Publications by authors named "T A Walzer"
Resting natural killer (NK) cells display immediate effector functions after recognizing transformed or infected cells. The environmental nutrients and metabolic requirements to sustain these functions are not fully understood. Here, we show that NK cells rely on the use of extracellular pyruvate to support effector functions, signal transduction and cell viability.
View Article and Find Full Text PDFTargeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer.
Nat Rev Drug Discov
December 2024
The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells.
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- NK cells often lose their function during tumor development, but the reasons for this are not fully understood.
- In mouse lymphoma models, the activation of NK cells led to changes resembling T cell exhaustion, including the expression of immune checkpoint proteins, but dysfunction occurred only in the activated NK cell group.
- Importantly, NK cell dysfunction can be reversed by stopping the stimulation and is positively influenced by interleukin-15, indicating that the dysfunction is a dynamic and reversible process not directly linked to immune checkpoint protein expression.
An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells.
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- DNA-PKcs is crucial for repairing DNA double-strand breaks and is linked to a rare immunodeficiency in humans, with few documented cases compared to the well-studied Scid mouse model.
- Seven patients with mutations in the PRKDC gene showed severe combined immunodeficiency symptoms, including granulomas and autoimmunity, highlighting a predominantly inflammatory clinical picture.
- Hematopoietic stem cell transplantation has proven effective for many, leading to meaningful recovery of T- and B-cell functions in the long-term follow-up of most patients.