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

BACKGROUND:CD4^- CD8^- double-negative (DN) αβ 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. METHODS: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. RESULTS:Deficiency of β2m-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 β2m 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. CONCLUSIONS:DN T cells, a unique population of kidney T cells, depend on nonclassical β2m 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.

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