DR. lyp/ lyp bone marrow maintains lymphopenia and promotes diabetes in lyp/ lyp but not in +/+ recipient DR. lyp BB rats

Abstract

Lymphopenia is due to a frameshift mutation in Gimap5 on rat chromosome 4 and is linked to type 1 diabetes in the diabetes prone (DP) BB rat. The hypothesis that bone marrow derived cells confer the lymphopenia phenotype was tested by reciprocal bone marrow transplantation in 40-day-old lethally irradiated diabetes resistant (DR) congenic DR. lyp / lyp (lymphopenia and diabetes) and DR. +/+ (no lymphopenia and no diabetes) rats. In two independent series of transplants, all DR. lyp / lyp rats ( n = 5 and 4) receiving DR. lyp / lyp bone marrow retained lymphopenia and developed insulitis (5/5 and 4/4) as well as diabetes in some (2/5 and 3/4). Both DR. +/+ and DR. lyp / lyp rats receiving DR. +/+ bone marrow cells as well as DR. +/+ rats receiving DR. lyp / lyp bone marrow cells showed no lymphopenia or diabetes. In accordance with earlier studies in non-congenic BB rats, the DR. +/+ rats receiving DR. lyp / lyp bone marrow cells recapitulated an intermediary phenotype rather than the +/+ or lyp/ lyp phenotypes. Our data demonstrate that BBDP rat lymphopenia and diabetes are transferred by bone marrow transplantation to syngeneic DR. lyp / lyp but not DR. +/+ recipients. The intermediary recapitulation of DR. lyp / lyp T cells in recipient DR. ±/± rats suggests that radiation resistant ±/± T cells, the Gimap5 mutation in bone marrow cells, or both may not support the development of lymphopenia.