T cells from patients with Candida sepsis display a suppressive immunophenotype

Spec, Andrej; Shindo, Yuichiro; Burnham, Carey-Ann D.; Wilson, Strother; Ablordeppey, Enyo; Beiter, Evan R.; Chang, Katherine; Drewry, Anne M.; Hotchkiss, Richard S.

doi:10.1186/s13054-016-1182-z

Cited by 102 publications

(90 citation statements)

References 35 publications

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“…Patients suffering from C. albicans fungal sepsis display elevated levels of PD-1 on CD8 + T cells, as well as increased expression of PD-L1 on both CD4 + and CD8 + T cells [114]. In this study, the control group was critically ill non-septic patients with no evidence of fungal infection, suggesting that septic infection with the fungal pathogen C. albicans was an important and specific determinant in activation of the PD signaling pathway.…”

Section: Immunoregulatory Signaling Pathwaysmentioning

confidence: 94%

Immunoregulation in Fungal Diseases

2016

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This review addresses specific regulatory mechanisms involved in the host immune response to fungal organisms. We focus on key cells and regulatory pathways involved in these responses, including a brief overview of their broader function preceding a discussion of their specific relevance to fungal disease. Important cell types discussed include dendritic cells and regulatory T cells, with a focus on specific studies relating to their effects on immune responses to fungi. We highlight the interleukin-10, programmed cell death 1, and cytotoxic T lymphocyte-associated protein 4 signaling pathways and emphasize interrelationships between these pathways and the regulatory functions of dendritic cells and regulatory T cells. Throughout our discussion, we identify selected studies best illustrating the role of these cells and pathways in response to specific fungal pathogens to provide a contextual understanding of the tightly-controlled network of regulatory mechanisms critical to determining the outcome of exposure to fungal pathogens. Lastly, we discuss two unique phenomena relating to immunoregulation, protective tolerance and immune reactivation inflammatory syndrome. These two clinically-relevant conditions provide perspective as to the range of immunoregulatory mechanisms active in response to fungi.

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Section: Immunoregulatory Signaling Pathwaysmentioning

confidence: 94%

Immunoregulation in Fungal Diseases

2016

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“…Given the fundamental role of Th17 in eradication of pathologic fungal infections, reduced Th17 cytokine production in sepsis is probably responsible for the increased susceptibility to fungal infections frequently observed in critically ill populations . Circulating CD4 + and CD8 + cells from patients with candidemia display an immune phenotype consistent with immune suppression, T‐cell exhaustion, and downregulation of positive co‐stimulatory molecules . Moreover, IL‐7 treatment has been demonstrated to increase Th17 cell responsiveness and reduce mortality from secondary fungal infections, making IL‐17 a potential therapeutic agent .…”

Section: Adaptive Immunitymentioning

confidence: 99%

“…190 Circulating CD4 + and CD8 + cells from patients with candidemia display an immune phenotype consistent with immune suppression, T-cell exhaustion, and downregulation of positive co-stimulatory molecules. 191 Moreover, IL-7 treatment has been demonstrated to increase Th17 cell responsiveness and reduce mortality from secondary fungal infections, making IL-17 a potential therapeutic agent. 177 These findings may help explain why patients with fungal sepsis have a high mortality despite appropriate antifungal therapy.…”

Section: T H Cell Subpopulationsmentioning

confidence: 99%

The immune system's role in sepsis progression, resolution, and long‐term outcome

Delano

Ward

2016

Immunological Reviews

620

488

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SUMMARY Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after “recovery” from acute events. Since so many sepsis survivors succumb later to persistent, recurrent, nosocomial and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality.

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“…T cell proliferation is also impaired during sepsis [22, 23, 51, 71]. Recent reports show that PD-1 expression is significantly increased on peripheral blood CD4+ and CD8+ T cells during Candida bloodstream infection associated with CD8+ T cell activation (increased CD69 expression), a decrease in co-stimulatory CD28 expression and IL-7R expression [72]. Another prospective clinical study showed that as sepsis progressed, T lymphocytes in blood show increased expression of TIM-3, LAG-3, CTLA-4 and decreased IL-7R expression and IFN-γ secretion upon ex vivo simulation, along with an increased PD-L1 expression on dendritic cells [56].…”

Section: Sepsis-induced T Cell Dysfunctionmentioning

confidence: 99%

Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression

Patil

Bohannon

Sherwood

2016

Pharmacological Research

135

123

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Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host responses to infection (Third International Consensus definition for Sepsis and septic shock). Despite decades of research, sepsis remains the leading cause of death in intensive care units. More than 40 clinical trials, most of which have targeted the sepsis-associated pro-inflammatory response, have failed. Thus, antibiotics and fluid resuscitation remain the mainstays of supportive care and there is intense need to discover and develop novel, targeted therapies to treat sepsis. Both pre-clinical and clinical studies over the past decade demonstrate unequivocally that sepsis not only causes hyper-inflammation, but also leads to simultaneous adaptive immune system dysfunction and impaired antimicrobial immunity. Evidences for immunosuppression include immune cell depletion (T cells most affected), compromised T cell effector functions, T cell exhaustion, impaired antigen presentation, increased susceptibility to opportunistic nosocomial infections, dysregulated cytokine secretion, and reactivation of latent viruses. Therefore, targeting immunosuppression provides a logical approach to treat protracted sepsis. Numerous pre-clinical studies using immunomodulatory agents such as interleukin-7, anti-programmed cell death 1 antibody (anti-PD-1), anti-programmed cell death 1 ligand antibody (anti-PD-L1), and others have demonstrated reversal of T cell dysfunction and improved survival. Therefore, identifying immunosuppressed patients with the help of specific biomarkers and administering specific immunomodulators holds significant potential for sepsis therapy in the future. This review focusses on T cell dysfunction during sepsis and discusses the potential immunotherapeutic agents to boost T cell function during sepsis and improve host resistance to infection.

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T cells from patients with Candida sepsis display a suppressive immunophenotype

Cited by 102 publications

References 35 publications

Immunoregulation in Fungal Diseases

Immunoregulation in Fungal Diseases

The immune system's role in sepsis progression, resolution, and long‐term outcome

Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression

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