Pathogenic IL‐23 signaling is required to initiate GM‐CSF‐driven autoimmune myocarditis in mice

Using a mouse model of experimental autoimmune myocarditis (EAM), we showed for the first time that IL‐23 stimulation of CD4⁺ T cells is required only briefly at the initiation of GM‐CFS‐dependent cardiac autoimmunity. IL‐23 signal, acting as a switch, turns on pathogenicity of CD4⁺ T cells, and becomes dispensable once autoreactivity is established. Il23a^?/? mice failed to mount an efficient Th17 response to immunization, and were protected from myocarditis. However, remarkably, transient IL‐23 stimulation ex vivo fully restored pathogenicity in otherwise nonpathogenic CD4⁺ T cells raised from Il23a^?/? donors. Thus, IL‐23 may no longer be necessary to uphold inflammation in established autoimmune diseases. In addition, we demonstrated that IL‐23‐induced GM‐CSF mediates the pathogenicity of CD4⁺ T cells in EAM. The neutralization of GM‐CSF abrogated cardiac inflammation. However, sustained IL‐23 signaling is required to maintain IL‐17A production in CD4⁺ T cells. Despite inducing inflammation in Il23a^?/? recipients comparable to wild‐type (WT), autoreactive CD4⁺ T cells downregulated IL‐17A production without persistent IL‐23 signaling. This divergence on the controls of GM‐CSF‐dependent pathogenicity on one side and IL‐17A production on the other side may contribute to the discrepant efficacies of anti‐IL‐23 therapy in different autoimmune diseases.     

IL‐33 promotes DC development in BM culture by triggering GM‐CSF production

Short‐term DC cultures generated with GM‐CSF and other cytokines have markedly improved our ability to study the immunobiology of DC. Here, we tested 65 cytokines individually for their potential to promote the generation of CD11c⁺ cells in a murine BM culture system. In addition to several cytokines known to promote DC survival and/or growth, IL‐33 was found to augment DC development time‐ and dose‐dependently. Although the resulting CD11c⁺ cells generated in the presence of IL‐33 exhibited a typical dendritic morphology, they expressed MHC class II molecules only at modest levels, showed negligible responses to TLR ligands, produced no detectable IL‐12 p70, displayed PD‐L1 and PD‐L2 on the surface, and failed to activate immunologically naïve T cells efficiently. IL‐33‐induced expansion of CD11c⁺ cells was completely blocked by anti‐GM‐CSF mAb, and GM‐CSF mRNA and protein expression in BM culture was markedly elevated by added IL‐33, indicating that IL‐33 promotes in vitro DC generation indirectly by a GM‐CSF‐dependent manner. With regard to the cellular source, IL‐33‐dependent GM‐CSF production was observed exclusively within the CD45⁺/FcεRI⁺ BM population. Not only do our results reinforce the notion that GM‐CSF serves as a primary DC growth factor, but they also reveal a previously unrecognized mechanism supporting DC development.     

CD8+ T cells producing IL‐3 and IL‐5 in non‐IgE‐mediated eosinophilic diseases

The cytokines IL‐5, IL‐3, and GM‐CSF are crucial for eosinophil development, survival, and function. To better understand their role in non‐IgE‐mediated eosinophilic diseases, we investigated plasma levels of these cytokines as well as cytokine expression in peripheral blood T cells. While we did not find any evidence for an involvement of T‐cell‐derived GM‐CSF, some of these patients did show an increased proportion of IL‐5‐ or IL‐3‐producing CD4⁺ T cells. However, in a significant proportion of patients, IL‐5‐producing CD8⁺ T cells, so‐called Tc2 cells, which in healthy donors can only be detected at very low levels, were prominent. Furthermore, increased IL‐3 production by CD8⁺ T cells was also observed, strongly supporting the notion that CD8⁺ T cells, not just CD4⁺ T cells, must also be considered as a potential source of the cytokines promoting eosinophilia.     

IL‐33 broadens its repertoire to affect DC

IL‐33 is a novel multi‐functional IL‐1 family member that, in contrast to other family members, is associated with Th2 responses. IL‐33 signals via a heterodimer composed of its receptor, IL‐1 receptor‐like‐1 (IL‐1RL1), more commonly known as ST2L, and the IL‐1R accessory protein. ST2L is expressed by endothelial cells, mast cells, basophils, Th2 cells, and DC. IL‐33 has been associated with several immune‐mediated disorders, including asthma, arthritis, and inflammatory bowel disease. In contrast, there is evidence that IL‐33 can inhibit atherosclerosis development. A report in this issue of the European Journal of Immunology reveals a novel function of IL‐33: the ability to promote myeloid DC generation in murine BM cell cultures, by triggering GM‐CSF production by other BM cells, likely basophils. DC generated in the presence of IL‐33 are maturation resistant, with only minimal T‐cell stimulatory ability, associated with comparatively high levels of programmed death receptor ligand expression. This commentary discusses several questions raised by these findings, and provides a basis for further evaluation of IL‐33 and ST2L in regulation of APC generation and function in both innate and adaptive immunity.     

Intravenous immunoglobulin (IVIg) or IVIg‐treated macrophages reduce DSS‐induced colitis by inducing macrophage IL‐10 production

Intravenous immunoglobulin (IVIg) is used to treat immune‐mediated diseases but its mechanism of action is poorly understood. We have reported that co‐treatment with IVIg and lipopolysaccharide activates macrophages to produce large amounts of anti‐inflammatory IL‐10 in vitro. Thus, we asked whether IVIg‐treated macrophages or IVIg could reduce intestinal inflammation in mice during dextran sulfate sodium (DSS)‐induced colitis by inducing macrophage IL‐10 production in vivo. Adoptive transfer of IVIg‐treated macrophages reduces intestinal inflammation in mice and collagen accumulation post‐DSS. IVIg treatment also reduces DSS‐induced intestinal inflammation and its activity is dependent on the Fc portion of the antibody. Ex vivo, IVIg induces IL‐10 production and reduces IL‐12/23p40 and IL‐1β production in colon explant cultures. Co‐staining tissues for mRNA, we demonstrate that macrophages are the source of IL‐10 in IVIg‐treated mice; and using IL‐10‐GFP reporter mice, we demonstrate that IVIg induces IL‐10 production by intestinal macrophages. Finally, IVIg‐mediated protection is lost in mice deficient in macrophage IL‐10 production (LysMcre^+/?IL‐10^fl/fl mice). Together, our data demonstrate a novel, in vivo mechanism of action for IVIg. IVIg‐treated macrophages or IVIg could be used to treat people with intestinal inflammation and may be particularly useful for people with inflammatory bowel disease, who are refractory to therapy.     

Altered expression of IL‐18 binding protein and IL‐18 receptor in basophils and mast cells of asthma patients

IL ‐18 is likely to contribute to asthma. However, little is known regarding the role of IL ‐18 binding protein (BP ) and IL ‐18 receptor (R) in asthma. Because the action of IL ‐18 in the body is regulated by IL ‐18BP and mast cells and basophils are key cell types involved in asthma, we investigated the expression of IL ‐18, IL ‐18BP and IL ‐18R in basophils and mast cells using flow cytometry and a mouse asthma model. We found that among basophils, approximately 53% and 51% were IL ‐18⁺, 85% and 81% were IL ‐18BP ⁺ basophils, and 19.8% and 8.6% were IL ‐18R⁺ in healthy control (HC ) and asthmatic blood, respectively. The allergens tested had little effect on the expression of IL ‐18 and related factors. Only 3.5%, 14.3% and 2.4% of dispersed mast cells expressed IL ‐18, IL ‐18BP and IL ‐18R, respectively, in asthmatic sputum. In a mouse asthma model, OVA ‐sensitized mice exhibited decreased IL ‐18BP ⁺ but increased IL ‐18R⁺ basophils in their blood. IL ‐18 increased the number of basophils but eliminated IL ‐18BP ⁺ basophils in mouse blood. IL ‐18 increased the number of mast cells and IL ‐18R⁺ mast cells in the lung as well as increased the mast cell numbers and IL ‐18BP ⁺ mast cells in the bronchoalveolar lavage fluid (BALF ) of OVA ‐sensitized mice. Thus, basophils and mast cells may be involved in asthma pathogenesis via an IL ‐18‐associated mechanism.     

IL‐18, but not IL‐15, contributes to the IL‐12‐dependent induction of NK‐cell effector functions by Leishmania infantum in vivo

Activation of NK cells is a hallmark of infections with intracellular pathogens. We previously showed that the protozoan parasite Leishmania infantum triggered a rapid NK‐cell response in mice that required TLR9‐positive myeloid DC and IL‐12, but no IFN‐α/β. Here, we investigated whether IL‐15 or IL‐18 mediate the activity of IL‐12 or function as independent activators of NK cells. In contrast to earlier studies that described IL‐15 as crucial for NK‐cell priming in response to TLR ligands, the expression of IFN‐γ, FasL, perforin and granzyme B by NK cells in L. infantum‐infected mice was completely preserved in the absence of IL‐15, whereas the proliferative capacity of NK cells was lower than in WT mice. IFN‐γ secretion, cytotoxicity and FasL expression of NK cells from infected IL‐18^?/? mice were significantly reduced compared with controls, but, unlike IL‐12, IL‐18 was not essential for NK‐cell effector functions. Part of the NK‐cell‐stimulatory effect of IL‐12 was dependent on IL‐18. We conclude that IL‐15 is not functioning as a universal NK‐cell priming signal and that IL‐18 contributes to the NK‐cell response in visceral leishmaniasis. The cytokine requirements for NK‐cell activation appear to differ contingent upon the infectious pathogen.     

IL‐34‐ and M‐CSF‐induced macrophages switch memory T cells into Th17 cells via membrane IL‐1α

Macrophages orchestrate the immune response via the polarization of CD4⁺ T helper (Th) cells. Different subsets of macrophages with distinct phenotypes, and sometimes opposite functions, have been described. M‐CSF and IL‐34 induce the differentiation of monocytes into IL‐10^high IL‐12^low immunoregulatory macrophages, which are similar to tumor‐associated macrophages (TAMs) in ovarian cancer. In this study, we evaluated the capacity of human macrophages induced in the presence of M‐CSF (M‐CSF macrophages) or IL‐34 (IL‐34 macrophages) and ovarian cancer TAMs to modulate the phenotype of human CD4⁺ T cells. Taken together, our results show that M‐CSF‐, IL‐34 macrophages, and TAMs switch non‐Th17 committed memory CD4⁺ T cells into conventional CCR4⁺ CCR6⁺ CD161⁺ Th17 cells, expressing or not IFN‐gamma. Contrary, the pro‐inflammatory GM‐CSF macrophages promote Th1 cells. The polarization of memory T cells into Th17 cells is mediated via membrane IL‐1α (mIL‐1α), which is constitutively expressed by M‐CSF‐, IL‐34 macrophages, and TAMs. This study elucidates a new mechanism that allows macrophages to maintain locally restrained and smoldering inflammation, which is required in angiogenesis and metastasis.     

IL‐12‐polarized Th1 cells produce GM‐CSF and induce EAE independent of IL‐23

CD4⁺ T‐helper (Th) cells reactive against myelin antigens mediate the mouse model experimental autoimmune encephalomyelitis (EAE) and have been implicated in the pathogenesis of multiple sclerosis (MS). It is currently debated whether encephalitogenic Th cells are heterogeneous or arise from a single lineage. In the current study, we challenge the dogma that stimulation with the monokine IL‐23 is universally required for the acquisition of pathogenic properties by myelin‐reactive T cells. We show that IL‐12‐modulated Th1 cells readily produce IFN‐γ and GM‐CSF in the CNS of mice and induce a severe form of EAE via an IL‐23‐independent pathway. Th1‐mediated EAE is characterized by monocyte‐rich CNS infiltrates, elicits a strong proinflammatory cytokine response in the CNS, and is partially CCR2 dependent. Conversely, IL‐23‐modulated, stable Th17 cells induce EAE with a relatively mild course via an IL‐12‐independent pathway. These data provide definitive evidence that autoimmune disease can be driven by distinct CD4⁺ T‐helper‐cell subsets and polarizing factors.     

IL‐22 modulates IL‐17A production and controls inflammation and tissue damage in experimental dengue infection

Dengue virus (DENV), a mosquito‐borne flavivirus, is a public health problem in many tropical countries. IL‐22 and IL‐17A are key cytokines in several infectious and inflammatory diseases. We have assessed the contribution of IL‐22 and IL‐17A in the pathogenesis of experimental dengue infection using a mouse‐adapted DENV serotype 2 strain (P23085) that causes a disease that resembles severe dengue in humans. We show that IL‐22 and IL‐17A are produced upon DENV‐2 infection in immune‐competent mice. Infected IL‐22^?/? mice had increased lethality, neutrophil accumulation and pro‐inflammatory cytokines in tissues, notably IL‐17A. Viral load was increased in spleen and liver of infected IL‐22^?/? mice. There was also more severe liver injury, as seen by increased transaminases levels and tissue histopathology. γδ T cells and NK cells are sources of IL‐17A and IL‐22, respectively, in liver and spleen. We also show that DENV‐infected HepG2 cells treated with rhIL‐22 had reduced cell death and decreased IL‐6 production. IL‐17RA^?/? mice were protected upon infection and IL‐17A‐neutralizing‐Ab‐treatment partially reversed the phenotype observed in IL‐22^?/?‐infected mice. We suggest that disrupting the balance between IL‐22 and IL‐17A levels may represent an important strategy to reduce inflammation and tissue injury associated with severe dengue infection.     

Immunisation route‐dependent expression of IL‐4/IL‐13 can modulate HIV‐specific CD8+ CTL avidity

All HIV‐1 ‘systemic vaccine trials’ in humans have yielded poor outcomes. Thus, it is important to understand whether the route of delivery influences the quality of protective CTL immunity. Using heterologous poxvirus immunisation we have shown that systemically (i.m./i.m.) immunised CD8⁺ T cells generated higher levels of IL‐4/IL‐13 compared to mucosal delivery and expression also correlated with i.m./i.m. immunised mice eliciting CTL of lower avidity. Studies using IL‐4^?/? and IL‐13^?/? KO mice have shown that the capacity to express IFN‐γ, IL‐4 and/or IL‐13 by K^dGag_197–205‐specific CTL differed between these groups and was inversely correlated with CTL avidity (IL‐13^?/?>IL‐4^?/?>BALB/c), although no significant differences in the magnitude of CTL responses were observed between IL‐13^?/? and wild type mice. When IL‐13 was reconstituted in IL‐13^?/? splenocytes in vitro, their ability to bind tetramers also decreased significantly. Our data reveal that total absence of IL‐13 can greatly enhance CTL avidity. In contrast, extracellular IL‐4 appears to be important in maintaining long‐term Th1/Th2 balance in CTL, even though expression of IL‐4 by CTL markedly reduced avidity. STAT6^?/? mice also showed memory CTL of higher avidity. Furthermore, CCL5 expression in K^dGag_197–205‐specific CTL was also regulated by IL‐4/IL‐13.     

Suppressive and pro‐inflammatory roles for IL‐4 in the pathogenesis of experimental drug‐induced liver injury

The pathogenesis of immune‐mediated drug‐induced liver injury (DILI) following halogenated anesthetics, carbamazepine or alcohol has not been fully elucidated. Detecting cytochrome P450 2E1 (CYP2E1) IgG4 auto‐antibodies in anesthetic DILI patients suggests a role for IL‐4 in this hapten‐mediated process. We investigated IL‐4‐mediated mechanisms using our model of experimental DILI induced by immunizing BALB/c (WT) and IL‐4^?/? (KO) mice with S100 liver proteins covalently modified by a trifluoroacetyl chloride (TFA) hapten formed following halogenated anesthetic metabolism by CYP2E1. WT mice developed more hepatitis, TFA and S100 antibodies (p<0.01), as well as T‐cell proliferation to CYP2E1 and TFA (p<0.01) than KO mice. Additionally, WT CD4⁺ T cells adoptively transferred hepatitis to naïve Rag^?/? mice (p<0.01). Pro‐inflammatory cytokines were expectedly decreased in TFA hapten‐stimulated KO splenocyte supernatants (p<0.001); however, IL‐2 and IFN‐γ (p<0.05), as well as IL‐6 and IL‐10 (p<0.001) levels were elevated in CYP2E1‐stimulated KO splenocyte supernatants, suggesting dual IL‐4‐mediated pro‐inflammatory and regulatory responses. Anti‐IL‐10 administered to KO mice increased hepatitis, TFA and CYP2E1 antibodies in KO mice confirming a critical role for IL‐4. This is the first demonstration of dual roles for IL‐4 in the pathogenesis of immune‐mediated DILI by suppressing auto‐antigen‐induced regulatory responses while promoting hapten‐induced pro‐inflammatory responses.     

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4+ T cells

TGF‐β and IL‐4 were recently shown to selectively upregulate IL‐9 production by naïve CD4⁺ T cells. We report here that TGF‐β interactions with IL‐1α, IL‐1β, IL‐18, and IL‐33 have equivalent IL‐9‐stimulating activities that function even in IL‐4‐deficient animals. This was observed after in vitro antigenic stimulation of immunized or unprimed mice and after polyclonal T‐cell activation. Based on intracellular IL‐9 staining, all IL‐9‐producing cells were CD4⁺ and 80–90% had proliferated, as indicated by reduced CFSE staining. In contrast to IL‐9, IL‐13 and IL‐17 were strongly stimulated by IL‐1 and either inhibited (IL‐13) or were unaffected (IL‐17) by addition of TGF‐β. IL‐9 and IL‐17 production also differed in their dependence on IL‐2 and regulation by IL‐1/IL‐23. As IL‐9 levels were much lower in Th2 and Th17 cultures, our results identify TGF‐β/IL‐1 and TGF‐β/IL‐4 as the main control points of IL‐9 synthesis.     

IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

Although IL‐12 is believed to contribute to protective immune responses, the role played by IL‐23 (a member of the IL‐12 family) in malaria is elusive. Here, we show that IL‐23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL‐23 (p19KO) had higher parasitemia and died earlier than wild‐type (WT) controls. Interestingly, p19KO mice had lower numbers of IL‐17‐producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL‐17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL‐23‐mediated protection is dependent on induction of IL‐17 during infection. We found that macrophages were responsible for IL‐17 production in response to IL‐23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL‐17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage‐depleted mice confirmed that macrophage‐derived IL‐17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL‐17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL‐23, IL‐17, and macrophages reduce the severity of infection with blood‐stage malaria parasites.     

IL‐21 promotes the production of anti‐DNA IgG but is dispensable for kidney damage in lyn−/− mice

The autoimmune disease systemic lupus erythematosus is characterized by loss of tolerance to nuclear Ags and a heightened inflammatory environment, which together result in end organ damage. Lyn‐deficient mice, a model of systemic lupus erythematosus, lack an inhibitor of B‐cell and myeloid cell activation. This results in B‐cell hyper‐responsiveness, plasma cell accumulation, autoantibodies, and glomerulonephritis (GN). IL‐21 is associated with autoimmunity in mice and humans and promotes B‐cell differentiation and class switching. Here, we explore the role of IL‐21 in the autoimmune phenotypes of lyn^–/– mice. We find that IL‐21 mRNA is reduced in the spleens of lyn^–/–IL‐6^–/– and lyn^–/–Btk^lo mice, neither of which produce pathogenic autoantibodies or develop significant GN. While IL‐21 is dispensable for plasma cell accumulation and IgM autoantibodies in lyn^–/– mice, it is required for anti‐DNA IgG antibodies and some aspects of T‐cell activation. Surprisingly, GN still develops in lyn^–/–IL‐21^–/– mice. This likely results from the presence of IgG autoantibodies against a limited set of non‐DNA Ags. These studies identify a specific role for IL‐21 in the class switching of anti‐DNA B cells and demonstrate that neither IL‐21 nor anti‐DNA IgG is required for kidney damage in lyn^–/– mice.     

Interleukin (IL)‐39 [IL‐23p19/Epstein–Barr virus‐induced 3 (Ebi3)] induces differentiation/expansion of neutrophils in lupus‐prone mice

Interleukin (IL)‐12 family cytokines play critical roles in autoimmune diseases. Our previous study has shown that IL‐23p19 and Epstein–Barr virus‐induced 3 (Ebi3) form a new IL‐12 family heterodimer, IL‐23p19/Ebi3, termed IL‐39, and knock‐down of p19 or Ebi3 reduced diseases by transferred GL7⁺ B cells in lupus‐prone mice. In the present study, we explore further the possible effect of IL‐39 on murine lupus. We found that IL‐39 in vitro and in vivo induces differentiation and/or expansion of neutrophils. GL7⁺ B cells up‐regulated neutrophils by secreting IL‐39, whereas IL‐39‐deficient GL7⁺ B cells lost the capacity to up‐regulate neutrophils in lupus‐prone mice and homozygous CD19^cre (CD19‐deficient) mice. Finally, we found that IL‐39‐induced neutrophils had a positive feedback on IL‐39 expression in activated B cells by secreting B cell activation factor (BAFF). Taken together, our results suggest that IL‐39 induces differentiation and/or expansion of neutrophils in lupus‐prone mice.     

Sca‐1+ cardiac fibroblasts promote development of heart failure

The causative effect of GM‐CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM‐CSF‐producing cardiac fibroblast subset and the specific deletion of IL‐17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45^?CD31^?CD29⁺mEF‐SK4⁺PDGFRα⁺Sca‐1⁺periostin⁺ (Sca‐1⁺) cardiac fibroblast subset as the main GM‐CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL‐17A signaling to Sca‐1⁺periostin⁺ cardiac fibroblasts (Postn^CreIl17ra^fl/fl) protected mice from post‐infarct heart failure and death. Moreover, Postn^CreIl17ra^fl/fl mice had significantly fewer GM‐CSF‐producing Sca‐1⁺ cardiac fibroblasts and inflammatory Ly6C^hi monocytes in the heart. Sca‐1⁺ cardiac fibroblasts were not only potent GM‐CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GM‐CSF‐positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GM‐CSF‐producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca‐1⁺ cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure.     

IL‐17‐producing CD4+ T cells contribute to the loss of B‐cell tolerance in experimental autoimmune myasthenia gravis

The role of Th17 cells in the pathogenesis of autoantibody‐mediated diseases is unclear. Here, we assessed the contribution of Th17 cells to the pathogenesis of experimental autoimmune myasthenia gravis (EAMG), which is induced by repetitive immunizations with Torpedo californica acetylcholine receptor (tAChR). We show that a significant fraction of tAChR‐specific CD4⁺ T cells is producing IL‐17. IL‐17^ko mice developed fewer or no EAMG symptoms, although the frequencies of tAChR‐specific CD4⁺ T cells secreting IL‐2, IFN‐γ, or IL‐21, and the percentage of FoxP3⁺ T_reg cells were similar to WT mice. Even though the total anti‐tAChR antibody levels were equal, the complement fixating IgG2b subtype was reduced in IL‐17^ko as compared to WT mice. Most importantly, pathogenic anti‐murine AChR antibodies were significantly lower in IL‐17^ko mice. Furthermore, we confirmed the role of Th17 cells in EAMG pathogenesis by the reconstitution of TCR β/δ^ko mice with WT or IL‐17^ko CD4⁺ T cells. In conclusion, we show that the level of IgG2b and the loss of B‐cell tolerance, which results in pathogenic anti‐murine AChR‐specific antibodies, are dependent on IL‐17 production by CD4⁺ T cells. Thus, we describe here for the first time how Th17 cells are involved in the induction of classical antibody‐mediated autoimmunity.     

EAE mediated by a non‐IFN‐γ/non‐IL‐17 pathway

Previous studies have shown that EAE can be elicited by the adoptive transfer of either IFN‐γ‐producing (Th1) or IL‐17‐producing (Th17) myelin‐specific CD4⁺ T‐cell lines. Paradoxically, mice deficient in either IFN‐γ or IL‐17 remain susceptible to EAE following immunization with myelin antigens in CFA. These observations raise questions about the redundancy of IFN‐γ and IL‐17 in autoimmune demyelinating disease mediated by a diverse, polyclonal population of autoreactive T cells. In this study, we show that an atypical form of EAE, induced in C57BL/6 mice by the adoptive transfer of IFN‐γ‐deficient effector T cells, required IL‐17 signaling for the development of brainstem infiltrates. In contrast, classical EAE, characterized by predominant spinal cord inflammation, occurred in the combined absence of IFN‐γ and IL‐17 signaling, but was dependent on GM‐CSF and CXCR2. Our findings contribute to a growing body of data, indicating that individual cytokines vary in their importance across different models of CNS autoimmunity.