Autopathogenic T Helper Cell Type 1 (Th1) and Protective Th2 Clones Differ in Their Recognition of the Autoantigenic Peptide of Myelin Proteolipid Protein

Abstract

We previously generated a panel of T helper cell 1 (Th1) clones specific for an encephalitogenic peptide of myelin proteolipid protein (PLP) peptide 139–151 (HSLGKWLGHPDKF) that induces experimental autoimmune encephalomyelitis (EAE) upon adoptive transfer. In spite of the differences in their T cell receptor (TCR) gene usage, all these Th1 clones required W144 as the primary and most critical TCR contact residue for the activation. In this study, we determined the TCR contact residues of a panel of Th2/Th0 clones specific for the PLP peptide 139–151 generated either by immunization with the PLP 139–151 peptide with anti– B7-1 antibody or by immunization with an altered peptide Q144. Using alanine-substituted peptide analogues of the native PLP peptide, we show that the Th2 clones have shifted their primary contact residue to the NH2-terminal end of the peptide. These Th2 cells do not show any dependence on the W144, but show a critical requirement for L141/G142 as their major TCR contact residue. Thus, in contrast with the Th1 clones that did not proliferate to A144-substituted peptide, the Th2 clones tolerated a substitution at position 144 and proliferated to A144 peptide. This alternative A144 reactive repertoire appears to have a critical role in the regulation of autoimmune response to PLP 139–151 because preimmunization with A144 to expand the L141/G142-reactive repertoire protects mice from developing EAE induced with the native PLP 139–151 peptide. These data suggest that a balance between two different T cell repertoires specific for same autoantigenic epitope can determine disease phenotype, i.e., resistance or susceptibility to an autoimmune disease.

Natural killer type 2 bias in remission of multiple sclerosis

“…Here we focused on the cytokine profile of NK cells in MS to gain insights into the immunoregulation of MS. We demonstrate first that NK cells in remission predominantly produce IL-5 but express lesser amounts of IL-12Rβ2 than do controls. The result indicates that the NK cells share some properties with Th2 cells (1,14,15), in that they are capable of competing with pathogenic autoimmune Th1 cells.…”

“…In experimental autoimmune encephalomyelitis (EAE) (1-4), the prototype autoimmune disease mediated by Th1 cells, cell depletion or adoptive transfer studies have established the role of regulatory αβT cells (1,2), B cells (3), and NK cells (4) in the regulation of the disease. However, it remains obscure how deeply involved are such regulatory cells in human Th1-mediated autoimmune diseases like multiple sclerosis (MS).…”

Pertussis Toxin Modulates the Immune Response to Neuroantigens Injected in Incomplete Freund’s Adjuvant: Induction of Th1 Cells and Experimental Autoimmune Encephalomyelitis in the Presence of High Frequencies of Th2 Cells

“…Th2 cells have been associated with protection from autoimmune disease (32,33,41,42). However, this notion has come under scrutiny.…”

Costimulation-Dependent Modulation of Experimental Autoimmune Encephalomyelitis by Ligand Stimulation of Vα14 NK T Cells

“…EAE is a Th1 cell-mediated disease that is principally subject to Th2 cell control (30,31). However, ␣-GC stimulation induces not only Th2 (IL-4) but also Th1 cytokine (IFN-␥) (14 -17).…”