Transgenic Expression of CTLA-4 Controls Lymphoproliferation in IL-2-Deficient Mice

Abstract

IL-2-deficient mice develop a lymphoproliferative and autoimmune disease characterized by autoimmune hemolytic anemia (AHA) and inflammatory bowel disease. We have previously reported that IL-2 is necessary for optimal up-regulation of CTLA-4, an inducible negative regulator of T cell activation. In this study, we have tested the hypothesis that reduced expression of CTLA-4 in IL-2-deficient T cells contributes to the pathogenesis of disease in IL-2-deficient mice. Expression of CTLA-4 as a transgene completely prevented lymphoaccumulation and AHA in IL-2-deficient mice. The normalization of T cell numbers was due to inhibition of expansion of conventional CD4+CD25− T cells rather than to rescue of the numbers or function of CD4+CD25+ regulatory T cells, suggesting that CTLA-4 expression on conventional T cells plays a role in maintaining normal T cell homeostasis. In addition, the inhibitory effect of the CTLA-4 transgene on T cell expansion was at least in part independent of CD28 expression. Our results suggest that deficient CTLA-4 expression on conventional T cells contributes to the pathophysiology of the lymphoproliferative disease and AHA in IL-2-deficient mice. Thus, restoring CTLA-4 expression in T cells may be an attractive strategy to control clinical autoimmune diseases in which CTLA-4 expression is reduced.

CTLA-4 Overexpression Inhibits T Cell Responses through a CD28-B7-Dependent Mechanism

“…A recent study has addressed the role of CTLA-4 expression in the development of autoimmune disease in IL-2 Ϫ/Ϫ mice (50). In this study CTLA-4 transgenic overexpression was shown to partially rescue the lymphoproliferative disorder seen in IL-2 Ϫ/Ϫ mice.…”

Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo

“…For example, when Ag was expressed as an "endogenous" tissue Ag in islets (a setting more relevant to transplantation), an intact CTLA-4 locus prevented diabetes by reducing the accumulation of "autoreactive" TCR-transgenic CD4 cells, but did not induce anergy in terms of proliferative response ex vivo (43). Transgenic overexpression of CTLA-4 appears to inhibit autoimmunity in IL-2-deficient mice by limiting effector cell responsiveness (44). Similarly, transplantation in the face of CTLA-4 blockade suggests that CTLA-4 normally limits activation of alloreactive CD4 and CD8 cells, thereby decreasing their frequency and differentiation (12).…”

A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

“…(30.4) and when, in a separate susceptibility gene combination, the resistance allele in mouse Ctla4 can completely mask the potent disease-causing effect of a particular susceptibility allele at another locus. It has also been shown that a third locus, insulin dependent diabetes susceptibility 3 (Idd3), which is believed to be the interleukin-2 gene [32,33] can influence the production of CTLA-4 [30,34]. We, therefore, propose that AITD, type 1 diabetes and cooccurring type 1 diabetes and AITD manifest due to different, but overlapping combinations of susceptibility and resistance alleles of multiple loci, and that in isolated type 1 diabetes (up to 90% of cases) the constellations of alleles giving rise to this disease mask the allelically variable effect of CTLA4 to a much greater degree than the combination of alleles causing AITD or type 1 diabetes + TPOAbs as studied here.…”