Mycobacterium tuberculosis-Specific IL-21+IFN-γ+CD4+ T Cells Are Regulated by IL-12

Li, Li; Jiang, Yu-Xia; Lao, Suihua; Yang, Baofeng; Yu, S.; Zhang, Yannan; Wu, Changyou

doi:10.1371/journal.pone.0147356

Cited by 29 publications

(34 citation statements)

References 47 publications

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“…An emerging literature supports that anti-microbial effector CD4 T cells can exhibit mixed Th1- and Tfh-like phenotype and function (Carpio et al, 2015, Li et al, 2016, Nakayamada et al, 2011, Obeng-Adjei et al, 2015, Velu et al, 2016, Wikenheiser et al, 2016). Viral infections are linked to expansion of effector Tfh cells that express CXCR3 and co-produce IFN-γ and IL-21 following experimental SIV infection (Velu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Th1-like Plasmodium -Specific Memory CD4 + T Cells Support Humoral Immunity

et al. 2017

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Summary Effector T-cells exhibiting features of either T helper 1 (Th1) or T follicular helper (Tfh) populations are essential to control experimental Plasmodium infection and are believed to be critical for resistance to clinical malaria. To determine whether Plasmodium-specific Th1- and Tfh-like effector cells generate memory populations that contribute to protection, we developed transgenic parasites that enable high-resolution study of anti-malarial memory CD4 T-cells in experimental models. We found that populations of both Th1- and Tfh-like Plasmodium-specific memory CD4 T-cells persist. Unexpectedly, Th1-like memory cells exhibit phenotypic and functional features of Tfh cells during recall and provide potent B-cell help and protection following transfer, characteristics that are enhanced following ligation of the T-cell co-stimulatory receptor OX40. Our findings delineate critical functional attributes of Plasmodium-specific memory CD4 T-cells and identify a host-specific factor that can be targeted to improve resolution of acute malaria and provide durable, long-term protection against Plasmodium parasite re-exposure.

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Section: Discussionmentioning

confidence: 99%

Th1-like Plasmodium -Specific Memory CD4 + T Cells Support Humoral Immunity

et al. 2017

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“…In human Mtb infection, NKT cells from plural fluids of tuberculosis patients produce IL-21 to help B cells to secrete IgG and IgA (18), pulmonary tuberculosis patients have less circulating IL-21 levels (19) and IL-21 regulates Mtb specific IFN-γ+CD4+ T cell responses (35) suggesting a role for IL-21 in human Mtb infection. In a mouse model of Mtb infection, IL-21 enhances immunogenicity of a DNA vaccine containing Ag85A (21).…”

Section: Discussionmentioning

confidence: 99%

IL-21 Receptor Signaling Is Essential for Optimal CD4+ T Cell Function and Control of Mycobacterium tuberculosis Infection in Mice

Cheekatla

Tripathi

Venkatasubramanian

et al. 2017

The Journal of Immunology

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In the current study we determined the role of IL-21 receptor signaling in Mycobacterium tuberculosis (Mtb) infection, using IL-21 receptor knockout (IL-21R KO) mice. Fifty percent of Mtb H37Rv infected IL-21R KO mice died in six months compared to no deaths in infected wild type (WT) mice. Mtb infected IL-21R KO mice had enhanced bacterial burden and reduced infiltration of antigen specific T-cells in lungs compared to Mtb infected WT mice. Antigen specific T-cells from the lungs of Mtb infected IL-21R KO mice had increased expression of T-cell inhibitory receptors, reduced expression of chemokine receptors, proliferated less and produced less IFN- γ, compared to antigen specific T cells from the lungs of Mtb infected WT mice. T cells from Mtb infected IL-21R KO mice were unable to induce optimal macrophage responses to Mtb. This may be due to a decrease in the antigen specific T cell population. We also found that IL-21R signaling is associated with reduced expression of a transcriptional factor Eomesodermin (Eomes) and enhanced functional capacity of antigen specific T-cells of Mtb infected mice. The sum of our findings suggests that IL-21 receptor signaling is essential for the optimal control of Mtb infection.

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“…In mice, IL-21 correlates with vaccine efficacy272829, and following primary infection, M. tuberculosis -specific CD4 + T cells make IL-21 and frequently co-produce IFNγ, IL-2 and/or TNF30. A single study measured bacterial growth in IL-21 −/− mice following infection, and found comparable bacillary loads in WT and KO mice through day 200 post-infection31.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we argue that IL-21 acts as a ‘Signal 3’ cytokine and is important for initiation of the CD8 + T cell responses in the LN. In this way, IL-21 functions similarly to IL-12 by promoting early T cell proliferation and cytokine production3044.…”

Section: Discussionmentioning

confidence: 99%

IL-21 signaling is essential for optimal host resistance against Mycobacterium tuberculosis infection

Booty

Barreira-Silva

Carpenter

et al. 2016

Sci Rep

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IL-21 is produced predominantly by activated CD4+ T cells and has pleiotropic effects on immunity via the IL-21 receptor (IL-21R), a member of the common gamma chain (γc) cytokine receptor family. We show that IL-21 signaling plays a crucial role in T cell responses during Mycobacterium tuberculosis infection by augmenting CD8+ T cell priming, promoting T cell accumulation in the lungs, and enhancing T cell cytokine production. In the absence of IL-21 signaling, more CD4+ and CD8+ T cells in chronically infected mice express the T cell inhibitory molecules PD-1 and TIM-3. We correlate these immune alterations with increased susceptibility of IL-21R−/− mice, which have increased lung bacterial burden and earlier mortality compared to WT mice. Finally, to causally link the immune defects with host susceptibility, we use an adoptive transfer model to show that IL-21R−/− T cells transfer less protection than WT T cells. These results prove that IL-21 signaling has an intrinsic role in promoting the protective capacity of T cells. Thus, the net effect of IL-21 signaling is to enhance host resistance to M. tuberculosis. These data position IL-21 as a candidate biomarker of resistance to tuberculosis.

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Mycobacterium tuberculosis-Specific IL-21+IFN-γ+CD4+ T Cells Are Regulated by IL-12

Cited by 29 publications

References 47 publications

Th1-like Plasmodium -Specific Memory CD4 + T Cells Support Humoral Immunity

Th1-like Plasmodium -Specific Memory CD4 + T Cells Support Humoral Immunity

IL-21 Receptor Signaling Is Essential for Optimal CD4+ T Cell Function and Control of Mycobacterium tuberculosis Infection in Mice

IL-21 signaling is essential for optimal host resistance against Mycobacterium tuberculosis infection

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