Double negative (DN) αβ T cells: misperception and overdue recognition

Abstract

CD4(-)CD8(-)double negative (DN) αβ T cells are legitimate components of the normal immune system. However, they are poorly understood and largely ignored by immunologists because of their historical association with the lymphoproliferation that occurs in mice (lpr and gld) and humans (autoimmune lymphoproliferative syndromes patients) with impaired Fas-mediated apoptosis where they are considered abnormal T cells. We believe that the traditional view that DN T cells that cause lymphoproliferation (hereafter referred to as lpr DN T cells) are CD4 and CD8 T cells that lost their coreceptor, conceived more than two decades ago, is flawed and that conflating lpr DN T cells with DN T cells found in normal immune system (hereafter referred to as nDN T cells) is unnecessarily dampening interest of this potentially important cell type. To begin rectifying these misperceptions, we will revisit the traditional view of lpr DN T cells and show that it does not hold true in light of recent immunological advances. In lieu of it, we offer a new model proposing that Fas-mediated apoptosis actively removes normally existing DN T cells from the periphery and that impaired Fas-mediated apoptosis leads to accumulation of these cells rather than de novo generation of DN T cells from activated CD4 or CD8 T cells. By doing so, we hope to provoke a new discussion that may lead to a consensus about the origin of lpr DN T cells and regulation of their homeostasis by the Fas pathway and reignite wider interest in nDN T cells.

Figure 1. DN T cell lymphoaccumulation in mice with impaired Fas pathway is limited to secondary lymphoid organs

lpr and gld mutations cause massive expansion of DN T cells in the peripheral lymphoid organs (spleen and lymph nodes) without affecting DN T cell homeostasis in the thymus, kidney (not shown) or the gut epithelium.

Figure 2. Pros and cons of the traditional and newly proposed models

According to the traditional model, death of chronically activated CD4 (Act. CD4) or CD8 (Act. CD8) T cells by Fas-mediated apoptosis accounts for the paucity of DN T cells in secondary lymphoid organs of WT mice and that loss-of-function mutations in the Fas pathway prevent death of activated CD4 and CD8 T cells that subsequently downregulate their coreceptors and persist as DN T cells. In contrast, our newly proposed model suggests DN T cells represent an independent subset that is normally rare in the secondary lymphoid organs because they are actively removed by Fas-mediated apoptosis, but gradually accumulate in these organs when the Fas death pathway is impaired. The new model also accounts for the exponential expansion of CD4 and CD8 T cells in mutant mice due to their persistence as such without coreceptor downregulation in mutant mice.