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

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. It is a disease with a high incidence, mortality, and recurrence rate and frequently results in its survivors requiring readmission into hospitals. The readmission is mainly due to recurrent sepsis. Patients with recurrent sepsis are more susceptible to secondary infections partly due to immune dysfunction, leading to a higher mortality in the long term. However, there remains a gap in the understanding of immunological characteristics and underlying mechanisms of recurrent sepsis. In this study, we used mouse models of acute and recurrent sepsis to investigate their different immunological characteristics. And then we subjected the two mouse models to a secondary influenza A virus (H1N1) infection and characterized the different immune responses. Here, we demonstrated that CD4+ T cells present an exacerbated exhaustion phenotype in response to recurrent sepsis as illustrated by the decreased frequency of CD4+ T cells, reduced co-stimulatory CD28 and increased inhibitory PD-1 and Tim-3 expression on CD4+ T cells, increased frequency of regulatory T cells, and reduced MHC-II expression on antigen-presenting cells. Moreover, we showed that antiviral immune responses decrease in the recurrent sepsis mouse model subjected to a secondary infection as illustrated by the reduced pathogen clearance and inflammatory response. This may be a consequence of the exacerbated CD4+ T cell exhaustion. In summary, recurrent sepsis exacerbates CD4+ T cell exhaustion and decreases antiviral immune responses, contributing to significant morbidity, increased late mortality, and increased health care burden in recurrent sepsis patients.

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

“…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).…”

“…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).…”

“…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.…”

“…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.…”

“…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.…”