{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:07:40Z","timestamp":1786133260821,"version":"build-2736575974"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JASN"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>\n                      Understanding how each immune cell type functions in the kidney is necessary to develop new immunotherapies for cell-mediated kidney diseases, including transplant rejection, AKI, and GN. Although CD4\n                      <jats:sup>\u2212<\/jats:sup>\n                      CD8\n                      <jats:sup>\u2212<\/jats:sup>\n                      double-negative (DN) T cells are a significant kidney T cell subpopulation that is anti-inflammatory and protective during ischemic AKI, little is known about the role of various MHC class I and II molecules in regulating their function. In addition to showing that mouse kidney DN T cells have IL-2\u2013dependent proliferation, the authors identified two subsets of kidney DNT cells: a classical MHC class I\u2013dependent NK1.1\n                      <jats:sup>+<\/jats:sup>\n                      subset and an MHC-independent programmed cell death protein-1 receptor (PD-1\n                      <jats:sup>+<\/jats:sup>\n                      ) subset that is highly responsive to ischemia-reperfusion injury. The presence of both subsets in human kidneys suggests that these findings are clinically relevant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      CD4\n                      <jats:sup>\u2212<\/jats:sup>\n                      CD8\n                      <jats:sup>\u2212<\/jats:sup>\n                      double-negative (DN)\n                      <jats:italic toggle=\"yes\">\u03b1\u03b2<\/jats:italic>\n                      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 \u201csterile\u201d inflammation remain poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Deficiency of\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      subset of DN T cells. The remaining DN T cells in\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      2m knockout mice mainly comprised a programmed cell death protein-1 receptor (PD-1\n                      <jats:sup>+<\/jats:sup>\n                      ) subset that depends on IL-2 provided by conventional T cells for optimal homeostasis. However, this PD-1\n                      <jats:sup>+<\/jats:sup>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      subset and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells had minimal responses. We found both DN T cell subsets in normal and cancerous human kidneys, indicating possible clinical relevance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      DN T cells, a unique population of kidney T cells, depend on nonclassical\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      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\u2013mediated kidney diseases.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2018080815","type":"journal-article","created":{"date-parts":[[2019,1,8]],"date-time":"2019-01-08T16:05:34Z","timestamp":1546963534000},"page":"277-292","source":"Crossref","is-referenced-by-count":36,"title":["Activation and Proliferation of PD-1+ Kidney Double-Negative T Cells Is Dependent on Nonclassical MHC Proteins and IL-2"],"prefix":"10.1681","volume":"30","author":[{"given":"Mohanraj","family":"Sadasivam","sequence":"first","affiliation":[{"name":"Department of Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeev","family":"Noel","sequence":"additional","affiliation":[{"name":"Division of Nephrology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sul 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