Involvement of CD28/CTLA4-B7 Costimulatory Pathway in the Development of Lymphadenopathy and Splenomegaly in MRL/lpr Mice

Abstract

ABSTRACT. MRL/lpr mouse is an established animal model which develops autoimmune diseases including glomerulonephritis, sialoadenitis, hepatitis and inflammatory lung disease. Additionally, it has been reported that lpr strains uniquely accumulate CD3 + CD4 -CD8 -B220 + (double negative, DN) T cells in lymphoid organs leading to lymphadenopathy and splenomegaly. To investigate the role of CD28/ CTLA4-B7 pathway in the development of lymphadenopathy and splenomegaly, 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 pathway, (ii) the CD28/CTLA4-B7 pathway was required for the development of lymphadenopathy and splenomegaly, (iii) the CD28/CTLA4-B7 pathway was important for the accumulation of various cell populations in the lymph node and spleen, (iv) composition of the accumulating cell populations was not altered by CTLA4IgG treatment, and (v) activation of conventional T cells and IL-4 production from conventional T cells were the CD28/CTLA4-B7 pathway dependent. Thus, we concluded that the CD28/ CTLA4-B7 pathway was required for the development of full-blown lymphadenopathy and splenomegaly in MRL/lpr mice.-KEY WORDS: costimulatory signal, CTLA4IgG, IL-4, lymphadenopathy, MRL/lpr.

A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS

“…Finally, the increase of FC T cells in patients with CTLA4 deficiency indicates that CD28 also plays a role in FC T cell expansion. This is supported by the significant reduction of absolute DNT numbers after treatment of neonatal lpr mice with abatacept ( Takiguchi et al, 2000 ).…”

“…8 E ). While a role for CTLA4 in controlling DNT in lpr mice has been described ( Takiguchi et al, 2000 ), the role of STAT3 signals is less clear. We found that ex vivo phosphorylated STAT3 (pSTAT3) levels were increased in FC T cells compared with cDNTs and total CD4 + or CD8 + T cells, indicating active STAT3 signaling in vivo ( Figs.…”

Transmission and Immunopathogenesis of FIV in Cats as a Model for HIV

“…B7.1 (CD80) and B7.2 (CD86) are co-stimulatory molecules found on professional antigen presenting cells that regulate the immune response via interactions with CD28 and CTLA4 on T cells [211,220]. B7 engagement of CD28, which is constitutively expressed on T cells, is necessary for sustained IL-2 production and T cell proliferation, both critical features for development of an immune response.…”