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.