Circulating immunoglobulin-bound transforming growth factor β at a late tumour-bearing stage impairs antigen-specific responses of CD4+ T cells

Abstract

In order to elucidate the mechanisms by which tumour-specific CD4+ T-cell responses are impaired during tumour development, an attempt was made to identify factors which impair CD4+ T-cell responses at a late tumour-bearing stage. Plasma from mice bearing B16 melanoma for 30 days (plasma d30) showed a more profound immunosuppressive effect on the in vitro proliferation of unrelated antigen-specific CD4+ T cells in the presence of both antigen and antigen-presenting cells (APC) than plasma from naïve mice. The level of plasma transforming growth factor (TGF)-β was elevated in mice bearing B16 melanoma for 30 days compared with naïve mice, and the suppressive effect of plasma d30 was partially diminished by the neutralization of TGF-β. Interestingly, immunoglobulin (IgG)-bound TGF-β, but not IgG-unbound TGF-β, in plasma d30 was suggested to be responsible for the immuno-suppressive activity. In addition, no suppressive effect of plasma d30 was observed when antigen was added as a class II peptide, thus suggesting that the impaired proliferation of CD4+ T cells in the presence of plasma d30 was due to a dysfunction of antigen uptake/processing by APC. Furthermore, dissociation between IgG and TGF-β resulted in a loss of the suppressive activity of plasma d30. Taken together, these results suggest that circulating IgG-bound TGF-β is, at least in part, responsible for the impaired responses of CD4+ T cells at the late tumour-bearing stage by suppressing antigen uptake/ processing by APC.