To Achieve an Earlier IFN-γ Response Is Not Sufficient to Control Mycobacterium tuberculosis Infection in Mice

Vilaplana, Cristina; Prats, Clara; Marzo, Elena; Barril, Carles; Vegué, Marina; Díaz, J.F.; Valls, Joaquim; López, Daniel; Cardona, Père-Joan

doi:10.1371/journal.pone.0100830

Cited by 22 publications

(21 citation statements)

References 21 publications

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“…These results suggest that the mechanisms by which IFN-γ may limit protective recall immunity in a pulmonary model as shown in this study, may be different from recall immunity in systemic infection models. Our findings are further supported by a recent study that used both experimental and mathematical approaches to demonstrate that the control of Mtb burden in the lung was not immediate after onset of IFNγ responses in the lung 41 . As IFN-γ production has been conventionally used as a correlate for vaccine efficacy against TB, our findings instead project an important role for targeting IL-17 while limiting IFNγ in vaccine design for TB, and as such needs to explored in different preclinical vaccine models.…”

Section: Discussionsupporting

confidence: 86%

Immune requirements for protective Th17 recall responses to Mycobacterium tuberculosis challenge

et al. 2015

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Tuberculosis (TB) vaccine development has focused largely on targeting T helper type 1 (Th1) cells. However, despite inducing Th1 cells, the recombinant TB vaccine MVA85A failed to enhance protection against TB disease in humans. In recent years, Th17 cells have emerged as key players in vaccine-induced protection against TB. However, the exact cytokine and immune requirements that enable Th17-induced recall protection remain unclear. In this study, we have investigated the requirements for Th17 cell-induced recall protection against Mtb challenge by utilizing a tractable adoptive transfer model in mice. We demonstrate that adoptive transfer of Mtb-specific Th17 cells into naïve hosts, and upon Mtb challenge, results in Th17 recall responses that confer protection at levels similar to vaccination strategies. Importantly, while IL-23 is critical, IL-12 and IL-21 are dispensable for protective Th17 recall responses. Unexpectedly, we demonstrate that IFN-γ produced by adoptively transferred Th17 cells impairs long-lasting protective recall immunity against Mtb challenge. In contrast, CXCR5 expression is crucial for localization of Th17 cells near macrophages within well-formed B cell follicles to mediate Mtb control. Thus, our data identify new immune characteristics that can be harnessed to improve Th17 recall responses for enhancing vaccine design against TB.

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Section: Discussionsupporting

confidence: 86%

Immune requirements for protective Th17 recall responses to Mycobacterium tuberculosis challenge

et al. 2015

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“…of Mtb did not improve vaccine-induced Mtb control (Supplementary Fig. 1a)23. T regulatory cells induced in response to Mtb infection are known to suppress early T-cell responses24.…”

Section: Resultsmentioning

confidence: 96%

Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy

et al. 2016

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The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive. Absence of sterilizing immunity induced by TB vaccines may be due to delayed activation of mucosal dendritic cells (DCs), and subsequent delay in antigen presentation and activation of vaccine-induced CD4+ T-cell responses. Here we show that pulmonary delivery of activated M. tuberculosis antigen-primed DCs into vaccinated mice, at the time of M. tuberculosis exposure, can overcome the delay in accumulation of vaccine-induced CD4+ T-cell responses. In addition, activating endogenous host CD103+ DCs and the CD40–CD40L pathway can similarly induce rapid accumulation of vaccine-induced lung CD4+ T-cell responses and limit early M. tuberculosis growth. Thus, our study provides proof of concept that targeting mucosal DCs can accelerate vaccine-induced T-cell responses on M. tuberculosis infection, and provide insights to overcome bottlenecks in TB vaccine efficacy.

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“…Specifically for TB, the temporal correlation of Mtb growth arrest with the accumulation of CD4 + IFN-␥ + T cells suggests a critical role for this population in the control of the infection [8]. However, previous observations that IFN-␥ is not a good correlate of protection [14][15][16], achieving an early IFN-␥ response is not enough to control Mtb infection [37], and the data presented herein suggest that the CD4 + T cell populations that mediate immunity to TB are likely not IFN-␥-single producing Th1 cells, but subpopulations of this phenotype together with other cells whose effector function is not mediated by IFN-␥ [38,39].…”

Section: Discussionmentioning

confidence: 99%

BCG vaccination-induced long-lasting control of Mycobacterium tuberculosis correlates with the accumulation of a novel population of CD4+IL-17+TNF+IL-2+ T cells

Cruz

Torrado

Carmona

et al. 2015

Vaccine

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Mycobacterium bovis Bacille Calmette-Guerin (BCG) is the only vaccine in use to prevent Mycobacterium tuberculosis (Mtb) infection. Here we analyzed the protective efficacy of BCG against Mtb challenges 21 or 120 days after vaccination. Only after 120 days post-vaccination were mice able to efficiently induce early Mtb growth arrest and maintain long-lasting control of Mtb. This protection correlated with the accumulation of CD4(+) T cells expressing IL-17(+)TNF(+)IL-2(+). In contrast, mice challenged with Mtb 21 days after BCG vaccination exhibited only a mild and transient protection, associated with the accumulation of CD4(+) T cells that were mostly IFN-γ(+)TNF(+) and to a lesser extent IFN-γ(+)TNF(+)IL-2(+). These data suggest that the memory response generated by BCG vaccination is functionally distinct depending upon the temporal proximity to BCG vaccination. Understanding how these responses are generated and maintained is critical for the development of novel vaccination strategies against tuberculosis.

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To Achieve an Earlier IFN-γ Response Is Not Sufficient to Control Mycobacterium tuberculosis Infection in Mice

Cited by 22 publications

References 21 publications

Immune requirements for protective Th17 recall responses to Mycobacterium tuberculosis challenge

Immune requirements for protective Th17 recall responses to Mycobacterium tuberculosis challenge

Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy

BCG vaccination-induced long-lasting control of Mycobacterium tuberculosis correlates with the accumulation of a novel population of CD4+IL-17+TNF+IL-2+ T cells

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