On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy inlprMice.
Fas induces massive apoptosis in T cells after repeatedin vitroT cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although thein vitroFas apoptotic mechanism has been defined, there is a large conceptual gap between thisin vitrophenomenon and the pathway that leads toin vivodevelopment of lymphadenopathy and autoimmunity. A striking abnormality inlprmice 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 oflprT cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of alllprT cell subtypes and lymphadenopathy inlprmice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy inlprmice and, with earlier studies, suggest that Fas apoptosis-independent pathways controllprT cell hyperproliferation.lprT cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulatedlprT cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly causelprT cell hyperactivation/hyperproliferationin 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 inlprmice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype oflprmice and lead to therapeutics for related human syndromes.
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), UAM Campus de Cantoblanco , Madrid , Spain.
Dimitrios
D
Balomenos
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), UAM Campus de Cantoblanco , Madrid , Spain.
Rahman
R
Shokri
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), UAM Campus de Cantoblanco , Madrid , Spain.
Lidia
L
Daszkiewicz
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), UAM Campus de Cantoblanco , Madrid , Spain.
Cristina
C
Vázquez-Mateo
Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), UAM Campus de Cantoblanco , Madrid , Spain.
Carlos
C
Martínez-A
Fas; alternative functions; double-negative T cells; hyperactivation; hyperproliferation; lupus autoimmunity; memory T cells; p21