CD4+ T cells are trigger and target of the glucocorticoid response that prevents lethal immunopathology in toxoplasma infection

Kugler, David; Mittelstadt, Paul R.; Ashwell, Jonathan D.; Sher, Alan; Janković, Dragana

doi:10.1084/jem.20122300

Cited by 49 publications

(38 citation statements)

References 30 publications

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“…We believe that this true ex vivo analysis reveals the tightly regulated dynamics of T cell activation that occurs in vivo . This concept is supported by a recent report in which the role of glucocorticoids in the regulation of T cell responses was only evident when experiments were performed in the way we report here; T cells were hyperactive if analyzed after the traditional in vitro restimulation [34]. …”

Section: Discussionsupporting

confidence: 83%

Phenotype of the anti-Rickettsia CD8+ T cell response suggests cellular correlates of protection for the assessment of novel antigens

Caro-Gómez

Gaži

Cespedes

et al. 2014

Vaccine

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The obligately intracellular bacteria Rickettsia infect endothelial cells and cause systemic febrile diseases that are potentially lethal. No vaccines are currently available and current knowledge of the effective immune response is limited. Natural and experimental rickettsial infections provide strong and cross-protective cellular immunity if the infected individual survives the acute infection. Although resistance to rickettsial infections is attributed to the induction of antigen-specific T cells, particularly CD8+ T cells, the identification and validation of correlates of protective cellular immunity against rickettsial infections, an important step towards vaccine validation, remains a gap in this field. Here, we show that after a primary challenge with Rickettsia typhi in the C3H mouse model, the peak of anti-Rickettsia CD8+ T cell-mediated responses occurs 7 days post-infection (dpi), which coincides with the beginning of rickettsial clearance. At this time point, both effector-type and memory-type CD8+ T cells are present, suggesting that 7 dpi is a valid time point for the assessment of CD8+ T cell responses of mice previously immunized with protective antigens. Based on our results, we suggest four correlates of cellular protection for the assessment of protective rickettsial antigens: 1) production of IFN-γ by antigen experienced CD3+CD8+CD44high cells, 2) production of Granzyme B by CD27lowCD43low antigen-experienced CD8+ T cells, 3) generation of memory-type CD8+ T cells [Memory Precursor Effector Cells (MPECs), as well as CD127highCD43low, and CD27highCD43low CD8+ T cells], and 4) generation of effector-like memory CD8+ T cells (CD27lowCD43low). We propose that these correlates could be useful for the general assessment of the quality of the CD8+ T cell immune response induced by novel antigens with potential use in a vaccine against Rickettsia.

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Section: Discussionsupporting

confidence: 83%

Phenotype of the anti-Rickettsia CD8+ T cell response suggests cellular correlates of protection for the assessment of novel antigens

Caro-Gómez

Gaži

Cespedes

et al. 2014

Vaccine

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“…WT mice survived this challenge, yet mice lacking T-bet succumbed to infection between days 9 and 14 post-infection (Figure 3a). In many instances, susceptibility to T. gondii is either a consequence of an inability to control parasite replication (21, 38, 39) or the development of T cell-mediated immune pathology (40–43). In order to determine the cause of the increased mortality seen in T-bet −/− mice, parasite burden and levels of immune-mediated damage were assessed.…”

Section: Resultsmentioning

confidence: 99%

Diverse Roles for T-bet in the Effector Responses Required for Resistance to Infection

Pritchard

Hall

Christian

et al. 2015

The Journal of Immunology

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The transcription factor T-bet has been most prominently linked to natural killer (NK) and T cell production of interferon-γ (IFN-γ), a cytokine required for the control of a diverse array of intracellular pathogens. Indeed, in mice challenged with the parasite Toxoplasma gondii, NK and T cell responses are characterized by marked increases of T-bet expression. Unexpectedly, T-bet−/− mice infected with T. gondii develop a strong NK cell IFN-γ response that controls parasite replication at the challenge site, but display high parasite burdens at secondary sites colonized by T. gondii and succumb to infection. The loss of T-bet had a modest effect on T cell production of IFN-γ but did not impact on the generation of parasite-specific T cells. However, the absence of T-bet resulted in lower T cell expression of CD11a, Ly6C, KLRG-1, and CXCR3 and fewer parasite-specific T cells at secondary sites of infection, associated with a defect in parasite control at these sites. Together, these data highlight T-bet independent pathways to IFN-γ production, and reveal a novel role for this transcription factor in coordinating the T cell responses necessary to control this infection in peripheral tissues.

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“…gondii (Kugler et al, 2013), only limited recovery in thymocyte numbers in WT mice was observed during the chronic phase of infection ( Fig. 6 A), although overall thymocyte composition appeared to normalize ( Fig.…”

Section: Persistent Loss Of Thymic Function During Chronic T Gondii mentioning

confidence: 97%

“…We have previously shown that GCs are induced during acute T. gondii infection (Kugler et al, 2013), and this type of stress response is known to lead to thymic atrophy caused by loss of CD4 + CD8 + (double-positive; DP) thymocytes. Nevertheless, in T. gondii-infected mice, the loss in thymocytes was more general and not restricted to this DP population ( Fig.…”

Section: T Gondii Infection Induces a Persistent Thymic Atrophy Thatmentioning

confidence: 99%

Systemic toxoplasma infection triggers a long-term defect in the generation and function of naive T lymphocytes

et al. 2016

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CD4+ T cells are trigger and target of the glucocorticoid response that prevents lethal immunopathology in toxoplasma infection

Abstract: CD4+ T cells regulate their own activity during toxoplasma infection by driving a glucocorticoid response, which results in feedback inhibition of Th1 cytokine production.

Cited by 49 publications

References 30 publications

Phenotype of the anti-Rickettsia CD8+ T cell response suggests cellular correlates of protection for the assessment of novel antigens

Phenotype of the anti-Rickettsia CD8+ T cell response suggests cellular correlates of protection for the assessment of novel antigens

Diverse Roles for T-bet in the Effector Responses Required for Resistance to Infection

Systemic toxoplasma infection triggers a long-term defect in the generation and function of naive T lymphocytes

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