Recurrent Sepsis Exacerbates CD4+ T Cell Exhaustion and Decreases Antiviral Immune Responses

He, Wanxue; Xiao, Kun; Xu, Jiaruo; Guan, Wei; Xie, Sheling; Wang, Kaifei; Peng, Yan; Fang, Min; Xie, Lixin

doi:10.3389/fimmu.2021.627435

Cited by 19 publications

(27 citation statements)

References 63 publications

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“…Research on the epidemiology, prevention, and management of sepsis is an important topic for critical care medicine, surgery, and anesthesiology, where clarification of the complex pathophysiological mechanism of sepsis is a fundamental problem (14,23,24). Since 1992, the definitions of sepsis, severe sepsis, and septic shock, as well as associated clinical and laboratory studies have relied on the presence of infection and the characteristics of systemic inflammatory response syndrome (SIRS) (1,(24)(25)(26)(27)(28).…”

Section: Sepsismentioning

confidence: 99%

“…Compelling experimental and clinical evidence has indicated that sepsis is a multi-dimensional heterogeneous syndrome, which is reflected in the host's variable immune responses (23,135,136). (40,76,80); therefore, these studies do not fully reflect the heterogeneous characteristics of sepsis (91,135).…”

Section: Host-dependent Treg Patterns In Sepsismentioning

confidence: 99%

“…Some evidence demonstrates that ICU-acquired infections contribute to the overall mortality of septic patients. Patients with septic shock who have secondary infections are at a 5.8 times higher risk of late-stage death than those without because of their unique immunosuppressive status, especially T cell exhaustion caused by aging and recurrent sepsis (2,23,52,59,142). In a clinically relevant cecal slurry (CS) induced model of recurrent sepsis, increased T cell exhaustion and poor prognosis (including reduced survival rate and body weight) was observed in aged (18-24 months old) compared with young (5 week old) female or male C57BL6/J mice.…”

Section: Host-dependent Treg Patterns In Sepsismentioning

confidence: 99%

“…Thus, a 106 times higher (1-25 mg/kg) dose is required for mice compared to humans, who only need 2-4 ng/kg to induce SIRS (124,162,176). Furthermore, in most current experiments using LPS, the regimens and dosages of LPS vary widely among different mouse strains, animal ages, and animal facilities (23,70,87,98,109,117,118). For example, BALB/c mice induced by intraperitoneal injection of LPS (0.2 mg/g of body weight or 5 mg/ mouse per day) for 5 consecutive days, showed significant decreases of CD4+, CD8+, CD3z+, and CD19+ cells and an increase of the percentage of CD25+Foxp3+ Tregs, accompanied with increased production of IL-6, TNF-a, and IL-18 in the serum.…”

Section: Limitations Of Treg Models In Sepsismentioning

confidence: 99%

“…Due to their relatively stable genetic uniformity, inbred BALB/c and C57BL/6 mice are most frequently used in sepsisrelated studies (47,59,65,70,83,86,98,118,177). Nevertheless, researchers are beginning to emphasize the importance of using genetically heterogeneous organisms in experiments since they can better simulate the heterozygosity of humans, especially in multi-dimensional heterogeneous syndromes such as sepsis (19,23,67,85,100,135,136). BALB/c (inbred) and CD-1 (outbred) mice underwent unilateral femoral fracture, splenectomy, and hemorrhagic shock, with increased circulating granulocytes (LY6G+CD11+) in both strains at 24 and 48 hours later.…”

Section: Limitations Of Treg Models In Sepsismentioning

confidence: 99%

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Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

et al. 2022

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Sepsis is a syndrome characterized by life-threatening organ dysfunction caused by the dysregulated host response to an infection. Sepsis, especially septic shock and multiple organ dysfunction is a medical emergency associated with high morbidity, high mortality, and prolonged after-effects. Over the past 20 years, regulatory T cells (Tregs) have been a key topic of focus in all stages of sepsis research. Tregs play a controversial role in sepsis based on their heterogeneous characteristics, complex organ/tissue-specific patterns in the host, the multi-dimensional heterogeneous syndrome of sepsis, the different types of pathogenic microbiology, and even different types of laboratory research models and clinical research methods. In the context of sepsis, Tregs may be considered both angels and demons. We propose that the symptoms and signs of sepsis can be attenuated by regulating Tregs. This review summarizes the controversial roles and Treg checkpoints in sepsis.

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Section: Sepsismentioning

confidence: 99%

Section: Host-dependent Treg Patterns In Sepsismentioning

confidence: 99%

Section: Host-dependent Treg Patterns In Sepsismentioning

confidence: 99%

Section: Limitations Of Treg Models In Sepsismentioning

confidence: 99%

Section: Limitations Of Treg Models In Sepsismentioning

confidence: 99%

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Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

et al. 2022

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Immunosenescence: an unexplored role in glomerulonephritis

2022

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Immunosenescence is a natural ageing phenomenon with alterations in innate and especially adaptive immunity and contributes to reduced antimicrobial defence and chronic low‐grade inflammation. This is mostly reflected by an increase in organ‐directed and/or circulating reactive and cytolytic terminally differentiated T cells that have lost their expression of the costimulatory receptor CD28. Apart from being induced by a genetic predisposition, ageing or viral infections (particularly cytomegalovirus infection), immunosenescence is accelerated in many inflammatory diseases and uraemia. This translates into an enhancement of vascular inflammation and cardiovascular disease varying from endothelial dysfunction to plaque rupture. Emerging data point to a mechanistic role of CD28null T cells in glomerulonephritis, where they initiate and propagate local inflammation in concordance with dendritic cells and macrophages. They are suitably equipped to escape immunological dampening by the absence of homing to lymph nodes, anti‐apoptotic properties and resistance to suppression by regulatory T cells. Early accumulation of senescent CD28null T cells precedes glomerular or vascular injury, and targeting these cells could open avenues for early treatment interventions that aim at abrogating a detrimental vicious cycle.

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Inhibition of endoplasmic reticulum stress and the downstream pathways protects CD4⁺ T cells against apoptosis and immune dysregulation in sepsis

Lü

et al. 2022

IUBMB Life

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Immunosuppression mediated by CD4 + T cell apoptosis and dysfunction is a key factor in promoting the progression of sepsis. Endoplasmic reticulum (ER) stress participates in the apoptosis and dysfunction of immune cells. We aimed to investigate the role of ER stress inhibition in CD4 + T cells in both in vitro and in vivo models of sepsis. In vitro model of sepsis was established with lipopolysaccharide (LPS) and the rat model of sepsis was established using cecal ligation and puncture (CLP). After the LPS treatment or CLP, ER stress inhibitors including 4-PBA, SNJ-1945, and SP600125 were used to treat cells or rats, and the CD4 + T cells were obtained by magnetic bead sorting. The effects of ER stress inhibitors on apoptosis and the function of CD4 + T cells were evaluated. After the LPS stimulation or CLP, the levels of ER stress and downstream markers (PERK, eIF2α, IRE-1α, ATF6, ATF4, XBP-1 s, GRP78, CHOP, and p-JNK) were increased in CD4 + T cells at the beginning of sepsis. Meanwhile, the number of apoptotic CD4 + T cells markedly increased. In addition, sepsis impaired the function of CD4 + T cells, manifested by the increased population of Th1, Th2, Th17, and Treg, as well as the production of TNF-α, interleukin (IL)-6, IL-4, and IL-10. However, inhibitors of ER stress, JNK, and calpain all decreased the induction of Th1 and Th17, enhanced the increase of Th2 and Treg, decreased the production of TNF-α and IL-6, and enhanced the production of IL-4 and IL-10. Our findings indicate that ER stress inhibitors may play a protective role by reducing CD4 + T cell apoptosis and maintaining CD4 + T cell function, which may be useful for enhancing the immune function and poor prognosis of patients with sepsis.

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Recurrent Sepsis Exacerbates CD4+ T Cell Exhaustion and Decreases Antiviral Immune Responses

Cited by 19 publications

References 63 publications

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

Immunosenescence: an unexplored role in glomerulonephritis

Inhibition of endoplasmic reticulum stress and the downstream pathways protects CD4⁺ T cells against apoptosis and immune dysregulation in sepsis

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Recurrent Sepsis Exacerbates CD4+ T Cell Exhaustion and Decreases Antiviral Immune Responses

Cited by 19 publications

References 63 publications

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

Immunosenescence: an unexplored role in glomerulonephritis

Inhibition of endoplasmic reticulum stress and the downstream pathways protects CD4+ T cells against apoptosis and immune dysregulation in sepsis

Contact Info

Product

Resources

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Inhibition of endoplasmic reticulum stress and the downstream pathways protects CD4⁺ T cells against apoptosis and immune dysregulation in sepsis