Limits...
Autopathogenic T helper cell type 1 (Th1) and protective Th2 clones differ in their recognition of the autoantigenic peptide of myelin proteolipid protein.

Das MP, Nicholson LB, Greer JM, Kuchroo VK - J. Exp. Med. (1997)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

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.

Show MeSH

Related in: MedlinePlus

Preimmunization  with A144 ameliorates EAE. Animals were preimmunized with  the native peptide W144 (open  squares), A141 (open triangle),  A142 (open circle), or A144 (closed  circle) and 7 d later reimmunized  with the native PLP peptide  139–151 and assessed daily for  signs of clinical disease.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2199041&req=5

Figure 4: Preimmunization with A144 ameliorates EAE. Animals were preimmunized with the native peptide W144 (open squares), A141 (open triangle), A142 (open circle), or A144 (closed circle) and 7 d later reimmunized with the native PLP peptide 139–151 and assessed daily for signs of clinical disease.

Mentions: Because encephalitogenic Th1 and protective Th2 cells show a dramatic difference in activation with A144 peptide in that A144 peptide activates PLP 139–151-specific Th2 clones but not the Th1 clones, we tested the effect of preimmunization with A144 peptide on the induction of EAE. Groups of SJL mice were preimmunized either with the native W144, A141, A142, or A144 peptides in CFA and then challenged with the encephalitogenic PLP 139– 151 to induce EAE. As shown in Fig. 4, preimmunization with A144 protected mice from the development of EAE. In contrast, preimmunization with A142 did not show significant protection and A141 showed slight inhibition of disease, which was not significant. However, in other experiments preimmunization with A141 and A142 accelerated the day of onset and enhanced severity of disease (data not shown). These data suggest that preimmunization with A144 probably leads to the expansion of the A144-reactive protective repertoire that inhibited the disease induced with the native peptide.


Autopathogenic T helper cell type 1 (Th1) and protective Th2 clones differ in their recognition of the autoantigenic peptide of myelin proteolipid protein.

Das MP, Nicholson LB, Greer JM, Kuchroo VK - J. Exp. Med. (1997)

Preimmunization  with A144 ameliorates EAE. Animals were preimmunized with  the native peptide W144 (open  squares), A141 (open triangle),  A142 (open circle), or A144 (closed  circle) and 7 d later reimmunized  with the native PLP peptide  139–151 and assessed daily for  signs of clinical disease.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199041&req=5

Figure 4: Preimmunization with A144 ameliorates EAE. Animals were preimmunized with the native peptide W144 (open squares), A141 (open triangle), A142 (open circle), or A144 (closed circle) and 7 d later reimmunized with the native PLP peptide 139–151 and assessed daily for signs of clinical disease.
Mentions: Because encephalitogenic Th1 and protective Th2 cells show a dramatic difference in activation with A144 peptide in that A144 peptide activates PLP 139–151-specific Th2 clones but not the Th1 clones, we tested the effect of preimmunization with A144 peptide on the induction of EAE. Groups of SJL mice were preimmunized either with the native W144, A141, A142, or A144 peptides in CFA and then challenged with the encephalitogenic PLP 139– 151 to induce EAE. As shown in Fig. 4, preimmunization with A144 protected mice from the development of EAE. In contrast, preimmunization with A142 did not show significant protection and A141 showed slight inhibition of disease, which was not significant. However, in other experiments preimmunization with A141 and A142 accelerated the day of onset and enhanced severity of disease (data not shown). These data suggest that preimmunization with A144 probably leads to the expansion of the A144-reactive protective repertoire that inhibited the disease induced with the native peptide.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

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.

Show MeSH
Related in: MedlinePlus