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J Am Soc Nephrol. 2019 Jan 8. pii: ASN.2018080815. doi: 10.1681/ASN.2018080815. [Epub ahead of print]

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

Author information

1
Department of Pathology.
2
Division of Nephrology, and.
3
Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland hrabb1@jhmi.edu.
5
Division of Nephrology, and hrabb1@jhmi.edu.

Abstract

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.

KEYWORDS:

T cells; immunology; ischemia-reperfusion

PMID:
30622155
DOI:
10.1681/ASN.2018080815

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