Papel de FAS y p21 en la limitación de las células T de memoria y la enfermedad autoinmune

Resumen

The extraordinary capacity of the immune system to prevent responses elicited by self antigens is known as self tolerance, and is essential for the maintenance of immune homeostasis. The processes of T cell activation, proliferation and cell death must be precisely regulated to avoid the development of autoimmune diseases such as systemic lupus erythematosus or autoimmune lymphoproliferative syndrome (ALPS). The FAS receptor has classically been associated with a role in apoptosis. Mice with defects in FAS (lpr) and ALPS patients both show a clear loss of tolerance that leads to autoimmunity and development of lymphadenopathy, with marked T cell hyperproliferation of unknown origin. FAS-dependent activation induced cell death (AICD) was initially considered the basis of the lpr mouse phenotype. Nevertheless, although the role of FAS-mediated cell death is well established in vitro, its relevance in apoptosis induction in vivo is debated. Defective apoptosis alone does not account for accumulation of activated T cells; clear evidence is derived from the analysis of mice deficient in other molecules involved in the FAS-activated apoptotic pathway, such as FADD (FAS Associated Death Domain) or C-8 (caspase-8). These mice lack T cell apoptosis but, unlike lpr mice, develop neither autoimmune disease nor lymphadenopathy but are affected by immunodeficiency. This suggests that, in addition to apoptosis, FAS might have other functions in homeostasis control. Since lpr T cells hyperproliferate in vivo and their apoptotic defects are nonetheless insufficient to justify the lymphadenopathy and autoimmunity observed in these mice, we explored the relationship between loss of tolerance and the excessive proliferation of autoreactive T cells in lpr mice. Our results showed that, in addition to its proapoptotic effect, the FAS receptor is a crucial regulator of activation (NF-kB, ERK- 1/2, pro-inflamatory cytokines) and proliferation in activated/memory T cells generated after repeated stimulation by an antigen with low affinity for the TCR (T cell receptor). We have described p21 as a suppressor of autoimmunity, shown by its implication in the control of apoptosis-surviving T cell proliferation after secondary antigen challenge. This led us to speculate that p21 overexpression in lpr mice might reduce the autoimmune disorder, since their T cells hyperproliferate after restimulation. Our data indicate that a reduction in memory T cell proliferation, mediated by T cell-directed p21 overexpression, efficiently reduces lymphadenopathy and disease manifestations in lprp21tg mice. In accordance with these results, lpr-p21-/- mice showed excessive memory T cell activation/ proliferation, leading to severe autoimmune disease and an increased early mortality rate compared to lpr mice. T cell hyperproliferation thus has evident physiological relevance in autoimmunity development in FAS-deficient mice. We propose that both FAS and p21 have an essential function in tolerance establishment, mediated by their functions as negative regulators of memory T cell activation/proliferation.