Our recent results on newly diagnoses RRMS patients we notice alterations on T cell populations in comparison to healthy controls. Surprisingly, RRMS patients have lower numbers of memory CD4+ and CD8+ T cells, specifically effector memory and terminally differentiated CD45RA+ EM cells (TemRA). Unexpectedly, these alterations tip T cells’ phenotype towards a less activated phenotype in newly diagnosed RRMS patients, and strongly suggest broad peripheral immune system alterations, not exclusively related to myelin-reactive T cells, as they are estimated to represent only ~0.0001% of the total peripheral T cells. In this project, our AIM is to explore the mechanisms underlying the lowering of memory T cell numbers, and to understand how can these observations and mechanisms be integrated in the current model of MS pathophysiology. For this, we will perform functional assays that will allow us to understand if in these patients: i) naive T cells have altered homeostatic proliferation; ii) naive T cells’ T cell receptor (TCR) activation threshold is altered, thus impairing their differentiation into memory T cells, and; iii) memory T cells are less proliferative and/or more prone to die.