Suppressing Antigen Presentation with STAT3

Science's STKE  22 Nov 2005:
Vol. 2005, Issue 311, pp. tw416
DOI: 10.1126/stke.3112005tw416

Dendritic cells present antigen bound to major histocompatibility complex class II (MHCII). Newly synthesized MHCII is retained within a specialized lysosomal compartment and requires enzymatic processing to release an inhibitory peptide (li), which prevents presentation of endogenous peptides. Maturation signals trigger cleavage of li, and antigen peptides are then exchanged for the cleaved li (now called CLIP), and the MHCII-peptide complex is delivered to the cell surface to present the antigen. Interleukin 6 (IL-6) inhibits MHCII surface expression through a STAT3 (signal transducer and activator of transcription 3) pathway. Kitamura et al. used knock-in mice that either overstimulated the STAT3 pathway (gp130F759/F759) or could not activate STAT3 (gp130FxxQ/FxxQ) to show that IL-6 acting through STAT3 decreased the abundance of li-MHCII dimers and of the MHCII chaperone H2-DM. The activities of cathepsins S, B, and L increased in IL-6-treated bone marrow-derived dendritic cells (BMDCs), and this was enhanced in the cells from the gp130F759/F759 mice and lacking in the cells from the gp130FxxQ/FxxQ mice. Although a small increase in the mRNA for cathepsin L and B was noted, IL-6 acting through STAT3 reduced the expression and abundance of cystatin C, which is an inhibitor of cathepsin S, in BMDCs. Forced overexpression of cystatin C blocked the IL-6-mediated enhancement of cathepsin S activity and prevented the loss of MHCII, li, and H2-DM. Overexpression of cathepsin S in dendritic cells attenuated the activation of T cells (measured as secretion of IL-2). Thus, the mechanism by which IL-6 suppresses dendritic cells' maturation by decreasing the MHCII available to present antigens appears to involve altered expression of a cathepsin inhibitor.

H. Kitamura, H. Kamon, S.-i. Sawa. S.-J. Park, N. Katunuma, K. Ishahara, M. Murakami, T. Hirano, IL-6-STAT3 controls intracellular MHC class II αβ dimer level through cathepsin S activity in dendritic cells. Immunity 23, 491-502 (2005). [PubMed]