Kroetz and Deepe (1) report on the role of CCR5 and one of its ligands, CCL4, during fungal infections in mice. Their main conclusion is that CCR5 dictates pathogen persistence by regulating the balance between regulatory T cells (Tregs) and Th17 cells.
However, the data presented can also be interpreted in a different way, based on our previous work demonstrating that CCL4 is a CD8 T cell secreted immunoregulatory effector molecule (2). In particular, the late effects observed by the authors, notably increased clearance of Histoplasma capsulatum infection in CCR5−/− mice, could be explained by reduced Treg activity: CCR5−/− deficient T cells would be insensitive to CCL4-mediated suppression and thus more potent in eliminating the infection. In addition, in early-phase infection, these Tregs might contribute to recruiting inflammatory cells through CCL4 or other mechanisms (3) and their subsequent regulation at the site of infection.
The increased frequency of Th17 cells may then be the result of decreased inhibition of Th17 by CCL4-producing Tregs. Because Th17 cells are relatively resistant to suppression by classical Tregs (4), yet express CCR5 (S.A. Joosten and T.M.H. Ottenhoff, unpublished observations) (4), Th17 cells may be particularly susceptible to immune regulation by CD8 Treg-produced CCL4, and thus could be more active in CCR5/CCL4 axis deficiency.
Taken together, the data presented in this manuscript can be alternatively interpreted, at least in part, by the activity of CCL4-producing Tregs.
