Highly heterogeneous, activated, and short-lived regulatory T cells during chronic filarial infection.

The mechanisms underlying the increase in the numbers of regulatory T (Treg) cells in chronic infection settings remain unclear. Here we have delineated the phenotype and transcriptional profiles of Treg cells from 18 filarial-infected (Fil(+) ) and 19 filarial-uninfected (Fil(-) ) subjects. We found that the frequencies of Foxp3(+) Treg cells expressing CTLA-4, GITR, LAG-3, and IL-10 were significantly higher in Fil(+) subjects compared with that in Fil(-) subjects. Foxp3-expressing Treg-cell populations in Fil(+) subjects were also more heterogeneous and had higher expression of IL-10, CCL-4, IL-29, CTLA-4, and TGF-ß than Fil(-) subjects, each of these cytokines having been implicated in immune suppression. Moreover, Foxp3-expressing Treg cells from Fil(+) subjects had markedly upregulated expression of activation-induced apoptotic genes with concomitant downregulation of those involved in cell survival. To determine whether the expression of apoptotic genes was due to Treg-cell activation, we found that the expression of CTLA-4, CDk8, RAD50, TNFRSF1A, FOXO3, and RHOA were significantly upregulated in stimulated cells compared with unstimulated cells. Taken together, our results suggest that in patent filarial infection, the expanded Treg-cell populations are heterogeneous, short-lived, activated, and express higher levels of molecules known to modulate immune responsiveness, suggesting that filarial infection is associated with high Treg-cell turnover.