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The TH17 lineage is a novel CD4+ T cell effector subset that plays a key role in inflammatory and autoimmune responses, via its ability to produce IL-17 and IL-21. Given the potentially deleterious effects of TH17 cells, their generation needs to be strictly controlled. The regulatory pathways that prevent the inappropriate development of TH17 cells have not been fully elucidated. IRF-4 is a transcription factor that has recently emerged as a key regulator of TH17 differentiation. Our laboratory has isolated a protein, which interacts with IRF-4, that we have termed IBP (IRF-4 Binding Protein). Our studies previously demonstrated that IBP can act as an activator of Rho GTPases and that mice deficient in IBP develop a lupus-like syndrome upon aging. Here we show that TCR transgenic IBP deficient mice rapidly develop rheumatoid arthritis-like joint disease and large-vessel vasculitis. The pathology observed in the absence of IBP is associated with an enhanced responsiveness of T cells to low-levels of stimulation and with the inappropriate synthesis of IL-17 and IL-21. Furthermore, we demonstrate that the effect of IBP on cytokine production is due to its ability to sequester IRF-4 and prevent it from targeting the transcriptional regulatory regions of the IL-17 and IL-21 genes. Consistent with this finding, the enhanced ability of IBP deficient T cells to produce IL-17 and IL-21 is abolished by the concurrent lack of IRF-4. Taken together these studies suggest that IBP plays a key regulatory role in the prevention of T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens.

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Candida albicans is a dimorphic commensal fungus that causes severe oral infections in immunodeficient patients. Invasion of C. albicans hyphae into oral epithelium is an essential virulence trait. IL-17 signaling is required for both innate and adaptive immunity to C. albicans. During the innate response, IL-17 is produced by γδ-T cells and a poorly understood population of innate-acting CD4+TCRαβ+ cells, but only the TCRαβ+ cells expand during acute infection. Confirming the innate nature of these cells, the TCR was not detectably activated during the primary response, evidenced by Nur77eGFP mice that report antigen-specific signaling through the TCR. Rather, expansion of innate TCRαβ+ cells was driven by both intrinsic and extrinsic IL-1R signaling. Unexpectedly, there was no requirement for CCR6/CCL20-dependent recruitment or prototypical fungal pattern recognition receptors. However, C. albicans mutants that cannot switch from yeast to hyphae showed impaired TCRαβ+ cell proliferation and Il17a expression. This prompted us to assess the role of Candidalysin, a hyphal-associated peptide that damages oral epithelial cells and triggers production of inflammatory cytokines including IL-1. Indeed, Candidalysin-deficient strains failed to upregulate Il17a or drive proliferation of innate TCRαβ+ cells. Moreover, Candidalysin signaled synergistically with IL-17, which further augmented expression of IL-1α/β and other cytokines. Thus, IL-17 and C. albicans, via secreted Candidalysin, amplify inflammation in a self-reinforcing feed-forward loop. These findings challenge the paradigm that hyphal formation per se is required for the oral innate response, and demonstrate that establishment of IL-1- and IL-17-dependent innate immunity is induced by tissue-damaging hyphae.

Ocular neovascularization often results in vision impairment. Frequently vascular endothelial cell growth factors (VEGFs) are mainly responsible for the pathological neovascularization as in the case in neovascularization induced by CpG oligodeoxynucleotides and herpes simplex virus infection in this report. siRNAs targeting either VEGFA, VEGFR1, VEGFR2, or a mix of the three were shown to significantly inhibit neovascularization induced by CpG when given locally or systemically. The efficacy of systemic administration was facilitated by the use of a polymer delivery vehicle. Additional experiments showed a significant inhibitory effect of the siRNAs mix when given either locally or systemically in vehicle against herpes simplex virus-induced angiogenesis as well as against lesions of stromal keratitis. These results indicate that the use of VEGF pathway-specific siRNAs represents a useful therapy against neovascularization-related eye diseases.

SUMMARY Interleukin-17 (IL-17) induces pathology in autoimmunity and infections; therefore constraint of this pathway is an essential component of its regulation. We demonstrate that the signaling intermediate MCPIP1 (also termed Regnase-1, encoded by Zc3h12a) is a feedback inhibitor of IL-17 receptor signal transduction. MCPIP1 knockdown enhanced IL-17-mediated signaling, requiring MCPIP1’s endoribonuclease but not deubiquitinase domain. MCPIP1 haploinsufficient mice showed enhanced resistance to disseminated Candida albicans infection, which was reversed in an Il17ra−/− background. Conversely, IL-17-dependent pathology in Zc3h12a+/− mice was exacerbated in both EAE and pulmonary inflammation. MCPIP1 degraded Il6 mRNA directly, but only modestly downregulated the IL-6 promoter. However, MCPIP1 strongly inhibited the Lcn2 promoter by regulating the mRNA stability of Nfkbiz, encoding the IκBζ transcription factor. Unexpectedly, MCPIP1 degraded Il17ra and Il17rc mRNA, independently of the 3’ UTR. The cumulative impact of MCPIP1 on IL-6, IκBζ and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.

Oropharyngeal candidiasis (OPC), caused by the commensal fungus Candida albicans, is an opportunistic infection associated with infancy, AIDS and IL-17-related primary immunodeficiencies. The Th17-associated cytokines IL-23 and IL-17 are crucial for immunity to OPC, but the mechanisms by which they mediate immunity are poorly defined. IL-17RA-deficient humans and mice are strongly susceptible to OPC, with reduced levels of CXC chemokines and concomitantly impaired neutrophil recruitment to the oral mucosa. Paradoxically, humans with isolated neutropenia are typically not susceptible to candidiasis. To determine whether immunity to OPC is mediated via neutrophil recruitment, mice lacking CXCR2 were subjected to OPC, and were found to be highly susceptible, although there was no dissemination of fungi to peripheral organs. To assess whether the entire neutrophil response is IL-17-dependent, IL-17RA−/− and IL-23−/− mice were administered neutrophil-depleting antibodies and subjected to OPC. These mice displayed increased oral fungal burdens compared to IL-17RA−/− or IL-23−/− mice alone, indicating that additional IL-17-independent signals contribute to the neutrophil response. WT mice treated with anti-Gr-1 antibodies exhibited a robust infiltrate of CD11b+Ly-6GlowF4/80− cells to the oral mucosa, but were nonetheless highly susceptible to OPC, indicating that this monocytic influx is insufficient for host defense. Surprisingly, Ly-6G antibody treatment did not induce the same strong susceptibility to OPC in WT mice. Thus, CXCR2+ and Gr-1+ neutrophils play a vital role in host defense against OPC. Moreover, defects in the IL-23/17 axis cause a potent but incomplete deficiency in the neutrophil response to oral candidiasis.

Female mice lacking DEF6 and SWAP70 develop a lupus-like syndrome through dysregulation of IRF4 in activated B cells and plasma cells.