultured in vitro produced significantly larger amounts of IFN-gamma and IL-4 than SOCS-1(+/+) cells. Similarly, SOCS-1(+/-) CD4(+) T cells produced more IFN-gamma and IL-4 than SOCS-1(+/+) cells after infection with Listeria monocytogenes and Nippostrongyrus braziliensis respectively. Since IL-12-induced STAT4 and IL-4-induced STAT6 activation is sustained in SOCS-1(-/-) T cells, the enhanced T(h) functions in SOCS-1(-/-) and SOCS-1(+/-) mice appear to be due to the enhanced effects of these cytokines. These results suggest that SOCS-1 plays a regulatory role in both T(h)1 and T(h)2 polarizations.     

CpG oligodeoxynucleotide vaccination suppresses IgE induction but may fail to down-regulate ongoing IgE responses in mice

Antigen-specific IgE plays an important role in the pathogenesisof allergic disorders. Immunostimulatory CpG motifs (CpG) inbacterial DNA or synthesized oligodeoxynucleotides (ODN) aregaining recognition as potential immunomodulators for switchingon protectiveT_h1-mediated immunity and preventing or potentiallyinhibiting T_h2-dependent allergic responses. To date, allergicmodels used in CpG ODN studies have been established by immunizationof mice with allergen in the presence of adjuvant. This, inaddition to failure to assess specific IgE production in mostof the studies, has limited understanding of the role of CpGODN vaccination in allergic responses. Here, we examine theeffects of synthesized CpG ODN on both developing and ongoingIgE responses in mice sensitized using a recombinant mosquitosalivary antigen (rAed a 2) without adjuvant. Pretreatment ofmice with CpG ODN mixed with rAed a 2 successfully inhibitedsubsequent induction of serum rAed a 2-specific IgE (but notIgG1) and antigen-induced IL-4 and IL-5 production in spleencells. This was associated with an increase of serum IgG2a andIL-12, and increased IFN- and IL-12 production by spleen cells.In this model, however, co-administration of CpG ODN with rAeda 2 to presensitized mice failed to down-regulate ongoing IgEresponses despite significant up-regulation of serum IL-12 andspecific IgG2a. Strikingly, a transient skin delayed-type hypersensitivityreaction occurred in CpG ODN-treated mice. These observationsprovide a new insight into the potential therapeutic applicationof CpG ODN to allergic disorders.     

Effects of prostaglandin E2 on Th0-type human T cell clones: modulation of functions of nuclear proteins involved in cytokine production

The effects of prostaglandin E₂ (PGE₂) on cytokine productionand proliferation of the CD4⁺ human helper T cell clone SP-B21were investigated. In cells stimulated with antl-CD3 mAb, PGE₂inhibited cell proliferation and the production of all the cytokinesexamined. Addition of rlL-2 fully restored the prollferatlveresponse and partially restored the production of IL-4 and IL-5,but not that of other cytokines. In contrast, In cells stimulatedwith phorbol myrlstate acetate (PMA)/A23187, PGE₂ enhanced theproduction of IL-4 and IL-5, and only partially inhibited theproduction of other cytokines. Therefore, the effects of PGE₂vary depending on the mode of T cell activation, and the IL-4and IL-5 are regulated differently from other cytokines. Ina mobility shift assay, only the NF-B (p50/p5O) homodlmer wasobserved in a complex formed with the B sequence in unstlmulatedSP-B21 cells. When cells were stimulated with antl-CD3 mAb orPMA/A23187, a complex formation of NF-B (p50/p65) heterodlmerwith the B sequence was induced. Interestingly, PGE₂ or di-butyryl(Bt₂cAMP abolished the binding of NF-B (p50/p65) heterodlmerto the B sequence in cells stimulated with antl-CD3 mAb butnot with PMA/A23187. Our results suggest that the target ofPGE₂ action is a component in the signal transductlon pathwayleading to the activation of protein klnase C. However, theinhibition of the T cell activation signals by PGE₂ is selective.PGE₂ enhanced the complex formation with NF-AT, AP-1 and CLEOsequences when the cells were activated by either anti-CD3 mAbor PMA/A23187 stimulation. It seems therefore that PGE₂, byelevating cAMP levels, interferes with the activation pathwayfor NF-B but not for NF-AT, AP-1 or CLEO binding protein.     

Antigen-specific cellular hyporesponsiveness in a chronic human helminth infection is mediated by T(h)3/T(r)1-type cytokines IL-10 and transforming growth factor-beta but not by a T(h)1 to T(h)2 shift

Exposure to infective larvae of the filarial nematode Onchocerca volvulus (Ov) either results in patent infection (microfilaridermia) or it leads to a status called putative immunity, characterized by resistance to infection. Similar to other chronic helminth infections, there is a T cell proliferative hyporesponsiveness to Ov antigen (OvAg) by peripheral blood mononuclear cells (PBMC) from individuals with patent infection, i.e. generalized onchocerciasis (GEO), compared to PBMC from putatively immune (PI) individuals. In this study, mechanisms mediating this cellular hyporesponsiveness in GEO were investigated: the low proliferative response in PBMC from GEO individuals was associated with a lack of IL-4 production and significantly lower production of IL-5 compared to those from PI individuals, arguing against a general shift towards a T(h)2 response being the cause of hyporesponsiveness. In contrast, IL-10 and transforming growth factor (TGF)-beta, two cytokines associated with a T(h)3 response, seemed to mediate hyporesponsiveness: PBMC from individuals with GEO produced significantly more IL-10, and T cell proliferative hyporesponsiveness in this group could be reversed by the addition of anti-IL-10 and anti-TGF-beta antibodies. Hyporesponsiveness was specific for OvAg and not observed upon stimulation with related nematode antigens, arguing for a T cell-mediated, Ov-specific down-regulation. Ov-specific T cells could be cloned from GEO PBMC which have a unique cytokine profile (no IL-2 but high IL-10 and/or TGF-beta production), similar to the T cell subsets known to suppress ongoing inflammation (T(h)3 and T(r)1), indicating that this cell type which has not been found so far in infectious diseases may be involved in maintaining Ov-specific hyporesponsiveness.     

Differential roles for IFN-gamma and IL-17 in experimental autoimmune uveoretinitis

IL-17-producing CD4(+) T cells, so called T(h)17 cells, constitute a newly identified inflammatogenic cell population, which is critically involved in some inflammatory diseases. To explore the role of T(h)17 cells in murine experimental autoimmune uveoretinitis (EAU), a model of human autoimmune uveitis where T(h)1 responses predominantly participate in the pathogenesis, IL-17(-/-) mice were immunized with interphotoreceptor retinoid-binding protein peptide 1-20 for disease induction. Funduscopic examination revealed that EAU was induced in IL-17(-/-) mice just like in wild-type (WT) mice at early phases of the disease. However, at later/maintenance phases, the severity was significantly reduced in IL-17(-/-) mice. Expression of IFN-gamma and MCP-1 was comparable between WT and IL-17(-/-) mice during the time course. In vivo blockade of IFN-gamma and IL-4 resulted in exacerbation of EAU at later phases with augmented IL-17 production. Taken together, our data demonstrated that IL-17/T(h)17 participates in the late phases of EAU and also that T(h)1 and T(h)17 responses are differentially required for EAU.