Nydiaris Hernández-Santos

CD4+CD25+Foxp3+ Regulatory T Cells Promote Th17 Cells In Vitro and Enhance Host Resistance in Mouse Candida albicans Th17 Cell Infection Model

Th17 cells and CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells are thought to promote and suppress inflammatory responses, respectively. Here we explore why under Th17 cell polarizing conditions, Treg cells did not suppress, but rather upregulated, the expression of interleukin-17A (IL-17A), IL-17F, and IL-22 from responding CD4(+) Txa0cells (Tresp cells). Upregulation of IL-17 cytokines in Tresp cells was dependent onxa0consumption of IL-2 by Treg cells, especially at early time points both inxa0vitro and inxa0vivo. During an oral Candida albicans infection in mice, Treg cells induced IL-17 cytokines in Tresp cells, which markedly enhanced fungal clearance and recovery from infection. These findings show how Treg cells can promote acute Th17 cell responses to suppress mucosal fungus infections and reveal that Treg cellsxa0have a powerful capability to fight infections besides their role in maintaining tolerance or immune homeostasis.

Th17 Cells in Immunity to Candida albicans

Our understanding of immunity to fungal pathogens has advanced considerably in recent years. Particularly significant have been the parallel discoveries in the C-type lectin receptor family and the Th effector arms of immunity, especially Th17 cells and their signature cytokine, IL-17. Many of these studies have focused on the most common human fungal pathogen, Candida albicans, which is typically a commensal microbe in healthy individuals but causes various disease manifestations in immunocompromised hosts, ranging from mild mucosal infections to lethal disseminated disease. Here, we discuss emerging fundamental discoveries with C.xa0albicans that have informed our overall molecular understanding of fungal immunity. In particular, we focus on the importance of pattern recognition receptor-mediated fungal recognition and subsequent IL-17 responses in host defense against mucosal candidiasis. In light of these recent advances, we also discuss the implications for anticytokine biologic therapy and vaccine development.

IL-17RC Is Required for Immune Signaling via an Extended SEF/IL-17R Signaling Domain in the Cytoplasmic Tail

IL-17 mediates essential inflammatory responses in host defense and autoimmunity. The IL-17A–IL-17F signaling complex is composed of IL-17RA and IL-17RC, both of which are necessary for signal transduction. To date, the specific contribution of IL-17RC to downstream signaling remains poorly understood. To define the regions within the IL-17RC cytoplasmic tail required for signal transduction, we assayed signaling by a panel of IL-17RC deletion mutants. These findings reveal that IL-17RC inducibly associates with a specific glycosylated IL-17RA isoform, in a manner independent of the IL-17RC cytoplasmic tail. Using expression of the IL-17 target genes IL-6 and 24p3/lipocalin-2 as a readout, functional reconstitution of signaling in IL-17RC−/− fibroblasts required the SEF/IL-17R signaling domain (SEFIR), a conserved motif common to IL-17R family members. Unexpectedly, the IL-17RC SEFIR alone was not sufficient to reconstitute IL-17–dependent signaling. Rather, an additional sequence downstream of the SEFIR was also necessary. We further found that IL-17RC interacts directly with the adaptor/E3 ubiquitin ligase Act1, and that the functional IL-17RC isoforms containing the extended SEFIR region interact specifically with a phosphorylated isoform of Act1. Finally, we show that IL-17RC is required for in vivo IL-17–dependent responses during oral mucosal infections caused by the human commensal fungus Candida albicans. These results indicate that IL-17RC is vital for IL-17–dependent signaling both in vitro and in vivo. Insight into the mechanisms by which IL-17RC signals helps shed light on IL-17–dependent inflammatory responses and may ultimately provide an avenue for therapeutic intervention in IL-17–mediated diseases.

Oral-resident natural Th17 cells and γδ T cells control opportunistic Candida albicans infections

Conti et al. show that IL-17 is produced by tongue-resident populations of γδ T cells and nTh17 cells in response to oropharyngeal candidiasis in mice.

Th17 cells confer long-term adaptive immunity to oral mucosal Candida albicans infections

Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by Candida albicans. Despite its prevalence, little is known about C. albicans-specific immunity in the oral mucosa. Vaccines against Candida generate both T helper type 1 (Th1) and Th17 responses, and considerable evidence implicates interleukin (IL)-17 in immunity to OPC. However, IL-17 is also produced by innate immune cells that are remarkably similar to Th17 cells, expressing the same markers and localizing to similar mucosal sites. To date, the relative contribution(s) of Th1, Th17, and innate IL-17-producing cells in OPC have not been clearly defined. Here, we sought to determine the nature and function of adaptive T-cell responses to OPC, using a new recall infection model. Mice subjected to infection and re-challenge with Candida mounted a robust and stable antigen-specific IL-17 response in CD4+ but not CD8+ T cells. There was little evidence for Th1 or Th1/Th17 responses. The Th17 response promoted accelerated fungal clearance, and Th17 cells could confer protection in Rag1−/− mice upon adoptive transfer. Surprisingly, CD4 deficiency did not cause OPC but was instead associated with compensatory IL-17 production by Tc17 and CD3+CD4−CD8− cells. Therefore, classic CD4+Th17 cells protect from OPC but can be compensated by other IL-17-producing cells in CD4-deficient hosts.

IL-17 signaling in host defense against Candida albicans

The discovery of the Th17 lineage in 2005 triggered a major change in how immunity to infectious diseases is viewed. Fungal infections, in particular, have long been a relatively understudied area of investigation in terms of the host immune response. Candida albicans is a commensal yeast that colonizes mucosal sites and skin. In healthy individuals, it is non-pathogenic, but in conditions of immune deficiency, this organism can cause a variety of infections associated with considerable morbidity. Candida can also cause disseminated infections that have a high mortality rate and are a major clinical problem in hospital settings. Although immunity to Candida albicans was long considered to be mediated by Th1 cells, new data in both rodent models and in humans have revealed an essential role for the Th17 lineage, and in particular its signature cytokine IL-17.

Role of Neutrophils in IL-17–Dependent Immunity to Mucosal Candidiasis

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 Abs and subjected to OPC. These mice displayed increased oral fungal burdens compared with 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 Abs 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 Ab 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.

A bone-protective role for IL-17 receptor signaling in ovariectomy-induced bone loss.

Post‐menopausal osteoporosis is considered to be an inflammatory process, in which numerous pro‐inflammatory and T‐cell‐derived cytokines play a bone‐destructive role. IL‐17A is the signature cytokine of the pro‐inflammatory Th17 population and plays dichotomous roles in diseases that affect bone turnover. Although IL‐17A promotes bone loss in rheumatoid arthritis, it is protective against pathogen‐induced bone destruction in a periodontal disease model. We used a model of ovariectomy‐induced osteoporosis (OVX) in IL‐17 receptor (IL‐17RA)−/− mice to evaluate the role of the IL‐17A in bone loss caused by estrogen deficiency. Unexpectedly, IL‐17RA−/− mice were consistently and markedly more susceptible to OVX‐induced bone loss than controls. There were no changes in prototypical Th1, Th2 or Th17 cytokines in serum that could account for increased bone loss. However, IL‐17RA−/− mice exhibited constitutively elevated leptin, which further increased following OVX. Consistently, IL‐17A and IL‐17F treatment of 3T3‐L1 pre‐adipocytes inhibited adipogenesis, leading to reduced production of leptin. In addition to its role in regulating metabolism and satiety, leptin can regulate bone turnover. Accordingly, these data show that IL‐17A negatively regulates adipogenesis and subsequent leptin expression, which correlates with increased bone destruction during OVX.

The adaptor CARD9 is required for adaptive but not innate immunity to oral mucosal Candida albicans infections

ABSTRACT Oropharyngeal candidiasis (OPC [thrush]) is an opportunistic infection caused by the commensal fungus Candida albicans. OPC is common in individuals with HIV/AIDS, infants, patients on chemotherapy, and individuals with congenital immune defects. Immunity to OPC is strongly dependent on the interleukin-23 (IL-23)/IL-17R axis, as mice and humans with defects in IL-17R signaling (IL17F, ACT1, IL-17RA) or in genes that direct Th17 differentiation (STAT3, STAT1, CARD9) are prone to mucocutaneous candidiasis. Conventional Th17 cells are induced in response to C. albicans infection via signals from C-type lectin receptors, which signal through the adaptor CARD9, leading to production of Th17-inducing cytokines such as IL-6, IL-1β, and IL-23. Recent data indicate that IL-17 can also be made by numerous innate cell subsets. These innate “type 17” cells resemble conventional Th17 cells, but they can be activated without need for prior antigen exposure. Because C. albicans is not a commensal organism in rodents and mice are thus naive to this fungus, we had the opportunity to assess the role of CARD9 in innate versus adaptive responses using an OPC infection model. As expected, CARD9−/− mice failed to mount an adaptive Th17 response following oral Candida infection. Surprisingly, however, CARD9−/− mice had preserved innate IL-17-dependent responses to Candida and were almost fully resistant to OPC. Thus, CARD9 is important primarily for adaptive immunity to C. albicans, whereas alternate recognition systems appear to be needed for effective innate responses.

Correction: Role of Neutrophils in IL-17–Dependent Immunity to Mucosal Candidiasis

Huppler, A. R., H. R. Conti, N. Hernandez-Santos, T. Darville, P. S. Biswas, and S. L. Gaffen. 2014. Role of neutrophils in IL-17–dependent immunity to mucosal candidiasis. J. Immunol. 192: [1745–1752][1].nnThere was an inadvertent error in the calculation of the absolute neutrophil count due