Involvement of CD28/CTLA4-B7 costimulatory pathway in the development of lymphadenopathy and splenomegaly in MRL/lpr mice

MRL/lpr mouse is an established animal model which develops autoimmune dise ases including glomerulonephritis, sialoadenitis, hepatitis and inflammator y lung disease. Additionally, it has been reported that lpr strains uniquel y accumulate CD3(+)CD4(-)CD8(-)B220(+) (double negative, DN) T cells in lym phoid organs leading to lymphadenopathy and splenomegaly. To investigate th e role of CD28/CTLA4-B7 pathway in the development of lymphadenopathy and s plenomegaly, MRL/lpr mice were treated with soluble form of CTLA4 molecules . CTLA4IgG, which efficiently blocks this pathway. It was demonstrated that (i) the development of DN T cells was independent of the CD28/CTLA4-B7 pat hway, (ii) the CD28/CTLA4-B7 pathway was required for the development of ly mphadenopathy and splenomegaly, (iii) the CD28/CTLA4-B7 pathway was importa nt for the accumulation of various cell populations in the lymph node and s pleen, (iv) composition of the accumulating cell populations was not altere d by CTLA4IgG treatment, and (v) activation of conventional T cells and IL- 4 production from conventional T cells were the CD28/CTLA4-B7 pathway depen dent. Thus, we concluded that the CD28/CTLA4-B7 pathway was required for th e development of full-blown lymphadenopathy and splenomegaly in MRL/lpr mic e.