AUTHOR=Balomenos Dimitrios , Shokri Rahman , Daszkiewicz Lidia , Vázquez-Mateo Cristina , Martínez-A Carlos 

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

JOURNAL=Frontiers in Immunology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00237

DOI=10.3389/fimmu.2017.00237

ISSN=1664-3224

ABSTRACT=<p>Fas induces massive apoptosis in T cells after repeated <italic>in vitro</italic> T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (<italic>lpr</italic>) mice. Although the <italic>in vitro</italic> Fas apoptotic mechanism has been defined, there is a large conceptual gap between this <italic>in vitro</italic> phenomenon and the pathway that leads to <italic>in vivo</italic> development of lymphadenopathy and autoimmunity. A striking abnormality in <italic>lpr</italic> mice is the excessive proliferation of CD4<sup>+</sup> and CD8<sup>+</sup> T cells, and more so of the double-negative TCR<sup>+</sup>CD4<sup>−</sup>CD8<sup>−</sup>B220<sup>+</sup> T cells. The basis of <italic>lpr</italic> T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all <italic>lpr</italic> T cell subtypes and lymphadenopathy in <italic>lpr</italic> 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 <italic>lpr</italic> mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control <italic>lpr</italic> T cell hyperproliferation. <italic>lpr</italic> T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated <italic>lpr</italic> T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause <italic>lpr</italic> T cell hyperactivation/hyperproliferation <italic>in vivo</italic>. 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 <italic>lpr</italic> mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of <italic>lpr</italic> mice and lead to therapeutics for related human syndromes.</p>