Sepsis shapes the human γδ TCR repertoire in an age- and pathogen-dependent manner.

Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T-cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0-16 years) with blood culture-proven bacterial sepsis caused by HMBPP-positive Escherichia coli or by HMBPP-negative Staphylococcus aureus or by HMBPP-negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal-derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens.

Destabilisation of T cell-dependent humoral immunity in sepsis.

Sepsis is a heterogeneous condition defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For some, sepsis presents as a predominantly suppressive disorder, whilst others experience a pro-inflammatory condition which can culminate in a 'cytokine storm'. Frequently, patients experience signs of concurrent hyper-inflammation and immunosuppression, underpinning the difficulty in directing effective treatment. Although intensive care unit mortality rates have improved in recent years, one-third of discharged patients die within the following year. Half of post-sepsis deaths are due to exacerbation of pre-existing conditions, whilst half are due to complications arising from a deteriorated immune system. It has been suggested that the intense and dysregulated response to infection may induce irreversible metabolic reprogramming in immune cells. As a critical arm of immune protection in vertebrates, alterations to the adaptive immune system can have devastating repercussions. Indeed, a marked depletion of lymphocytes is observed in sepsis, correlating with increased rates of mortality. Such sepsis-induced lymphopenia has profound consequences on how T cells respond to infection but equally on the humoral immune response that is both elicited by B cells and supported by distinct CD4+ T follicular helper (TFH) cell subsets. The immunosuppressive state is further exacerbated by functional impairments to the remaining lymphocyte population, including the presence of cells expressing dysfunctional or exhausted phenotypes. This review will specifically focus on how sepsis destabilises the adaptive immune system, with a closer examination on how B cells and CD4+ TFH cells are affected by sepsis and the corresponding impact on humoral immunity.

Weight gain leads to greater adverse metabolic responses in South Asian compared with white European men: the GlasVEGAS study.

South Asians (SAs) develop type 2 diabetes at lower body mass index values than white Europeans (WEs). This basic human experimental study aimed to compare the metabolic consequences of weight gain in SA and WE men without overweight or obesity. Fourteen SAs and 21 WEs had assessments of body composition, metabolic responses to mixed-meal ingestion, cardiorespiratory fitness and physical activity, and a subcutaneous abdominal adipose tissue biopsy, before and after 4-6 weeks of overfeeding to induce 5-7% weight gain. Here we show that body mass index and whole-body adipose tissue volume increases similarly between ethnic groups, but SAs gain less lean tissue. SAs experience a substantially greater decrease in insulin sensitivity compared with WEs (38% versus 7% decrease, P = 0.009), have fewer small (37.1% versus 60.0%, P = 0.003) and more large (26.2% versus 9.1%, P = 0.005) adipocytes at baseline and have a smaller decrease in very small adipocytes with weight gain (-0.1% versus -1.9%, P < 0.0001). Ethnic differences in adipocyte morphology are associated with SA's greater adverse metabolic changes with weight gain. ClinicalTrials.gov registration: NCT02399423 .

Flash Glucose Monitoring is Associated with HbA1c Improvement in Type 2 Diabetes Managed with Multiple Daily Injections of Insulin in the UK: A Retrospective Observational Study.

INTRODUCTION: There is a growing body of evidence demonstrating the benefit of flash glucose monitoring in people living with type 2 diabetes mellitus (T2DM). This real-world study aimed to evaluate the effect of initiating flash glucose monitoring on change in HbA1c after 3-6 months in adults living with T2DM treated with multiple daily injections of insulin. METHODS: A retrospective observational study using data from ten clinical centres in the UK for adults with T2DM treated with multiple daily injections of insulin for at least 1 year was conducted. Patients who had been using the FreeStyle Libre/Libre 2 Flash Glucose Monitoring System for at least 3 months with baseline HbA1c 64-108 mmol/mol (8.0-12.0%) recorded up to 3 months prior to system use were included. Pregnant patients and those on dialysis were excluded. Patients with an HbA1c value measured 3-6 months after commencing flash glucose monitoring were included in the final analysis for evaluation of change. RESULTS: In total, 87 patients were included in the final analysis (mean age, 60.0 ± 11.8 years, 60.9% male, mean body mass index (BMI), 31.6 ± 5.4 [mean ± SD]). From a mean baseline HbA1c of 80 ± 11 mmol/mol (9.5% ± 1.0%), HbA1c lowered by 11 ± 14 mmol/mol (1.0% ± 1.3%) at 3-6 months (p < 0.0001). A decrease was observed independent of age, baseline HbA1c, sex, duration of insulin use and BMI subgroups. CONCLUSIONS: Initiation of flash glucose monitoring was associated with a clinically and statistically significant improvement in HbA1c in a real-world setting at 3-6 months.