Adaptive and Innate TH1 and TH17 Responses in Elderly Hospitalised Patients with Infection and Sepsis

Abstract

Introduction: Sepsis carries a significant burden to health care. Almost a third of ICU patients have sepsis on admission or develop it during their admission. Sepsis carries a high mortality and affects all age groups but becomes more common with a rising mortality in the ageing population. Sepsis accounts for up to 63% of acute medical admissions to ICU for the age group of >60. Current treatment remains limited to antibiotics and good supportive care, as the pathophysiology of sepsis remains somewhat of a conundrum, and outcomes remain largely unchanged over the last few decades. Thus an improved understanding of the pathophysiology of sepsis is a prerequisite to the adoption of novel treatments into clinical practice. This study sought to examine the TH1 and TH17 response in adaptive and innate immunity in patients with sepsis. TH1 response to produce interferon-γ (IFN-γ) is classically stimulated by IL-12 and facilitated by the transcription factor T-Bet. TH17 response to produce IL-17A is classically stimulated by IL-23 and facilitated by the transcription factor RORγt. Methods: A prospective observational study of T cell immunophenotypes, followed by cell stimulation to assess the function of these cells (expression of transcription factors T-Bet and RORγt, and expression of IFN-γ and IL-17A) was performed. Flow cytometry was used extensively. The study compared 30 controls, 30 patients with infection but not sepsis, and 42 patients with sepsis. The patients with infection were sampled over 2 time points a week apart, and patients with sepsis were sampled on 4 time points a week apart to assess changes over time. Cell differentiation status was also examined. Patients who were immunocompromised were excluded. Results for adaptive T cell immunity: Circulating CD4+ T cells from patients with infection predominantly expressed effector-memory or terminally differentiated phenotypes, while CD4+ T cells from patients with severe sepsis predominantly expressed naive phenotypes (p<0.0001). CD4+ T cells expressing IL-23 receptor were less frequently found in patients with sepsis compared to patients with infection alone (p=0.007). RORγt expression by CD4+ T cells was less frequent in patients with sepsis (p<0.001), whereas T-Bet expressing CD8+ T cells, that did not express RORγt, were less frequent in the sepsis patients. HLA- DR expression by monocytes was lower in patients with sepsis. In septic patients fewer monocytes expressed IL-23. Results for innate T cell immunity: Mucosal-associated invariant T (MAIT) cell counts were lower in the septic group (p = 0.002) and the infection group (p < 0.001) than in the control group. MAIT cell T-Bet expression in the infection group was greater than in the septic group (p = 0.012). MAIT RORγt expression in the septic group was lower than in the control group (p = 0.003). The natural killer (NK) cell counts differed in the three groups (p < 0.001), with lower NK cell counts in the septic group (p < 0.001) and in the infection group (p = 0.001) than in the control group. The NK cell counts increased in the septic group in the 3 weeks following the onset of sepsis (p = 0.028). In lymphocyte stimulation experiments, fewer NK cells expressed T-Bet in the septic group than in the infection group (p = 0.002), and fewer NK cells expressed IFN-γ in the septic group than in the control group (p = 0.002). Natural killer T (NKT) cell counts were lower in the septic group than both the control group (p = 0.05) and the infection group (p = 0.04). Fewer NKT cells expressed T-Bet in the septic group than in the infection group (p = 0.004). Fewer NKT cells expressed RORγt in the septic group than in the control group (p = 0.003). Fewer NKT cells expressed IFN-γ in the septic group than in both the control group (p = 0.002) and the infection group (p = 0.036). Conclusion: Persistent failure of adaptive T cell activation was observed in patients with sepsis. Sepsis was associated with attenuated CD8+ TH1 and CD4+ TH17 based lymphocyte response. In sepsis failure of T lymphocyte activation may in turn be related to maladaptive responses in antigen presenting cells. The clinical presentation of infection and or sepsis in patients is linked with a mosaic of changes in the innate lymphocyte TH1 and TH17 phenotypes. The manipulation of the T lymphocyte phenotype offers a potential avenue for immune modulation in patients with sepsis and warrants further studies.