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

Abstract

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.

Interleukin 10 and dendritic cells are the main suppression mediators of regulatory T cells in human neurocysticercosis

“…For example, in the infections by Plasmodium vivax , Wuchereria bancrofti and Mansonella perstans , host T regs express CTLA‐4, LAG‐3 and GITR, suggesting a possible interaction between T regs and DCs. In addition, the presence of T regs is related to higher parasite loads . Conversely, parasites such as Trypanosoma cruzi , Plasmodium falciparum , P .…”

Helminth parasites and immune regulation

“…In peripheral blood, this polarized type 2 response occurs at the time of patency when egg laying (for example, S. mansoni ) 35 or microfilarial release (for example, Wuchereria bancrofti ) from adult females occurs 36 , resulting in a significant modulation of Th1 responses (IL-2 and interferon-gamma [IFN-γ]). However, this persistent dominant Th2 response over the course of the helminth infection also induces expansion of natural 37 – 39 and helminth-induced 40 , 41 regulatory T (Treg) cells and immunoregulatory monocytes 42 – 44 ; this same response drives B-cell class-switching to IgG4 45 . This new regulatory environment, characterized by low parasite antigen-specific lymphocyte proliferation, higher antigen-specific IgG4/IgE ratios, and increased levels of the regulatory cytokines IL-10 and transforming growth factor-beta (TGF-β), is the hallmark of an asymptomatic, chronic infection 46 – 49 .…”

Negative immunomodulation by parasitic infections in the human response to vaccines

“…In addition, multiple co-infections can occur in different endemic areas and complicate the scenario. For geohelminthosis, filarioidosis and trematodiosis, a high regulation of the immune response has been described [15][16][17]. This regulation is associated with tolerance to the parasitic infections, which leads to: a) limitation of the acute immune response against other pathogens; b) reduction of the antigen-specific response; and c) deficiency in the acquired immune response [15][16][17].…”

“…For geohelminthosis, filarioidosis and trematodiosis, a high regulation of the immune response has been described [15][16][17]. This regulation is associated with tolerance to the parasitic infections, which leads to: a) limitation of the acute immune response against other pathogens; b) reduction of the antigen-specific response; and c) deficiency in the acquired immune response [15][16][17]. Malaria usually is an acute disease, but can also be a chronic asymptomatic infection, which is mostly associated with increased regulation of the immune response [18,19].…”