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. 2005 Jun;73(6):3394-401.
doi: 10.1128/IAI.73.6.3394-3401.2005.

Transcriptional Control of Impaired Th1 Responses in Patent Lymphatic Filariasis by T-box Expressed in T Cells and Suppressor of Cytokine Signaling Genes

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Transcriptional Control of Impaired Th1 Responses in Patent Lymphatic Filariasis by T-box Expressed in T Cells and Suppressor of Cytokine Signaling Genes

Subash Babu et al. Infect Immun. .
Free PMC article

Abstract

T-bet (T-box expressed in T cells) and GATA-3 are transcription factors that play a critical role in the development of Th1 and Th2 cells, as do genes of the SOCS (suppressor of cytokine signaling) family, albeit indirectly. Another transcription factor, Foxp3, is a master regulator of natural regulatory T cells (Tregs). To identify the role of these factors in impaired Th1 responses of patent filarial infection, analysis of cytokine, SOCS, and transcription factor mRNA expression was performed on purified T cells of filaria-infected individuals (n = 6) and uninfected controls (n = 6). As expected (and in contrast to cells of uninfected individuals), there was a significant depression of gamma interferon (IFN-gamma) and a concomitant increase in interleukin-4 (IL-4), IL-5, and IL-10 mRNA expression following stimulation with parasite antigen (BmA) but not with a polyclonal T-cell (anti-CD3) stimulus. T-bet (but not GATA-3) was expressed at significantly lower levels in cells of filaria-infected individuals in response to BmA compared with those from the uninfected group, accounting, at least partially, for the diminished IFN-gamma expression. Second, we found no significant differences in expression of Foxp3 between the two groups, although induction of Foxp3 expression correlated with induced expression levels of IL-10, implicating Tregs in the IL-10 expression seen. Finally, parasite-specific T-cell expression of SOCS-1, SOCS-5, and SOCS-7 was significantly diminished among infected patients; in contrast, expression of SOCS-3 increased. Our data therefore indicate that the impaired Th1 responses observed in patent lymphatic filariasis are associated with decreased expression of T-bet, SOCS-1, SOCS-5, and SOCS-7 and increased expression of SOCS-3 in T cells.

Figures

FIG. 1.
FIG. 1.
Th1 and Th2 cytokine mRNA expression in INF and UN. (A) T-cell expression of IFN-γ, TNF-α, IL-8, IL-4, IL-5, and IL-10 levels after 24 h of stimulation with BmA is depicted as the n-fold change over the medium control in UN (n = 6) and INF (n = 6). (B) T-cell expression of IFN-γ. TNF-α, IL-8, IL-4, IL-5, and IL-10 levels after 24 h of stimulation with anti-CD3 is depicted as the n-fold change over the medium control. The results are expressed as box plots with the horizontal lines representing the 25th, 50th, and 75th percentiles and the vertical lines representing the 10th and 90th percentiles of the data. P values were calculated using the Mann-Whitney test. NS, not significant.
FIG. 2.
FIG. 2.
Expression of T-bet, GATA-3, and Foxp3 in filarial infections. (A) T-cell expression of T-bet, GATA-3, and Foxp3 following 24 h of stimulation with BmA is depicted as the n-fold change over the medium control. (B) T-cell expression of T-bet, GATA-3, and Foxp3 following 24 h of stimulation with anti-CD3 is depicted as the n-fold change over the medium control. The results are expressed as box plots with the horizontal lines representing the 25th, 50th, and 75th percentiles and the vertical lines representing the 10th and 90th percentiles of the data. P values were calculated using the Mann-Whitney test. NS, not significant.
FIG. 3.
FIG. 3.
Expression of CIS, SOCS-1, SOCS-2, SOCS-3, SOCS-4, SOCS-5, and SOCS-7 in filarial infections. (A) T-cell expression of CIS, SOCS-1 to SOCS-5, and SOCS-7 following 24 h of stimulation with BmA is depicted as the n-fold change over the medium control. (B) T-cell expression of CIS, SOCS-1 to SOCS-5, and SOCS-7 following 24 of h stimulation with anti-CD3 is depicted as the n-fold change over the medium control. The results are expressed as box plots with the horizontal lines representing the 25th, 50th, and 75th percentiles and the vertical lines representing the 10th and 90th percentiles of the data. P values were calculated using the Mann-Whitney test. NS, not significant.
FIG. 4.
FIG. 4.
Correlation between Foxp3 induction and IL-10 in endemic individuals. The n-fold induction of Foxp3 by BmA in the cohort of INF and UN (n = 12) was measured and plotted against the n-fold induction of IL-10 mRNA expression by BmA. Spearman rank correlation was used to measure the correlation between the variables.

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