Activated antigen-presenting cells select and present chemically modified peptides recognized by unique CD4 T cells

Abstract

CD4 T cells recognized posttranslationally modified peptides of the protein hen egg-white lysozyme (HEL), consisting of nitration of tyrosines and modifications of tryptophans in the T cell contact residues of the peptides. T cells were directed against modifications of a chemically dominant HEL peptide as well as a minor HEL peptide, bound to the class II histocompatibility molecule I-A k . The modified peptides were generated in vivo after immunization with native HEL molecules or were generated ex vivo by peroxynitrite treatment of HEL. Moreover, antigen-presenting cells (APC), either macrophages or dendritic cells activated in culture or in vivo, generated the modified HEL epitopes that stimulated the T cells. In transgenic mice expressing HEL, the T cells to the modified epitopes escaped negative selection and were found, albeit fewer in number than in normal mice. Infection with Listeria monocytogenes of the transgenic HEL mice generated APC containing the modifications. T cells to modified epitopes induced by activation of APC may be a component of antimicrobial immunity and autoimmune reactions.histocompatability molecules ͉ nitrotyrosine ͉ posttranslational modification P eptides bound to either class I or class II MHC molecules suffer posttranslational modifications of potential importance in the context of inducing unique T cell reactivities. A number of posttranslational changes were identified on peptides isolated from class I MHC proteins (1, 2), including phosphorylation of tyrosine residues (3). Unique T cell reactivities were ascribed to changes in the peptides bound to class II MHC molecules (reviewed in ref. 4). These included phosphorylations (5), conversions of asparagine or aspartic acid to isoaspartic acid (6, 7), glutamine to glutamic acid (8, 9), nitration of tyrosine (10), and addition of saccharide residues to a peptide (11-15). These results are reminiscent of early ones showing T cell reactions to proteins containing small reactive chemical groups, i.e., with ''haptens,'' first reported by Jones and Leskowitz (16) in delayed sensitivity reactions to arsanilic acid. Their observations were extended by others (17), including by using dinitrophenyl to derivatize class II molecules on cells (18). Clearly, T cells are highly discriminatory of large or small changes in the residues to which their receptor [T cell receptor (TCR)] establishes contact. Antibodies directed to posttranslationally modified proteins have also been identified (19,20).Activation of macrophages and dendritic cells (DC) takes place after their interactions with IFN-␥ together with cytokines like TNF or IL-1, or microbial products like LPS from Gram-negative bacteria. The activation includes the production of nitric oxide (NO) and reactive oxygen species with the formation of strong oxidizing molecules such as peroxynitrite (21-23) or other derivatives (24,25). These molecules induce a number of amino acid changes, including nitration of tyrosines (21, 22) and modification of tryptophans (26). The present study report...

Conversion of Tyrosine to the Inflammation-Associated Analog 3′-Nitrotyrosine at Either TCR- or MHC-Contact Positions Can Profoundly Affect Recognition of the MHC Class I-Restricted Epitope of Lymphocytic Choriomeningitis Virus Glycoprotein 33 by CD8 T Cells

“…In the present study, we provide evidence that, as previously observed with CD4 T cells (23,25), CD8 T cells can specifically recognize epitopes containing a tyrosine-to-nitrotyrosine conversion. Y4 of gp33 has previously been shown to comprise an important TCR-contact point for T cells recognizing NY-gp33 in the context of H-2D b (27,29).…”

“…These results imply that T cells bearing receptors capable of "recognizing" nitrated "self" peptides are not subject to the constraints of negative selection in the thymus (central tolerance) and that NYP formed during periods of inflammation may therefore constitute an important class of "neoautoantigens" that may play a role in inflammation and or autoimmune disease. Similar findings were recently reported for another MHC class II-restricted model Ag, hen egg lysozyme, that was treated to contain the oxidative modifications nitro-tryptophan or nitrotyrosine (25).…”

Cutting Edge: Unique T Cells That Recognize Citrullinated Peptides Are a Feature of Protein Immunization

“…We recently called attention to nitration of tyrosine residues (13) and oxidation of tryptophans on peptides from the protein, hen egg-white lysozyme (HEL), bound to the class II histocompatibility molecule I-A k (14). These changes took place when APCs were activated during immunological reactions including infections.…”

Identification of Immunoglobulins that Recognize 3-Nitrotyrosine in Patients with Acute Lung Injury after Major Trauma

“…For example, antibodies against oxidized phospholipids have been detected in patients with cardiovascular diseases and diabetic nephropathy (9)(10)(11)(12). However, it is not known at present if nitration of tyrosine residues in proteins will induce immune responses in humans, despite studies in rabbits and mice indicating that several tyrosine nitrated proteins and peptides readily induce the generation of anti-nitrotyrosine antibodies (13)(14)(15)(16)(17)(18)(19)(20).…”