OBJECTIVE: Rheumatoid arthritis (RA) is preceded by autoantibodies to citrullinated proteins (ACPA). Citrullins are arginine residues which have been modified by Peptidyl Arginyl Deiminases (PADs). PAD4 is the target of autoantibodies in RA. This suggests that ACPAs could arise because PAD4 is recognized by T cells which help the production of autoantibodies to proteins bound by PAD4. We previously found evidence for this hapten carrier model in mice. Here, we looked for evidence for this model in humans. METHODS: We analyzed antibody and T cell proliferation to PAD4 in 41 RA patients and 36 controls. We tested binding of 65 peptides from PAD4 to 5 HLA-DR alleles (DRB1*04:01, *04:02, *04:04, *01:01, *07:01). We selected 11 peptides from PAD4 for proliferation studies in 22 patients with RA and 27 controls. We performed FACS analysis for CD3, CD4, CD154 and TNF alpha expression after PAD4 stimulation on the PBLs of an extra 10 RA patients and 7 healthy controls RESULTS: Only patients with RA have both antibodies and T cell responses to PAD4. T cell response to peptide 8 (p8), a peptide from PAD4, is associated with RA, ACPAs and the shared epitope. CONCLUSION: ACPA immunity is associated with antibodies and T cell response to PAD4 and T cell response to peptides from PAD4. This is consistent with a hapten carrier model in which PAD4 is the carrier and citrullinated proteins are the haptens