Activation and Proliferation of PD-1 + Kidney Double-Negative T Cells Is Dependent on Nonclassical MHC Proteins and IL-2

• Published in: Journal of the American Society of Nephrology 2019-02, Vol.30 (2), p.277-292
• Main Authors: Sadasivam, Mohanraj, Noel, Sanjeev, Lee, Sul A, Gong, Jing, Allaf, Mohamad E, Pierorazio, Phillip, Rabb, Hamid, Hamad, Abdel Rahim A
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Antigens, Surface - immunology; Antigens, Surface - metabolism; Basic Research; Cells, Cultured; Disease Models, Animal; Histocompatibility Antigens Class II - metabolism; Interleukin-2 - immunology; Interleukin-2 - metabolism; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Programmed Cell Death 1 Receptor - immunology; Programmed Cell Death 1 Receptor - metabolism; Random Allocation; Reference Values; Sensitivity and Specificity; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2018080815

CD4 CD8 double-negative (DN) T cells with innate-like properties represent a significant component of T cells in human and mouse kidneys. They spontaneously proliferate in the steady state and protect against ischemic AKI. However, the mechanisms regulating DN T cell homeostasis and responses to external danger signals from "sterile" inflammation remain poorly understood. We used knockout mice, functional assays, and an established ischemic AKI model to investigate the role of various MHC class I and II molecules in regulating kidney DN T cells. We also studied human nephrectomy samples. Deficiency of 2m-dependent MHC class I (but not MHC class II) molecules led to significant reduction in frequency or absolute numbers of kidney DN T cells due to impaired activation, proliferation, increased apoptosis, and loss of an NK1.1 subset of DN T cells. The remaining DN T cells in 2m knockout mice mainly comprised a programmed cell death protein-1 receptor (PD-1 ) subset that depends on IL-2 provided by conventional T cells for optimal homeostasis. However, this PD-1 subset remained highly responsive to changes in milieu, demonstrated by responses to infused lymphocytes. It was also the major responder to ischemic AKI; the NK1.1 subset and CD8 T cells had minimal responses. We found both DN T cell subsets in normal and cancerous human kidneys, indicating possible clinical relevance. DN T cells, a unique population of kidney T cells, depend on nonclassical 2m molecules for homeostasis and use MHC-independent mechanisms to respond to external stimuli. These results have important implications for understanding the role these cells play during AKI and other immune cell-mediated kidney diseases.