A6: T cell memory differentiation in early autoimmune disease.

Background. Chronic T cell activation and memory differentiation contribute essentially to the perpetuation of ongoing autoimmune processes by diverse mechanisms (Ann Rheum Dis. 70:i85). Apart from this, chronically activated memory T cells can shut down synthesis of IL-2 which promotes Treg defects and which in turn facilitates tolerance breakdown. However, little is known about the factors which drive memory formation and chronicity in an early stage of autoimmune disease when clinical symptoms are still unapparent. In the (NZBxNZW) F1 mouse model of lupus, signs of increased T cell activation and memory differentiation are detectable in lymphoid tissues long before the development of organ manifestations and even before the generation of autoantibodies, proposing that aberrant T cell activation is an early event in autoimmunity. In addition, Treg from these mice are in a highly activated state suggesting that active counter-regulation is already taking place at this early stage of disease (Proc Natl Acad Sci USA. 107:204; Fig.A6-1).

Objectives. (i) To understand the mechanisms of T cell memory differentiation and their escape from immune-regulation in early murine lupus. (ii) To explore when and how chronically activated T cells shut down IL-2 synthesis as a major event in the breakdown of tolerance.

Work program. Lymphoid organs and peripheral blood from (NZBxNZW) F1 lupus-prone mice at ages between 2 and 20 weeks will be analyzed in detail for changes in T cell phenotype and T cell receptor repertoire in cooperation with A7. Expression of IL-2 repressors, of factors responsible for resistance to Treg-mediated suppression and epigenetic modifications of lineage markers will be determined in sorted cells subsets at different time points. Various mechanistic in vitro experiments will be performed in parallel. The inhibitory role of Treg on pathogenic important events will be assessed after depletion of Treg in these mice. This will lead to the identification of key factors driving early autoimmune processes that will help to better understand disease pathogenesis and to define novel therapeutic targets.