Dissecting the molecular mechanisms regulating proliferation, antigen responsiveness, and differentiation of CD4⁺ T lymphocytes : a central role for the mammalian target of Rapamycin (mTor)

Colombetti, Sara (2004). Dissecting the molecular mechanisms regulating proliferation, antigen responsiveness, and differentiation of CD4⁺ T lymphocytes : a central role for the mammalian target of Rapamycin (mTor). PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f9e5

Abstract

The intracellular events that regulate lymphocyte proliferation upon antigen encounter and the ability of the cells to respond to subsequent stimulation and to differentiate into effector cells remain largely to be understood. Several studies have linked T cell proliferation with the maintenance of antigen responsiveness and with the ability of the cells to differentiate and to acquire proper effector functions. The aim of my Ph.D. research project was to investigate the role of the TCR, CD28, and IL-2 generated intracellular events dictating CD4+ T lymphocyte proliferation and differentiation. In a model of CD3-induced clonal anergy, we have shown that antigen responsiveness was uniquely regulated by an IL-2/IL-2R-induced signalling event, which was delivered independently of IL-2-driven cell proliferation, and which was Rapamycin-sensitive. This indicates that proliferation and antigen responsiveness are independently regulated and that the latter specifically requires intact signalling through mTor, the mammalian target of Rapamycin. Moreover, we have shown that proper activation of p70S6k, one the known target of mTor, might play a crucial role in the maintenance of T lymphocyte responsiveness. We have also investigated the role of mTor in a model of in vitro antigen driven naive T cell differentiation. In this model, blocking mTor activity by the addition of Rapamycin during T cell activation, allowed comparable T cell expansion, but completely prevented polarization of effector cells. Together our results indicate that the intracellular events that dictate T cell proliferation are distinct from the intracellular signals that modulate the functional phenotype of activated T lymphocytes and suggest that, while mTor-dependent signalling is dispensable for T cell proliferation, it is primarily involved in the acquisition of proper T cell effector functions.