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

Fas induces massive apoptosis in T cells after repeated T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient () mice. Although the Fas apoptotic mechanism has been defined, there is a large conceptual gap between this phenomenon and the pathway that leads to development of lymphadenopathy and autoimmunity. A striking abnormality in mice is the excessive proliferation of CD4 and CD8 T cells, and more so of the double-negative TCRCD4CD8B220 T cells. The basis of T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all T cell subtypes and lymphadenopathy in 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 mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control T cell hyperproliferation. T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause T cell hyperactivation/hyperproliferation . 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 mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of mice and lead to therapeutics for related human syndromes.