On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

Abstract

Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4+ and CD8+ T cells, and more so of the double-negative TCR+CD4−CD8−B220+ T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes.

An early history of T cell-mediated cytotoxicity

“…FAS signalling also induced various functions in addition to cell death [155][156][157][158] . The lymphadenopathy that is prominent in mouse and human 159 mutants of the FAS pathway indicates that a main function of this pathway is to regulate the immune system, classically through the control of lymphocyte death although other mechanisms have been proposed 158,160 .…”

Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells

“…Exposure to apoptotic cell debris induces CD8 loss. In lpr mice, defects in apoptosis lead to increased rates of other forms of programmed cell death 24,25 . To investigate whether the accumulation of uncleared dead cell debris and the presence of associated antigens are mechanistically required for the generation of DN T cell from self-reactive CD8 T cells and whether the lupus milieu marked by MZM deficiency could facilitate this conversion, we co-transferred CFSE-labeled CD8 + OT-I TCR transgenic (Tg) T cells with apoptotic thymocytes derived from m-OVA Tg mice into B6 mice treated with or without Clodrosome.…”

Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming

“…Of note, PDA-infiltrating iαβTs constituted ∼30% of TCRαβ + cells in Fas lpr mice ( Fig. 1G), known to accumulate iαβTs in secondary lymphoid organs (7). To determine whether the thymic production of iαβTs is accelerated during pancreatic oncogenesis, we interrogated T-cell populations in the thymus of 6-month-old KC mice.…”