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-β 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.