W5-2 Lymphopenia-induced proliferation (LIP) triggers the development of follicular helper T (T<sub>FH</sub>) cells which have a distinctive ontogeny and a critical role in aberrant B cell responses

Abstract

Lymphopenia results in the homeostatic peripheral expansion of lymphocytes to maintain T cell homeostasis. Accumulating data show that lymphopenia-induced proliferation (LIP) has a pathogenic role in the development of autoimmunity in animal models and human systemic autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome and rheumatoid arthritis. To clarify the mechanism of anti-nuclear antibodies (ANA) production, we established a lymphopenic mouse model in which CD4+ T cell subsets from wild-type BALB/c mice were adoptively injected into BALB/c nude mice, which induced IgG-type ANA production. We observed that class switching and ANA production were enhanced when regulatory T cells were depleted. We identified IL-21-producing PD-1+ TFH cells which develop from conventional T cells during LIP and drive germinal center reactions with aberrant B cell responses. Compared with traditional TFH cells, this subset has a distinctive ontogeny and a critical role in breaking B cell tolerance. This study reveals the physiological mechanism how immunological tolerance is maintained during LIP and would help to understand the pathogenesis of systemic autoimmune diseases.