LITERATURE Watch Implications for transplantation

Abstract

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 IL-17 pathway, in particular, is gaining much attention. CD4+ T cells can differentiate into different effector phenotypes, including 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 with control of extracellular bacteria and fungi. T cells differentiate into Th17 cells when activated in the presence of TGF-β and IL-6, with contributions by IL-21, IL-23 and IL-1. Conversely, Th17 differentiation is inhibited by IFN-α/β, IFN-γ and IL-27 among others. As such, the balance between activation of the transcription factors STAT1 (downstream of IFN-α/β, IFN-γ, and IL-27) and of 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 NKT cells, γδT cells and neutrophils. The contribution of host genes to infection susceptibility is made clear by families presenting with recurrent infections with unique pathogens. Casanova and colleagues have been a leading force in causally associating specific infections with particular mutations in immune-related genes. Three recent papers link a defect in the IL-17 pathway to chronic mucocutaneous candidiasis (CMC), a condition thought to be controlled by the adaptive immune system, contrasting with neutrophil-requirement for prevention of invasive candidiasis. One report (1) 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. A second report (2) reveals 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 mycobacterial infections because of impaired IFN-γ signaling. The third report (3) examines patients with autosomal recessive autoimmune polyendocrinopathy 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, 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 naive T cells, and whether it 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 remains unclear. 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 develop recurrent skin and lung infections with S. aureus. Because hyper IgE syndrome patients can also present with C. 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. 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 harness these pathways to prevent or treat these common infections in transplant recipients.