Lack of regulation by CTLA-4 in the autoimmune NOD mouse

Recent studies have demonstrated that CTLA-4 through its interaction with B7 ligands generates an arresting signal to T-cells, thus controlling an ongoing immune response. This study was designed to examine differences in the inhibitory signal transduced by CTLA-4 in autoimmune and non-autoimmune mice. The nonobese diabetic (NOD) mouse is an excellent model of IDDM as the NOD develops a spontaneous form of diabetes closely resembling human disease. The BALB/c mouse is non-autoimmune and has been extensively used as a control mouse strain. Treatment of BALB/c mice with anti-CTLA-4 antibody enhanced in vitro T cell proliferation and IFNγ responses to islet cell antigen; CD25 upregulation on T cells was also increased. In contrast, anti-CTLA-4 antibody treatment in NOD mice resulted in no difference between control and anti-CTLA-4-treated mice with respect to T cell proliferation and CD25 expression, although when cytokine production was at its highest, levels of IFNγ in anti-CTLA-4 animals were higher than in controls. Our observations of increased T-cell responses with blockade of CTLA-4 in the BALB/c mouse are consistent with the role that CTLA-4 plays in the downregulation of T-cell responses. However, this paradigm of CTLA-4-mediated inhibition does not hold when it is applied to a spontaneously autoimmune animal such as the NOD mouse. Taken together, these results indicate that CTLA-4 modulates T-cell responses to a self-antigen differently in BALB/c mice than in NOD mice and it appears that NOD mice are not as tightly governed by CTLA-4 regulation.