RESEARCH SUMMARY

Apoptosis is considered a basic mechanism for limiting T cell memory expansion known as homeostasis. Nevertheless, we find that the control of activation of memory T cells and of proliferation are also fundamental for memory T cell homeostasis. We suggest that memory responses and homeostasis require a combination of control in activation, apoptosis and proliferation.The cell cycle inhibitor p21 suppreses autoimmunity and controls T cell memory responses.

We have shown that p21 is an autoimmunity suppressor, since p21 deficiency leads to autoimmunity. Indeed, p21 overexpresion in T cells of autoimmune lupus-prone Fas-deficient (lpr/lpr) mice reduces autoimmunity development by limiting the expansion of autoreactive lpr/lpr memory T cells. p21 plays an attenuating role in T cell expansion upon persistent stimulation of T cells through TCR. Our recent work unveils a novel function of p21 regulating of TCR-dependent activation of memory T cells. Thus we propose that p21 exerts two functions in the response of memory T cells, by first regulating their level of activation and second by controlling their proliferative potential. We are now studying the mechanism by which p21 controls memory T cell activation. A alternative function for the the Fas/FasL apoptosis system. Our analysis of memory T cell activation, apoptosis and cell cycle regulation events in immunity and autoimmune disease, have revealed a previously unknown role for Fas. Similarly, to the function of p21 as a regulator of repeatedly activated T cells we have established that Fas also plays a crucial attenuating role in the response of previously activated T cells but not of primary T cells. We are currently investigating the mechanistic aspects of this new role of the Fas/FasL system.

p21 REGULATES THE MACROPHAGE ACTIVATION PATHWAY.

p21 has a general role in the immune response since independently of its cell cycle inhibitory capacity, regulates macrophage activation by controlling the (NF-kB) pathway in the cytoplasm. p21 regulation of NF-kB activation is critical for progression of in vivo inflammation, since it decreases sensitivity to LPS-induced septic shock. We are studying the mechanism that defines the role of p21 in NF-kB activation, and whether p21 suppresses glomerulonefritis development thought its regulatory effect on innate immunity inflammation .