The role of Th17 cytokines in primary mucosal immunity
Introduction
CD4+ T helper cells are critical mediators of adaptive immune responses. Following interaction with class II MHC+ dendritic and other antigen presenting cells, naïve T cells receive signals by engagement of the T cell receptor (signal 1), costimulatory molecules (signal 2) and cytokine signals (signal 3) and undergo activation and differentiation into effector CD4+ T cells. Some of the strongest evidence that these cells are critical effector cells at mucosal surfaces is clearly evidenced by the HIV epidemic that leads to the depletion of these cells from the mucosa and periphery [1], [2], [3] leading to the acquired immunodeficiency syndrome (AIDS).
Pioneering work by Mosmann et al. described the first two CD4+ T-cells subsets based on discrete cytokine profiles [4]. Th1 effectors produce interferon-gamma (IFN-γ) and regulate cellular immunity against intracellular infections, whereas Th2 cells produce interleukin (IL)-4, IL-5 and IL-13 and mediate humoral immunity against parasite infections. However these two T-cell subsets do not completely account for some of the opportunistic infections seen in the context of congenital or acquired absence of CD4+ T-cells such as mucosal candidiasis, Pneumocystis carinii pneumonia, or some bacterial pneumonias. Mice deficient in Th1, Th2 responses (or both) are not permissive for P. carinii pneumonia [5], [6], a hallmark infection in AIDS patients with low CD4+ T-cell counts. These data suggested other CD4+ T-cell lineages are critical for host defenses against opportunistic infections. IL-17 was cloned from CD4+ memory cells in 1993 [7] and Infante-Duarte et al. demonstrated that IL-17 cells could be produced in response to bacterial lipopeptides [8]. Importantly this early study showed that IL-17 producing cells were distinct from Th1 cells and thus this provided the first evidence that T-cell derived IL-17 may have unique effector functions in host resistance against pathogens [8]. Recent evidence has shown that a major subset of cells that produce IL-17, are indeed distinct from Th1 and Th2 cells, and consist of a third subset of Th cells referred to as Th17 cells [9], [10], [11]. Th17 cells produce the cytokines IL-17A (IL-17) [10], [11] and IL-17F [9], as well as the cytokines IL-21 [12], [13] and IL-22 [14], [15] (Fig. 1). This new Th17 cell lineage fills in some of the holes in host immunity not fully explained by the Th1/Th2 paradigm.
Section snippets
Th17 effector cytokines: IL-17A, IL-17F, and IL-22
IL-17 is the prototype of Th17 cytokines and is the best studied of the Th17 cytokines. The first identified receptor for IL-17, IL-17RA is a Type I transmembrane protein and is ubiquitously expressed on various organs including lung, kidney and spleen [16]. This receptor can bind at least three members of the IL-17 family including IL-17A, the closely related molecule IL-17F, as well as the most distally related IL-17 family member IL-17E [17]. The best studied examples of cells that express
Regulation of IL-17 and IL-22 in the lung
The differentiation of Th17 cells is determined by the exposure to polarizing cytokines such as TGF-β, IL-6, IL-21, while IL-23 further stabilizes the commitment of Th17 cells to this lineage (reviewed in [39]). These polarizing cytokines act on newly primed cells to induce the expression of the transcription factor RORγT and RORα which are considered master regulators of Th17 differentiation [40], [41]. RORγT also control the expression of IL-23 inducible receptors on newly primed T cells, to
Th17 effector responses in the mucosa
Human bronchial lung epithelial (HBE) cells express both IL-17RA, IL-17RC, IL-22R and IL-10R2 and thus can responses to IL-17A, IL-17F, and IL-22 [25], [57], [58], [59]. The expression of IL-17RA and IL-17RC also appear to be expressed in a basolateral dominant fashion [57], [59] such that signaling only occurs in polarized epithelial cells are exposed to ligand provided to basolateral surface [59], [60]. Treatment of HBE cells with IL-17 induces CXC chemokines such as IL-8 [57], [61], G-CSF
Th17 cytokines and bacterial infections at the mucosa
As mentioned above, early work in IL-17RA KO mice demonstrating increased sensitivity to cutaneous S. aureus [24], [66], [67] and pulmonary K. pneumoniae [26] infection established critical role for IL-17 in protective immunity against extracellular bacteria. Further studies also show that Th17 cells play protective roles against extracellular bacterial infections in the gut mucosa. Citrobacter rodentum, a naturally occurring mouse pathogen requires the generation of IL-23-dependent protective
Th17 cytokines and fungal infections at the mucosa
The role of Th17 cytokines in fungal infection have been controversial but evidence in both experimental animal models and humans is clearly emerging that these cytokines play a critical role in mucosal infections. Initial observations suggested that Th17 cytokines, particularly IL-17 contributes to tissue pathology in invasive Aspergillus infection in the lung particularly in the setting of NADPH oxidase deficiency [48]. However IL-17 and IL-17RA signaling are critical for host resistance to
Th17 cytokines and viral infection
The role of Th17 cytokines in viral infection is a rapidly emerging area of research. Herpes simplex virus (HSV-1) infection of the cornea results in early induction of both IL-23 [88] and IL-17 [89] and IL-17RA KO mice have reduced early infiltration of neutrophils and corneal opacity following HSV infection [89]. In contrast, IL-23KO mice have exacerbated disease and pathology possibly due to HSV increased IL-12 responses and increased IFNγ producing cells [88]. In pulmonary influenza
Conclusions
We specifically did not address the role of Th17 cytokines in vaccine induced immunity as this has been recently reviewed [92]. Data to date suggest that Th17 cells have evolved to mediate protective immunity against a variety of pathogens at different mucosal sites. Moreover, deficient Th17 responses explain in part the increased susceptibility to certain infections such as mucocutaneous in HIES patients and depletion of Th17 cells by HIV explains some of the opportunistic infections in AIDS.
Acknowledgments
The authors have no conflicting financial interests. This work was supported by NIH grants P50HL084932 and R01HL061271 (to J.K.K.), and K99/R00 AI075105 and R21AI083541 (to S.A.K.).
Jay K. Kolls is professor of Genetics and Pediatrics and Chair, Department of Genetics at the Louisiana State University Health Sciences Center in New Orleans. Dr. Kolls was recruited on January 2009 from the Children's Hospital of Pittsburgh at the University of Pittsburgh in Pittsburgh, PA where he was the Niels K Jerne professor Pediatrics and Immunology. He earned his medical degree at the University of Maryland and completed his residency training in Internal Medicine/Pediatrics at Charity
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Cited by (0)
Jay K. Kolls is professor of Genetics and Pediatrics and Chair, Department of Genetics at the Louisiana State University Health Sciences Center in New Orleans. Dr. Kolls was recruited on January 2009 from the Children's Hospital of Pittsburgh at the University of Pittsburgh in Pittsburgh, PA where he was the Niels K Jerne professor Pediatrics and Immunology. He earned his medical degree at the University of Maryland and completed his residency training in Internal Medicine/Pediatrics at Charity Hospital in New Orleans, LA. After that he completed Fellowships in Adult and Pediatric Pulmonology at LSU and Tulane Health Sciences Center, respectively. He performed his research fellowship in the laboratory of Dr. Bruce Beutler at Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX. Dr. Kolls is a member of the American Association of Immunology, American Society of Microbiology, and the American Society of Clinical Investigation. Dr. Kolls has authored or co-authored more than 160 peer-reviewed articles. The major goal of Dr. Kolls’ research is to investigate mechanisms of mucosal host defenses in normal and immunocompromised hosts using genetic models. Presently, his lab is investigating how IL-23 and IL-17 and IL-22 regulate host defense against extracellular pathogens and epigenetic regulation of macrophage function. Additionally, he researches host susceptibility to opportunistic infection such as Pneumocystis and is developing pre-clinical gene-based vaccines against this pathogen.
Shabaana A. Khader received her PhD in Biotechnology from Madurai Kamaraj University, India where she studied host–pathogen interactions during the mycobacterial disease, leprosy. Dr. Khader then carried out her Post-doctoral training at the Trudeau Institute, NY where she continued studying host immune responses to another mycobacterial disease, tuberculosis. During her stay at the Trudeau Institute, Dr. Khader demonstrated a critical role for the cytokine Interleukin-17 in vaccine-induced immunity to tuberculosis. Dr. Khader joined the University of Pittsburgh in 2007 as assistant professor in the Department of Pediatrics where her lab continues to study the role of T helper subsets in immunity to intracellular pathogens. Recently, Dr. Khader received a Pathway to Independence Award from NIH and the Young Investigator Award from the International Cytokine Society. Dr. Khader is also an Associate Editor of the Journal of Immunology and on the Editorial Board of the Journal of Infectious Diseases and Immunity.