De Novo NAD+ Biosynthetic Impairment in Acute Kidney Injury in Humans
Poyan Mehr A, Tran MT, Ralto KM, et al. Nat Med. 2018;24:1351-1359.
Acute kidney injury (AKI) plays an important role for clinical outcomes in patients admitted to intensive care units or after major surgeries. In kidney transplant patients, delayed graft function secondary to AKI is an important and common clinical finding. Having a biomarker for this condition would be extremely useful to avoid many biopsies in patients with delayed graft function.
The authors identified a relationship between Nicotinamide adenine dinucleotide (NAD+) biosynthesis and AKI. A mouse model was used to explore the consequences of a transient renal ischemic episode resulting in AKI.
With an impaired NAD+ biosynthesis, mice were more prone to develop AKI. Mechanisms included a compromised ability to produce quinolinate phosphoribosyltransferase, resulting in a reduced expression of urinary quinolinate. Moreover, with an impaired NAD+ biosynthesis, an elevated ratio of urinary quinolinate to tryptophan (UQ/T) was observed representing a potential new biomarker for AKI. Finally, when administrating nicotinamide (a precursor of NAD+) before renal ischemia, mice were less prone to develop AKI, suggesting a role of NAD+ metabolism for renal protection.
To assess the clinical relevance of their experimental findings, the authors evaluated 12 patients undergoing cardiac surgery—6 who developed postoperative AKI and 6 who did not. Notably, in patients that developed AKI, UQ/T levels significantly increased by 24 h and persisted for 5 days after surgery.
In a separate large prospective study that included 215 patients admitted to intensive care unit, the authors found elevated UQ/T levels 2.5 days prior to the clinical diagnosis of AKI. Importantly, UQ/T levels identified patients at risk of developing AKI and predicted adverse clinical outcomes.
This important study presents a novel and clinically relevant biomarker and suggests a potential treatment option for AKI.
Differential IL-2 Expression Defines Developmental Fates of Follicular Versus Nonfollicular Helper T Cells
DiToro D, Winstead CJ, Pham D, et al. Science. 2018;361(1086).
Here, the authors delineated the impact of interleukin 2 (IL-2) production on the development of CD4+ T cells. Moreover, they investigated mechanisms that control the differentiation of DC4+ T cells into either T follicular helper (TFH) cells or non-TFH effector cells. These 2 subsets of T cells perform different functions: TFH cells are programmed to interact with B cells within lymphoid tissues to support production of high-affinity, class-switched antibodies, whereas non-TFH effector cells are programmed to egress from lymphoid tissues orchestrating innate immune cell function at sites of pathogen entry.
Interleukin-2 is produced by a subset of activated naïve T cells, suggesting a possible relationship between IL-2 production and effector cell fate determination. Therefore IL-2 may serve as an early marker of CD4+ T cells determination.
The authors developed 2 IL-2 reporter mice strains with complementary features that enabled the tracking and deletion of T cells based on differential IL-2 expression. They found that L-2 producers give rise to TFH cells, whereas IL-2 nonproducers give rise to non-TFH effector cells.
Naïve T cells that receive differing strengths of TCR signals stratify into those that exceed a threshold predisposing them to either IL-2 production and early TFH commitment or those that do not express IL-2. Therefore, IL-2 may serve as an early marker for T cell fate. Moreover, findings of the study by DiToro and others may also open the door to determine mechanisms of TFH and non-TFH effector cell differentiation in more detail.
Clinically, novel strategies modulating the balance of effector T cell responses may be developed based on the findings by DiToro.