A Failure to Repair Self-Proteins Leads to T Cell Hyperproliferation and Autoantibody Production

• Published in: The Journal of immunology (1950) Vol. 171; no. 6; pp. 2840 - 2847
• Main Authors: Doyle, Hester A, Gee, Renelle J, Mamula, Mark J
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-09-2003
• Subjects: Animals; Autoantibodies - biosynthesis; Autoantigens - immunology; Autoantigens - metabolism; Bone Marrow Transplantation - immunology; CD28 Antigens - pharmacology; Cell Division - genetics; Cell Division - immunology; Immunophenotyping; Isoaspartic Acid - metabolism; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Lymph Nodes - enzymology; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymph Nodes - pathology; Lymphocyte Activation - genetics; Lymphoid Tissue - enzymology; Lymphoid Tissue - metabolism; Lymphoid Tissue - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogens - pharmacology; Phosphorylation; Protein D-Aspartate-L-Isoaspartate Methyltransferase - deficiency; Protein D-Aspartate-L-Isoaspartate Methyltransferase - genetics; Protein D-Aspartate-L-Isoaspartate Methyltransferase - physiology; Receptors, Antigen, T-Cell - physiology; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.6.2840

It is clear that many factors can perturb T cell homeostasis that is critical in the maintenance of immune tolerance. Defects in the molecules that regulate homeostasis can lead to autoimmune pathology. This simple immunologic concept is complicated by the fact that many self-proteins undergo spontaneous posttranslational modifications that affect their biological functions. This is the case in the spontaneous conversion of aspartyl residues to isoaspartyl residues, a modification occurring at physiological pH and under conditions of cell stress and aging. We have examined the effect of isoaspartyl modifications on the effector functions of T lymphocytes in vivo using mice lacking the isoaspartyl repair enzyme protein carboxyl methyltransferase (PCMT). PCMT(-/-) CD4(+) T cells exhibit increased proliferation in response to mitogen and Ag receptor stimulation as compared with wild-type CD4(+) T cells. Hyperproliferation is marked by increased phosphorylation of members of both the TCR and CD28 signaling pathways. Wild-type mice reconstituted with PCMT(-/-) bone marrow develop high titers of anti-DNA autoantibodies and kidney pathology typical of that found in systemic lupus erythematosus. These observations, coupled with the fact that humans have polymorphisms in the pcmt gene, suggest that isoaspartyl self-proteins may alter the maintenance of peripheral immune tolerance.