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

Abstract

Background CD4 2 CD8 2 double-negative (DN) ab 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 b2m-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 b2m 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 b2m 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.

Renal double negative T cells: unconventional cells in search of a function

“…Interestingly though, in our hands murine renal DN T cells expressing Pd-1 are rare. Even though their frequency increases with ADPKD, we do not detect them at the same level as published by Sadasivam et al (16) (Figure 1C). This data may hint towards DN T cells having similar plasticity as other T cell subtypes where their phenotype, activation, and signaling is susceptible to microenvironmental stimuli.…”

“…However, other investigators have found different levels of this population. Zimmerman et al reported that only ~5% of all renal T cells are DN T cells in normal human kidney (15), and on the mouse side, renal DN T cells in 8-week-old wildtype C57Bl/6 mice have been reported to be either ~28% (16) or ~35% (14) of the total renal T cell population. While these discrepancies may be in part due to technical difficulties associated with studying DN T cells, which will be discussed later, it is likely that DN T cell frequency can change dependent on the age and strain of the mouse.…”

“…While the study from Sadasivam et al (16) provides new insight into the homeostasis of renal DN T cells, many questions remain regarding the role of these unconventional T cells in the kidney, especially given their newly defined subpopulations. Pd-1 + DN T cells have been previously described in the spleen and circulation as having an effector phenotype and being the main source of pro-inflammatory cytokines (24,25).…”

The Co-inhibitor BTLA Is Functional in ANCA-Associated Vasculitis and Suppresses Th17 Cells

“…Krieg et al noticed that the stimulation of murine T-cells in presence of an agonistic BTLA antibody results in decreased IL-2 production and diminished occurrence of CD25 + T-cells (27). There is evidence from animal studies that BTLA knockout leads to autoimmune diseases (20,28,29).…”

Reparative T lymphocytes in organ injury

“…More specifically, the PD-1 subset is highly responsive under ischemia/reperfusion injury (IRI) conditions (100, 101). IL-2 is required for DN αβ cell activation and function as well as DN αβ cell proliferation during the steady state (101). In vitro T cell function is suppressed by DN αβ T cells (100).…”