Jonathan S. Bromberg, MD, PhD, Section Editor
LITERATURE Watch Implications for transplantation
Article first published online: 13 JAN 2012
©Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 12, Issue 1, page 3, January 2012
How to Cite
ALEGRE, M.-L. and BROMBERG, J. S. (2012), LITERATURE Watch Implications for transplantation. American Journal of Transplantation, 12: 3. doi: 10.1111/j.1600-6143.2011.03937.x
- Issue published online: 13 JAN 2012
- Article first published online: 13 JAN 2012
The Anti-Infectious Role of the IL-17 Pathway
CITATION Liu L, Okada S, Kong XF, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 2011; 208: 1635–1648.
CITATION Puel A, Cypowyj S, Bustamante J, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 2011; 332: 65–68.
CITATION Puel A, Doffinger R, Natividad A, et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyen-docrine syndrome type I. J Exp Med 2010; 207: 291–297.
SUMMARY AND ANALYSIS
It is well established that the innate and adaptive immune systems cooperate to control microbial infections. In recent years, insight into the role of unique immune molecules in preventing infections has been gleaned from the study of patients with recurrent single-agent infections. The interleukin-17 (IL-17) pathway, in particular, is gaining much attention.
CD4+ T cells can differentiate into different effector phenotypes, including interferon-γ (IFN-γ)-producing Th1 cells, IL-4-producing Th2 cells and Th17 cells that can secrete IL-17A, IL-17F, IL-21 and IL-22. Whereas Th1 cells are associated with elimination of intracellular microbes and Th2 cells are associated with parasite eradication, the more newly described Th17 subset has been linked to control of extracellular bacteria and fungi. T cells differentiate into Th17 cells when activated in the presence of transforming growth factor-β (TGF-β) and IL-6, with contributions from IL-21, IL-23 and IL-1. Conversely, Th17 differentiation is inhibited by IFN-α/β, IFN-γ and IL-27, among others. Thus a balance between activation of the transcription factors STAT1 (signal transducer and activator of transcription 1; downstream of IFN-α/β, IFN-γ and IL-27) and STAT3 (downstream of IL-6, IL-21 and IL-23) is essential to determine whether a T cell becomes Th1 or Th17. Importantly, other cell types can make IL-17 without having to undergo a differentiation process, including a subset of Th17 cells naturally occurring in the thymus and subsets of natural killer T (NKT) cells, γδT cells and neutrophils.
The contribution of host genes to infection susceptibility is made clear by families presenting with recurrent infections and unique pathogens. Jean-Laurent Casanova, MD, PhD, who is the last author on all three papers above, and colleagues have been a leading force in causally associating specific infections with particular mutations in immune-related genes. The three recent papers here link a defect in the IL-17 pathway to chronic mucocutaneous candidiasis (CMC), a condition thought to be controlled by the adaptive immune system, in contrast to the neutrophil requirement for prevention of invasive candidiasis.
A 2011 report from Puel et al. identifies an autosomal recessive deficiency in the receptor for IL-17A and IL-17F (IL-17RA), and an autosomal dominant deficiency in IL-17F. In humans, IL-17A and -F heterodimerize such that IL-17RA deficiency results in complete abrogation of cellular responses triggered by IL-17A and IL-17F homo- and heterodimers, whereas IL-17F deficiency partially impairs this axis. Liu et al. reveal an autosomal dominant gain-of-function mutation in STAT1, resulting in enhanced inhibition of Th17 differentiation. This is in contrast to previously identified loss-of-function mutations of STAT1 that increase susceptibility to my-cobacterial infections because of impaired IFN-γ signaling. Another report from Puel et al. (2010) examines patients with autosomal recessive autoimmune polyendo-crinopathy syndrome-I (mutations in AIRE) who also develop CMC, often as their only infection. Patients with this condition have high titers of neutralizing autoantibodies against IL-17A, IL-17F and IL-22.
Together, these studies strongly link Th17 immunity with protection against CMC. However, it remains unclear whether protection is conferred by innate-like T cells such as the naturally occurring thymic Th17 or NKT cells, or by adaptive Th17 cells derived from naïve T cells, and whether protection is due to direct action of Th17 cytokines on epithelial and mucosal surfaces or secondary to the ability of Th17 cytokines to recruit innate immune cells.
Interestingly, Th17 cells have also been proposed to protect against Staphylococcus aureus infections, as patients with hyper-IgE syndrome have loss-of-function mutations in STAT3 abolishing Th17 differentiation, and they develop recurrent skin and lung infections with S. aureus. Because hyper-IgE syndrome patients can also present with Candida albicans mucocutaneous infections, and patients with CMC also occasionally develop local S. aureus infections, it is tempting to speculate that immunity to C. albicans and S. aureus shares some common pathways.
[ Proposed model of how genetic mutations affect the Th17 pathway. A gain-of-function mutation in STAT1 that antagonizes STAT3-mediated Th17 differentiation (1); a loss-of-function mutation in IL-17F (2); a mutation in AIRE resulting in neutralizing anti-IL-17 antibodies (3); and a loss-of-function mutation in the receptor for IL-17A/F (4) that are all associated with CMC. ]
Both C. albicans and S. aureus are commensals in healthy people but cause infections in immunosuppressed patients and notably in transplant recipients. It is conceivable that the immunosuppressive regimens administered to prevent graft rejection inhibit differentiation or function of Th17 cells, leaving patients susceptible to local invasion by these microbes. In addition, allelic variations in genes important for Th17 differentiation or signaling may predispose patients to these infections. Understanding the unique components of the immune system that normally control specific infections may help to harness these pathways in the prevention or treatment of these common infections in transplant recipients.
Dr. Alegre is associate professor of medicine, department of medicine, section of rheumatology, University of Chicago.