IL-17 and Th17 cells in tuberculosis

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Abstract

Tuberculosis is primarily a disease of the lung. Constant expression of cellular immunity in this organ is required to control Mycobacterium tuberculosis growth, but this can also result in chronic inflammation and pathologic consequences. During primary tuberculosis both IFN-γ and IL-17 are induced: both are potent inflammatory cytokines capable of inducing expression of chemokines that promote cell recruitment and granuloma organization throughout infection. During the chronic phase, a balance between Th1 and Th17 responses needs to be achieved to control bacterial growth and limit immunopathology, as a shift of the response towards excessive IL-17 production may sustain extensive neutrophil recruitment and tissue damage. Thus, regulation of Th1 and Th17 responses during tuberculosis is essential to promote anti-mycobacterial immunity and prevent extensive immunopathological consequences.

Introduction

Specialization of immune cells plays a central role in coordinating the immune response to different categories of pathogens. This specialization is typically best seen in CD4 T cell populations that produce discrete cytokines and display specific functions. For example, the control of pathogens that reside in phagocytes requires IFN-γ secreting CD4 T cells to activate the antimicrobial mechanisms of the phagocyte; these cells are generally referred to as T helper (Th)1 in contrast with Th2 cells that produce IL-4, IL-5 and IL-13 and are important in controlling extracellular helminthes [1]. Recently, a new Th cell population has been identified and referred to as Th17. Th17 cells produce IL-17A (simply referred to as IL-17) [2], [3], IL-17F [4], IL-21 [5] and IL-22 [6] as their signature cytokines.

As the IL-17 receptor (IL-17RA) is ubiquitously expressed in different organs, including lung, liver and spleen, cells capable of responding to IL-17 include dendritic cells (DCs) and macrophages, lymphocytes, epithelial cells, keratinocytes and fibroblasts [7], [8]. IL-17-induced responses include the expression of proinflammatory genes such as G-CSF, CXC chemokines, IL-6, and IL-8 (MIP-2 in mice), antimicrobial proteins such as defensins and S100 proteins, granulopoiesis, neutrophil recruitment and inflammation [9]. Indeed, in infection models, IL-17 and Th17 cells were first implicated in the protective immune response to rapidly growing extracellular bacteria in the lung and gut mucosal surfaces through efficient induction of neutrophil recruitment and tissue repair [10], [11], [12].

As this is a relatively newly identified subset, we are still learning about the complexity of Th17 cells and Th17-derived cytokines. Recent data suggest a broader and more complex role for these cells and cytokines in different infections including intracellular bacteria, fungi and virus at different mucosal surfaces [13]. Indeed, Th17 cells and Th17 derived cytokines were shown to be key inducers of inflammation and tissue damage in animal models of autoimmune diseases [14], [15] and infection [13]. Therefore, the balance between Th17 mediated protection and pathology is key in defining the outcome of infections at the mucosa. Understanding this fine balance is central in developing new and improved preventive and therapeutic strategies.

The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes the disease tuberculosis (TB), which kills over two million people every year [16]. It is thought that Th1 cells are important in the control of Mtb proliferation [17], [18], [19], [20], [21] however, despite vaccines having been developed to specifically potentiate this type of response none of these strategies have improved upon BCG, the currently used vaccine [22]. In order to improve BCG and generate more effective vaccination strategies, we need to more clearly understand what the components of the protective immune response are, and how they are regulated.

The potential for IL-17 to mediate immune pathology as seen in autoimmune diseases and infection models, suggests that IL-17 may have detrimental effect in chronic bacterial infections such as TB. In order to spread and infect new hosts, Mtb is actually dependent on effective immunity and generation of granulomatous responses. Specifically in susceptible individuals, the granuloma develops to eventually become necrotic (caseating tubercles), allowing bacilli to become extracellular and able to be expelled out of the lungs upon coughing. How this pathological response is regulated is still not well understood, but a balance between protective and damaging immunity needs to be achieved to allow control of Mtb proliferation and reduce transmission and morbidity.

The capacity of Th17 cells, and their associated cytokines, to be important players in combating infections and maintaining homeostasis of mucosal surfaces contrasts with their ability to be involved in tissue destruction. It is therefore of critical importance to understand their role both in the protective and in the damaging responses to Mtb infection. To help in this regard we here discuss new advances in the understanding on the role of IL-17 and Th17 derived cytokines in the host immune response to Mtb, with emphasis in the induction and regulation of these responses and the mechanisms of protection and pathology associated with IL-17 and Th17 cells.

Section snippets

Induction of IL-17 and Th17 responses in tuberculosis

Following deposition of Mtb in the lung, it is likely that DCs migrate to the draining lymph nodes (dLNs) where T cells are primed [23]. In the dLN, both IFN-γ and IL-17 producing T cells are induced and these cells then migrate to the lung where they exert effector function. Although we are still learning how mycobacteria stimulate innate immune receptors, cytokines produced by Mtb-primed DCs are likely to be crucial for balanced acquired cellular responses [23].

The development of Th17 cells

The protective immune response to primary M. tuberculosis infection: do IL-17 and Th17 derived cytokines play a role?

As discussed above, early studies using respiratory infection models, established a central role for IL-17 in the protective immune response to rapidly growing extracellular bacterial pathogens, mediated by efficient neutrophil recruitment and tissue repair [10], [11], [12]. In intracellular bacterial infections however, the role of IL-17 is not so well understood. Recent studies suggest that IL-17 enhances immunity against some intracellular pathogens; however the effect is not as dramatic as

Role of IL-17 in tuberculosis mediated immunopathology

Regulation of immunopathology during chronic Mtb infection is essential for host survival. As immunopathology is a central feature of Mtb lung infection, it is not surprising that IL-17 and Th17 cells have a role to play. Importantly, this role also seems to be mediated, at least in part, by neutrophils (Fig. 2).

As discussed earlier, neutrophil recruitment and survival may be one of the mechanisms by which IL-17 promotes granuloma organization. However, this response needs regulation since the

Cellular regulation of IL-17 dependent immunopathology in tuberculosis

As discussed, TGF-β is a central cytokine in the differentiation of Th17 cells; however this cytokine also acts in the differentiation of Foxp3-expressing Treg cells [84]. It has been shown that foxp3-expressing Treg cells expand during experimental Mtb infection and upon deletion Mtb bacterial burdens decrease [85]. In humans, there are more Treg cells in active TB patients than patients with latent infection [86] or in healthy tuberculin responders [87]. Overall these data suggest a largely

Conclusion

TB remains one of the leading causes of death from a single infectious agent worldwide. In order to generate better vaccination strategies we need to further define the protective and pathological mechanisms of the immune response to Mtb. While the IL-23/IL-17 axis does not seem to be essential for primary control of Mtb, recent data suggest a critical role of this axis in vaccine induced protection. In part, this effect is mediated by the release of chemokine gradients that recruit protective

Acknowledgements

Our work is supported by the Trudeau Institute, Inc., NIH grants AI46530, AI67723, AI69121 and an American Lung Association De Souza award.

Egídio Torrado earned his bachelor's degree in Biology from University of Aveiro in Portugal. During his graduate studies at the Life and Health Sciences Research Institute, University of Minho in Dr. Jorge Pedrosa's laboratory, he investigated the interaction of Mycobacterium ulcerans and the effects of mycolactone in the activation of host phagocytes. He is currently a post-doctoral fellow in Dr. Andrea Cooper's laboratory at the Trudeau Institute in Saranac Lake where his research is aimed

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    Egídio Torrado earned his bachelor's degree in Biology from University of Aveiro in Portugal. During his graduate studies at the Life and Health Sciences Research Institute, University of Minho in Dr. Jorge Pedrosa's laboratory, he investigated the interaction of Mycobacterium ulcerans and the effects of mycolactone in the activation of host phagocytes. He is currently a post-doctoral fellow in Dr. Andrea Cooper's laboratory at the Trudeau Institute in Saranac Lake where his research is aimed at better understanding the expression and regulation of the immune response to Mycobacterium tuberculosis in the lung.

    Dr. Andrea Cooper began her scientific career at The London School of Hygiene and Tropical Medicine where she helped describe the interaction between macrophages and protozoan parasites of the genus Leishmania. She then moved to the National Institutes of Health in Bethesda, Maryland, and expanded her investigation of leishmaniasis and leishmanial antigens to include the T-cell-mediated response of patients suffering from cutaneous, mucocutaneous and visceral forms of this disease. She then moved to the Mycobacterial Research Labs, Colorado State University and began studying the protective immune response to Mycobacterium tuberculosis. At Colorado State, Dr. Cooper elucidated the essential role of the Interferon-gamma [IFN-y]-Interleukin-12 [IL-12] pathway in protection from mycobacterial disease. Dr. Cooper then moved to the Trudeau Institute. This allowed her to focus her investigation on the cellular immune response to Mycobacterium tuberculosis. Recent work has resulted in the definition of the roles of IL-12, IL-23 and IL-27 in both the primary and vaccine-induced immune response to this pathogen in the lung.

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