Brief Definit ive Report

Presentation by MHC molecules of peptides bearing posttranslational modifications can elicit highly specific T cell responses, specu-lated to be a component of autoimmunities. The T cells usually recognize the modified residue in the framework of the unmodified TCR contact residues of the peptide (Anderton, 2004; Engelhard et al., 2006; Petersen et al., 2009). One of the most compelling findings linking posttranslationally modified self-proteins to autoimmunity is the antibody response to citrullinated proteins in rheumatoid arthritis (RA). The presence of citrulline in proteins is caused by the enzymatic deimination of arginine residues; citrulline is not a natural amino acid encoded in DNA. The conver-sion from peptidylarginine to peptidylcitrul-line is catalyzed by the peptidylarginine deiminase (PAD) family of enzymes, which differ in tissue expression. PAD2 and PAD4 are both expressed by cells of the immune system. In RA, the antibodies are found early in disease, at levels that correlate with sever-ity (Klareskog et al., 2008; Wegner et al., 2010). Moreover, there is a strong correlation between antibody reactivity and the presence of RA-susceptible HLA alleles (de Vries et al., 2006; van der Helm-van Mil and Huizinga, 2008). Citrullinated peptides were shown to bind with higher affinity to the RA-susceptible HLA allele DR4 as a result of the more favor-able interaction of the citrulline side chain with the positively charged P4 pocket (Hill et al., 2003). We previously reported that immuniza-tion with the protein hen egg-white lysozyme (HEL) gave rise to T cells that recognized different sets of HEL peptides presented by class II MHC molecules (Ireland et al., 2006). In this study, we correlate the response of a T cell that exclusively recognizes the chemically dominant HEL peptide, 48–62 (DGSTDYGILQINSRW), with a citrulline to arginine change at residue 61 (48–62-Cit61) to autophagy