There is a growing body of evidence showing that bacterial translocation through the damaged mucosal tissues of the gut plays an important role in the chronic immune activation observed in HIV-infected individuals.
Studies in recent years have suggested that depletion of the T helper type 17 (Th17) subset of CD4+ T cells might be part of the reason this bacterial translocation occurs, in that it leads to impaired mucosal immune responses against incoming microbes.
Now a team led by Daniel Douek of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID) has found further evidence to support this explanation. In people with Job’s syndrome, a genetic immune disorder characterized by recurrent and severe bacterial and fungal infections, Douek and colleagues observed a lack of Th17 cells (Nature 452, 773, 2008). This, Douek says, for the most part explains their increased vulnerability to attacks by bacteria and fungi. “Probably the lack of the Th17 cells is enough to account for the infections that they get,” he says.
The study found that T cells producing interleukin 17 (IL-17), the cytokine made by Th17 cells, were barely detectable in peripheral blood mononuclear cells (PBMCs) from Job’s syndrome patients. In addition, naïve T-cells from those patients were unable to differentiate into Th17 cells. “[The Th17] cells are not there nor can they be elicited,” Douek says. This is the first description of a human genetic disease where Th17 differentiation is absent. “Job’s syndrome is kind of like the Th17 knockout human,” he adds.
Douek also has unpublished observations that Job’s syndrome patients have bacterial lipopolysaccharides in their plasma, similar to what his group has observed before in HIV-infected individuals (Nature Medicine 12, 1365, 2006). This suggests they might also suffer from bacterial translocation through their guts. “In HIV infection we have bacterial translocation and the absence of Th17 cells,” Douek says. “So I think Job’s syndrome adds a nice confirmation for a hypothesis that Th17 cells may be important in HIV disease pathogenesis.”
A number of studies suggest that depletion of Th17 cells and an insult to the gut play an important role in explaining the chronic immune activation in AIDS patients (see Scanning the scientific horizon, IAVI Report, Jan.-Feb., 2008). For example, Satya Dandekar’s group at the University of California in Davis found that injectingSalmonella typhimurium into the guts of SIV-infected rhesus macaques resulted in the spread of the bacteria to other organs, whereas in uninfected macaques, the bacteria remained in the gut. She also found that the IL-17 response to the injected microbes was blunted in SIV-infected macaques. IL-17 is thought to induce antimicrobial immune responses in the gut epithelium, Dandekar says. Others have shown that Th17 cells in the gut of sooty mangabeys, natural SIV hosts that don’t develop AIDS, remain stable.
Donald Sodora of the Seattle Biomedical Research Institute says the latest data from Douek and colleagues are an additional piece of evidence for a key role of Th17 cells in preventing translocation by commensural gut bacteria, as has been postulated to occur during HIV and SIV infection. “It’s a good paper especially for identifying what Th17 cells are doing,” says Sodora, who studies immune activation during HIV and SIV infection.
Douek says he got the idea to look for Th17 cells in Job’s syndrome patients when others showed last year that these patients have a mutation in the stat3 gene (Nature 448, 1058, 2007; N. Engl. J. Med. 357, 1608, 2007). Because it was already known at the time that STAT3 is involved in the differentiation of Th17 cells (see, for example, J. Biol. Chem. 282, 9358, 2007), it seemed plausible that Job’s patients had a defect in Th17 cells. “We sort of put two and two together,” Douek says. —Andreas von Bubnoff