Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion

Condotta, Stephanie A.; Khan, Shaniya H.; Rai, Deepa; Griffith, Thomas S.; Badovinac, Vladimir P.

doi:10.4049/jimmunol.1402473

Cited by 53 publications

(63 citation statements)

References 69 publications

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“…Due to the importance of CD4 T cells in protection and memory against pathogens, understanding the role of microbiota on T cell responses to infection is crucial. It was assumed the intestinal commensals played a detrimental role in promoting systemic inflammation or infection in critically ill septic patients (27), where suppression of T cell immunity (6-9) and apoptosis of epithelial barriers (28) are recognized complications. With this in mind, we performed quantitative and qualitative analyses of CD4 T cell populations specific for Ag expressed by gut resident microbes in septic mice.…”

Section: Discussionmentioning

confidence: 99%

“…One reason for the high mortality rate from sepsis is the profound acute lymphopenia seen in humans and mouse models, such as cecal ligation and puncture (CLP) (2). The numerical reduction of multiple immune cell populations in septic individuals, including naïve and memory T cells, is typically observed as lymphopenia followed by prolonged immune suppression (immunoparalysis (3)) that decreases the ability of the host to respond to secondary infections (4-9). Consequently, understanding the mechanism(s) the lead to the immunoparalysis and susceptibility to pathogens normally cleared by the immune system in healthy individuals (10) are essential in developing future therapies for the medical management of sepsis.…”

Section: Introductionmentioning

confidence: 99%

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Gut Microbial Membership Modulates CD4 T Cell Reconstitution and Function after Sepsis

Cabrera-Pérez

Babcock

Dileepan

et al. 2016

The Journal of Immunology

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Transient lymphopenia is one hallmark of sepsis, and emergent data indicates the CD4 T cell compartment in sepsis survivors is numerically and functionally altered (when examined at the Ag-specific level) compared to non-septic controls. Previous data from our laboratory demonstrated Ag-independent, lymphopenia-induced homeostatic proliferation to be a contributing mechanism by which CD4 T cells numerically recover in sepsis survivors. However, we reasoned it is also formally possible that some CD4 T cells respond directly to Ag expressed by gut resident microbes released during polymicrobial sepsis. The effect of gut microbiome leakage on CD4 T cells is currently unknown. In this study, we explored the number and function of endogenous CD4 T cells specific for segmented filamentous bacterium (SFB) after cecal ligation and puncture (CLP)-induced sepsis using mice that either contained or lacked SFB as a normal gut resident microbe. Interestingly, SFB-specific CD4 T cells underwent Ag-driven proliferation in CLP-treated SFB+, but not in SFB−, mice. Moreover, CLP-treated SFB+ mice showed resistance to secondary lethal infection with recombinant SFB Ag-expressing virulent Listeria (but not wildtype virulent Listeria) suggesting the CLP-induced polymicrobial sepsis primed for a protective response by the SFB-specific CD4 T cells. Thus, our data demonstrate that the numerical recovery and functional responsiveness of Ag-specific CD4 T cells in sepsis survivors is, in part, modulated by the intestinal barrier’s “health” discreetly defined by individual bacterial populations of the host’s microbiome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gut Microbial Membership Modulates CD4 T Cell Reconstitution and Function after Sepsis

Cabrera-Pérez

Babcock

Dileepan

et al. 2016

The Journal of Immunology

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“…Polymicrobial sepsis was induced by CLP (11, 12, 43). Briefly, mice were anesthetized, the abdomen was shaved, disinfected, and a midline incision was made.…”

Section: Methodsmentioning

confidence: 99%

Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo

Strother

Danahy

Kotov

et al. 2016

The Journal of Immunology

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Patients surviving acute stages of sepsis often display impaired adaptive immune responses. Using the cecal ligation and puncture (CLP) model, we demonstrated that sepsis leads to substantial and long-lasting changes in the naïve CD8 T-cell repertoire affecting the capacity of the host to respond to new infections. However, the identity of CD8 T-cell extrinsic factor(s) and mechanism(s) that contribute to impaired CD8 T-cell responses after sepsis is currently unknown. Priming of naïve CD8 T-cells is critically dependent on the ability of dendritic cells (DCs) to provide Ag, co-stimulation, and inflammatory “signal 3” cytokines, therefore the sepsis-induced changes in the DC compartment might represent a contributing factor leading to diminished CD8 T-cell immunity in septic hosts. In a direct test of this hypothesis we show that in addition to numerical decline, sepsis leads to functional impairments in DCs diminishing their capacity to produce cytokines upon TLR stimulation in vitro or after infection in vivo. Importantly, we demonstrated a direct link between DC dysfunction and impairments in CD8 T-cell immunity after sepsis by directly targeting Ag to DCs. Finally, post-sepsis Flt3 ligand (Flt3L) treatment increased the number of DCs and improved DC function, including the ability to sense inflammation and produce IL-12 leading to improved primary CD8 T-cell responses to newly encountered antigens. Thus, sepsis-induced numerical and functional loss of DCs contributes to the observed defects in CD8 T-cell immunity, and therapeutic approaches designed to improve the status of the DC compartment after sepsis might facilitate the recovery of CD8 T-cell immunity.

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“…3). 69,74 The data also suggested that, due to the stochastic nature of the sepsis-induced changes in the composition of naive CD8 T cells, potential “holes” in the CD8 T-cell repertoire can be formed, further contributing to the reduction in primary CD8 T-cell responses to new infections in sepsis survivors. 69,96 Attempts to reverse the sepsis-induced reduction in the number of naive T cells has used exogenous addition of the prosurvival cytokines IL-7 and IL-15, which enhances T-cell expression of Bcl-2 and demonstrates some efficacy in experimental models.…”

Section: Role Of Sepsis In Shaping T-cell Responses To Newly Encomentioning

confidence: 98%

“…PD-1 and LAG-3), leading to increased viral burden. 74 Importantly, the impairments in the CD8 T-cell response to chronic infections were seen long after the initial septic event resolved. 74 Amelioration of the sepsis-enhanced CD8 T-cell exhaustion and improved control of chronic infection could be achieved in mice that received therapeutic blockade of PD-1 and LAG3.…”

Section: Role Of Sepsis In Shaping T-cell Responses To Newly Encomentioning

confidence: 99%

Clinical and Experimental Sepsis Impairs CD8 T-Cell-Mediated Immunity

et al. 2016

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Septic patients experience chronic immunosuppression resulting in enhanced susceptibility to infections normally controlled by T cells. Clinical research on septic patients has shown increased apoptosis and reduced total numbers of CD4 and CD8 T cells, suggesting contributing mechanism driving immunosuppression. Experimental models of sepsis, including cecal ligation and puncture, reverse translated this clinical observation to facilitate hypothesis-driven research and allow the use of an array of experimental tools to probe the impact of sepsis on T-cell immunity. In addition to numerical loss, sepsis functionally impairs the antigen-driven proliferative capacity and effector functions of CD4 and CD8 T cells. Sepsis-induced impairments in both the quantity and quality of T cells results in reduced protective capacity and increased susceptibility of mice to new or previously encountered infections. Therefore, the combined efforts of clinical and experimental sepsis research have begun to elucidate the impact of sepsis on T-cell-mediated immunity and potential T-cell-intrinsic and -extrinsic mechanisms driving chronic immunosuppression. Future work will explore the impact of sepsis on the recently appreciated tissue-resident memory (TRM) T cells, which provide robust protection against localized infections, and dendritic cells, which are needed to activate T cells and promote effective T-cell responses.

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Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion

Cited by 53 publications

References 69 publications

Gut Microbial Membership Modulates CD4 T Cell Reconstitution and Function after Sepsis

Gut Microbial Membership Modulates CD4 T Cell Reconstitution and Function after Sepsis

Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo

Clinical and Experimental Sepsis Impairs CD8 T-Cell-Mediated Immunity

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