Cathepsin S regulates class II MHC processing in human CD4+ HLA-DR+ T cells

Although it has long been known that human CD4(+) T cells can express functional class II MHC molecules, the role of lysosomal proteases in the T cell class II MHC processing and presentation pathway is unknown. Using CD4(+) T cell clones that constitutively express class II MHC, we determined that cathepsin S is necessary for invariant chain proteolysis in T cells. CD4(+)HLA-DR(+) T cells down-regulated cathepsin S expression and activity 18 h after activation, thereby ceasing nascent class II MHC product formation. This blockade resulted in the loss of the invariant chain fragment CLIP from the cell surface, suggesting that-like professional APC-CD4(+) HLA-DR(+) cells modulate self-Ag presentation as a consequence of activation. Furthermore, cathepsin S expression and activity, and concordantly cell surface CLIP expression, was reduced in HLA-DR(+) CD4(+) T cells as compared with B cells both in vitro and ex vivo.