TGF-beta1 and IFN-gamma cross-regulate antigen presentation to CD4 T cells by macrophages

We studied the interaction of transforming growth factor-beta1 (TGF-beta1) and interferon-gamma (IFN-gamma) in regulating Ag presentation in macrophages. TGF-beta1 blocked, and IFN-gamma enhanced Ag presentation of two T cell epitopes from the group A streptococcal M protein processed from viable Streptococcus pyogenes. Consistent with the functional data, TGF-beta1 reduced the constitutive expression of MHC class II transactivator (CIITA), MHC class II (MHC-II), invariant chain, and DO mRNA, whereas IFN-gamma up-regulated the expression of CIITA and MHC-II mRNA without affecting invariant chain or DO mRNA. However, neither cytokine affected DM mRNA expression. Treatment of macrophages with the two cytokines in combination showed that TGF-beta1 down-regulated IFN-gamma-mediated enhancement of antigen presentation and inhibited IFN-gamma-inducible CIITA and MHC-II class II mRNA expression. The effect of TGF-beta1 on Ag presentation was shown to be independent of the surface expression of CD80, CD86, or CD40 costimulatory molecules by flow cytometry. Our results show that TGF-beta1 and IFN-gamma cross-regulate Ag presentation by influencing the transcription of several genes associated with antigen presentation function, which may represent an important mechanism limiting T cell activation during an immune response.