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Decreased frequencies of circulating CD4⁺ T follicular helper cells associated with diminished plasma IL-21 in active pulmonary tuberculosis.

Kumar NP, Sridhar R, Hanna LE, Banurekha VV, Nutman TB, Babu S - PLoS ONE (2014)

Bottom Line: We found that both ex vivo and TB - antigen induced frequencies of Tfh cell subsets was significantly lower in PTB compared to LTB individuals.Similarly, antigen induced frequencies of Tfh cells expressing IL-21 was also significantly lower in PTB individuals and this was reflected in diminished circulating levels of IL-21 and IFNγ.Thus, PTB is characterized by adiminution in the frequency of Tfh cell subsets.

View Article: PubMed Central - PubMed

Affiliation: National Institutes of Health-International Center for Excellence in Research, Chennai, India; National Institute for Research in Tuberculosis, Chennai, India.

ABSTRACT

Background: Circulating T follicular helper (Tfh) cells represent a distinct subset of CD4+ T cells and are important in immunity to infections. Although they have been shown to play a role in experimental models of tuberculosis infection, their role in human tuberculosis remains unexplored.

Aims/methodology: To determine the distribution of circulating Tfh cells in human TB, we measured the frequencies of Tfh cells ex vivo and following TB - antigen or polyclonal stimulation in pulmonary TB (PTB; n = 30) and latent TB (LTB; n = 20) individuals, using the markers CXCR5, PD-1 and ICOS.

Results: We found that both ex vivo and TB - antigen induced frequencies of Tfh cell subsets was significantly lower in PTB compared to LTB individuals. Similarly, antigen induced frequencies of Tfh cells expressing IL-21 was also significantly lower in PTB individuals and this was reflected in diminished circulating levels of IL-21 and IFNγ. This was not accompanied by diminished frequencies of activated or memory B cell subsets. Finally, the diminution in frequency of Tfh cells in PTB individuals was dependent on IL-10, CTLA-4 and PD-L1 in vitro.

Conclusions: Thus, PTB is characterized by adiminution in the frequency of Tfh cell subsets.

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Related in: MedlinePlus

Diminished antigen - specific frequencies of IL-21 expressing Tfh cells in PTB.(A) Whole blood from PTB and LTB individuals was stimulated with PPD, CFP-10, ESAT-6 and anti-CD3 for 6 h, and the frequencies of CD4+ CXCR5+ IL-21+ T cells were estimated by flow cytometry. A representative dot plot is shown. (B) TB antigen- and anti-CD3-induced expansion of IL-21 expressing Tfh cells in PTB. (C) The spontaneous and TB - antigen stimulated frequencies of IL-21 expressing Tfh cells in PTB and LTB individuals. P values were calculated using either Wilcoxon signed rank test or Mann-Whitney U test.
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pone-0111098-g003: Diminished antigen - specific frequencies of IL-21 expressing Tfh cells in PTB.(A) Whole blood from PTB and LTB individuals was stimulated with PPD, CFP-10, ESAT-6 and anti-CD3 for 6 h, and the frequencies of CD4+ CXCR5+ IL-21+ T cells were estimated by flow cytometry. A representative dot plot is shown. (B) TB antigen- and anti-CD3-induced expansion of IL-21 expressing Tfh cells in PTB. (C) The spontaneous and TB - antigen stimulated frequencies of IL-21 expressing Tfh cells in PTB and LTB individuals. P values were calculated using either Wilcoxon signed rank test or Mann-Whitney U test.

Mentions: Since IL-21 expression is one hallmark of Tfh cells [3], we sought to determine the role of IL-21 expressing Tfh cells in TB and examined the baseline as well as antigen - induced frequencies of IL-21 expressing Tfh cells in PTB and LTB. As shown in Figure 3A, we were able to detect IL-21 expressing CXCR5+ CD4+ T cells in the circulation of PTB individuals. We then observed that stimulation with PPD, CFP-10, ESAT-6 and anti-CD3 all resulted in significant increase in the frequency of CD4+ CXCR5+ IL-21+ T cells in PTB individuals (Figure 3B). Next, as shown in Figure 3C, CFP-10, ESAT-6 and anti-CD3 induced frequencies of IL-21 expressing Tfh cells was significantly decreased in PTB compared to LTB individuals. Thus, PTB is characterized by a diminished frequencies of IL-21 expressing Tfh cells in the periphery, indicating diminished function of Tfh cells in PTB.


Decreased frequencies of circulating CD4⁺ T follicular helper cells associated with diminished plasma IL-21 in active pulmonary tuberculosis.

Kumar NP, Sridhar R, Hanna LE, Banurekha VV, Nutman TB, Babu S - PLoS ONE (2014)

Diminished antigen - specific frequencies of IL-21 expressing Tfh cells in PTB.(A) Whole blood from PTB and LTB individuals was stimulated with PPD, CFP-10, ESAT-6 and anti-CD3 for 6 h, and the frequencies of CD4+ CXCR5+ IL-21+ T cells were estimated by flow cytometry. A representative dot plot is shown. (B) TB antigen- and anti-CD3-induced expansion of IL-21 expressing Tfh cells in PTB. (C) The spontaneous and TB - antigen stimulated frequencies of IL-21 expressing Tfh cells in PTB and LTB individuals. P values were calculated using either Wilcoxon signed rank test or Mann-Whitney U test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4208798&req=5

pone-0111098-g003: Diminished antigen - specific frequencies of IL-21 expressing Tfh cells in PTB.(A) Whole blood from PTB and LTB individuals was stimulated with PPD, CFP-10, ESAT-6 and anti-CD3 for 6 h, and the frequencies of CD4+ CXCR5+ IL-21+ T cells were estimated by flow cytometry. A representative dot plot is shown. (B) TB antigen- and anti-CD3-induced expansion of IL-21 expressing Tfh cells in PTB. (C) The spontaneous and TB - antigen stimulated frequencies of IL-21 expressing Tfh cells in PTB and LTB individuals. P values were calculated using either Wilcoxon signed rank test or Mann-Whitney U test.
Mentions: Since IL-21 expression is one hallmark of Tfh cells [3], we sought to determine the role of IL-21 expressing Tfh cells in TB and examined the baseline as well as antigen - induced frequencies of IL-21 expressing Tfh cells in PTB and LTB. As shown in Figure 3A, we were able to detect IL-21 expressing CXCR5+ CD4+ T cells in the circulation of PTB individuals. We then observed that stimulation with PPD, CFP-10, ESAT-6 and anti-CD3 all resulted in significant increase in the frequency of CD4+ CXCR5+ IL-21+ T cells in PTB individuals (Figure 3B). Next, as shown in Figure 3C, CFP-10, ESAT-6 and anti-CD3 induced frequencies of IL-21 expressing Tfh cells was significantly decreased in PTB compared to LTB individuals. Thus, PTB is characterized by a diminished frequencies of IL-21 expressing Tfh cells in the periphery, indicating diminished function of Tfh cells in PTB.

Bottom Line: We found that both ex vivo and TB - antigen induced frequencies of Tfh cell subsets was significantly lower in PTB compared to LTB individuals.Similarly, antigen induced frequencies of Tfh cells expressing IL-21 was also significantly lower in PTB individuals and this was reflected in diminished circulating levels of IL-21 and IFNγ.Thus, PTB is characterized by adiminution in the frequency of Tfh cell subsets.

View Article: PubMed Central - PubMed

Affiliation: National Institutes of Health-International Center for Excellence in Research, Chennai, India; National Institute for Research in Tuberculosis, Chennai, India.

ABSTRACT

Background: Circulating T follicular helper (Tfh) cells represent a distinct subset of CD4+ T cells and are important in immunity to infections. Although they have been shown to play a role in experimental models of tuberculosis infection, their role in human tuberculosis remains unexplored.

Aims/methodology: To determine the distribution of circulating Tfh cells in human TB, we measured the frequencies of Tfh cells ex vivo and following TB - antigen or polyclonal stimulation in pulmonary TB (PTB; n = 30) and latent TB (LTB; n = 20) individuals, using the markers CXCR5, PD-1 and ICOS.

Results: We found that both ex vivo and TB - antigen induced frequencies of Tfh cell subsets was significantly lower in PTB compared to LTB individuals. Similarly, antigen induced frequencies of Tfh cells expressing IL-21 was also significantly lower in PTB individuals and this was reflected in diminished circulating levels of IL-21 and IFNγ. This was not accompanied by diminished frequencies of activated or memory B cell subsets. Finally, the diminution in frequency of Tfh cells in PTB individuals was dependent on IL-10, CTLA-4 and PD-L1 in vitro.

Conclusions: Thus, PTB is characterized by adiminution in the frequency of Tfh cell subsets.

Show MeSH
Related in: MedlinePlus