Isoaspartyl modification of ZAP70 signaling molecule alters T cell responses (555.9)

The immune system is designed to protect the host by distinguishing self‐proteins from invading pathogens. However, neo‐epitopes generated from self‐proteins by post‐translational modifications can trigger autoreactive immune cells to break such immune tolerance. One such modification, isoaspartyl (isoAsp), is believed to contribute the onset of autoimmune B and T cell responses and lupus pathology. Protein L‐isoaspartyl (D‐aspartyl) methyltransferase (PIMT) is the only known repair system for abnormal isoaspartyl residues. Previously, we found that the isoAsp content in lupus‐prone MRL autoimmune mice increased and accumulated with age in brain and kidney, the major target organs in systemic lupus erythematosus (SLE). Recently, we found that the content of isoAsp modification in erythrocytes is correlated with PIMT activity in humans with SLE. The aberrant lupus T cell hyperproliferation can be rescued by PIMT overexpression. Of interest, ZAP70 is an essential kinase in T cell signaling and several ZAP70 mutations have been reported for patients with T cell immunodeficiencies. We found that isoAsp modification is present within ZAP70. In addition, ZAP70 is hyperphosphorylated upon TCR engagemant in PIMT deficient mice. Taken together, these studies demonstrate that isoAsp modification of ZAP70 TCR signaling molecule alters T cell immune responses and is associated with lupus T cell defects. Grant Funding Source : These studies were supported by NIH grant AI‐48120 to MJM.