Identification of a suppressor of autoimmune disease that affects deoxynucleotide synthesis in T cells

Tuesday, September 23, 2014 — Poster Session III
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NIAID	IMMUNO-18

* FARE Award Winner

Authors

• T. Tarasenko
• W. Zheng
• B. Scott
• S. Bolland

Abstract

FcγRIIB-deficient mice represent a well-characterized animal model of systemic lupus erythematosus. They develop spontaneous lupus like disease when on the C57BL/6 background (B6.FcγRIIB -/- mice). In contrast, the same mutation on the BALB/c background (BALB.FcγRIIB -/- mice) is phenotypically benign. We identified a 151KB genomic fragment on chromosome 12 responsible for the suppressive effect in BALB/c mice. We generated a transgenic mouse line expressing this BALB/c genomic region directly in the C57BL/6 background (A12 Tg) and subsequently crossed to B6.FcγRIIB -/- mice to test the putative protective effect. The A12 transgene was able to suppress the spontaneous disease that normally develops in B6.FcγRIIB -/- mice. The A12 transgene also reduced the number of activated and memory T cells, as well as the number of follicular helper T cells when compared to the B6.FcγRIIB -/- mice. Additional studies suggest that reduction in the autoimmune phenotype is T cell-intrinsic. The A12 protective interval contains a single gene, Rrm2, which is responsible for the synthesis of deoxyribonucleotides. We hypothesize that reduced levels of this enzyme affect the ability of T cell to expand upon activation and that is why allelic differences can alter tolerance in mouse models of lupus.

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