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

In studying the role of adaptive immunity in disease, investigators have focused extensively on CD8+ T cells (effector T cells) and CD4+ T cells (helper T cells). For many years, double negative (DN) T cells (CD4？ CD8？) have been neglected by immunologists due to their overall rarity and lack of clear expression markers, making them difficult to study. However, within the last decade, these unconventional T cells have been found to be important in various disease presentations, resulting in increased interest in this population as a therapeutic target. Interestingly, DN T cells have been found to be both pro- and anti-inflammatory (1). Several studies hint towards DN T cells being key regulators of autoimmunity. For example, in Systemic Lupus Erythematosus (SLE) patients, DN T cell numbers were found to be significantly increased and were a major producer of IL-17, the key inflammatory cytokine in SLE (2). Similarly, in Autoimmune Lymphoproliferative Syndrome (ALPS) patients, peripheral DN T cell numbers have been reported to increase from 1% in controls to 40% of T cells, making DN T cell number a potential disease biomarker (3). Peripheral DN T cell numbers have also been shown to increase in HIV patients. Interestingly, these numbers decrease upon successful antiviral therapy, suggesting they may contribute to viral production and are sensitive to active antiretroviral therapy (4). Furthermore, DN T cells have been found to be the major responders to Francisella tularensis (5) and Listeria monocytogenes (6) infections. Contrary to their proinflammatory role, DN T cells have been proposed to be essential in maintenance of immune homeostasis and self-tolerance. In that respect, several studies have shown that DN T cells play an important role in the development of tolerance after transplantation (7). Additionally, DN T cells have been proposed to provide long lasting protection against type-I diabetes in diabetes-prone NOD mice (8)