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. 2012;6(5):e1655.
doi: 10.1371/journal.pntd.0001655. Epub 2012 May 29.

Regulatory T Cells in Human Lymphatic Filariasis: Stronger Functional Activity in Microfilaremics

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Free PMC article

Regulatory T Cells in Human Lymphatic Filariasis: Stronger Functional Activity in Microfilaremics

Linda J Wammes et al. PLoS Negl Trop Dis. .
Free PMC article

Abstract

Infection with filarial parasites is associated with T cell hyporesponsiveness, which is thought to be partly mediated by their ability to induce regulatory T cells (Tregs) during human infections. This study investigates the functional capacity of Tregs from different groups of filarial patients to suppress filaria-specific immune responses during human filariasis. Microfilaremic (MF), chronic pathology (CP) and uninfected endemic normal (EN) individuals were selected in an area endemic for Brugia timori in Flores island, Indonesia. PBMC were isolated, CD4CD25(hi) cells were magnetically depleted and in vitro cytokine production and proliferation in response to B. malayi adult worm antigen (BmA) were determined in total and Treg-depleted PBMC. In MF subjects BmA-specific T and B lymphocyte proliferation as well as IFN-gamma, IL-13 and IL-17 responses were lower compared to EN and CP groups. Depletion of Tregs restored T cell as well as B cell proliferation in MF-positives, while proliferative responses in the other groups were not enhanced. BmA-induced IL-13 production was increased after Treg removal in MF-positives only. Thus, filaria-associated Tregs were demonstrated to be functional in suppressing proliferation and possibly Th2 cytokine responses to BmA. These suppressive effects were only observed in the MF group and not in EN or CP. These findings may be important when considering strategies for filarial treatment and the targeted prevention of filaria-induced lymphedema.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Suppressed T cell and B cell proliferative response to filaria antigen in microfilaremics.
CFSE-labeled PBMC from uninfected endemic normals (EN), microfilaremic (MF) and chronic pathology (CP) subjects were stimulated with Brugia malayi adult worm antigen (BmA). After 4 days of culture cells were fixed, cryopreserved and after thawing CFSE division was analyzed by flow cytometry. Depicted are means and standard errors of net % divided subsets of CD4+CD25+ T cells (A) and CD19+ B cells (B), adjusted for age and sex. * p≤0.05 **p≤.01 ***p≤.001.
Figure 2
Figure 2. Altered filaria-specific cytokine production in different study groups.
PBMC from uninfected endemic normals (EN), microfilaremic (MF) and chronic pathology (CP) subjects were stimulated with BmA. After 4 days of culture supernatants were harvested and assessed for IFN-γ (A), IL-13 (B), IL-17 (C) and IL-10 (D) production. Plotted values are age- and sex-adjusted means and standard errors; *p≤.05 **p≤.01 ***p≤.001, p-values between 0.05 and 0.10 are indicated.
Figure 3
Figure 3. Efficient Treg depletion for all infection groups.
CD4+CD25hi T cells were isolated by magnetic bead separation. Treg frequencies were defined as percentages of CD25hiFOXP3+ cells from total CD4+ fractions for mock- and CD4+CD25hi cell -depleted PBMC that were cultured for 4 days in medium (representative example in A). Treg frequency of mock (M) and depleted (D) PBMC is shown for all donors (B) as well as for the different infection groups (C). Lines represent data points from one individual, data were analyzed by non-parametric paired tests; ***p≤0.001 ****p≤0.0001 or p-value as indicated.
Figure 4
Figure 4. Suppressed lymphocyte proliferation is restored after Treg depletion in microfilaremics.
Divided cell populations were assessed in mock- (M) and Treg-depleted (D) PBMC from EN, MF and CP subjects. CFSE dilution was analyzed for CD4+CD25+ T cells (A–B) and CD19+ B cells (C–D). Cultures were stimulated with BmA (left panel; A&C) or left unstimulated (cultured with medium) (right panel; B&D). Plotted lines represent data points from single individuals; tested by Wilcoxon signed rank test, *p≤.05 **p≤.01, p-values between 0.05 and 0.10 are indicated.
Figure 5
Figure 5. Removal of Tregs enhances filaria-specific Th1 and Th2 responses.
Cytokine secretion was assessed in mock- (M) and Treg-depleted (D) PBMC cultures from EN, MF and CP individuals. IFN-γ (A–B) and IL-13 (C–D) secretion is depicted for BmA- (left panel) and unstimulated (right panel) conditions. Connecting lines represent data points of one individual, for mock- and Treg-depleted cultures; tested by paired t-test *p≤.05 **p≤.01***p≤.001, p-values between 0.05 and 0.10 are indicated.

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