Skip to main content

Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling.

Publication ,  Journal Article
Racioppi, L; Ronchese, F; Matis, LA; Germain, RN
Published in: J Exp Med
April 1, 1993

Clonal activation of CD4+ and CD8+ T lymphocytes depends on binding of peptide-major histocompatibility complex (MHC) molecule complexes by their alpha/beta receptors, eventually resulting in sufficient aggregation to initiate second messenger generation. The nature of intracellular signals resulting from such T cell receptor (TCR) occupancy is believed to be independent of the specific structure of the ligand being bound, and to vary quantitatively, not qualitatively, with the concentration of ligand offered and the affinity of the receptor for the peptide-MHC molecule complex. In contrast to the expectations of this model, the analysis of the response of a T helper type 1 clone to mutant E alpha E beta k molecules in the absence or presence of a peptide antigen revealed that peptide inhibited the interleukin 2 (IL-2) response to an otherwise allostimulatory mutant form of this MHC class II molecule. The inhibition was not due to competition for formation of alloantigen, it required TCR recognition of peptide-mutant MHC molecule complexes, and it decreased IL-2 production without affecting receptor-dependent IL-3, IL-2 receptor alpha, or size enlargement responses. This preferential reduction in IL-2 secretion could be correlated with the costimulatory signal dependence of this cytokine response, but could not be overcome by crosslinking the CD28 molecule on the T cell. These results define a new class of TCR ligands with mixed agonist/antagonist properties, and point to a ligand-related variation in the quality of clonotypic receptor signaling events or their integration with other signaling processes. It was also found that a single TCR ligand showed greatly different dose thresholds for the elicitation of distinct effector responses from a cloned T cell population. The observations that changes in ligand structure can result in qualitative alterations in the effects of receptor occupancy and that quantitative variations in ligand density can be translated into qualitative differences in T cell responses have important implications for models of intrathymic selection and control of the results of active immunization.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Exp Med

DOI

ISSN

0022-1007

Publication Date

April 1, 1993

Volume

177

Issue

4

Start / End Page

1047 / 1060

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Signal Transduction
  • Receptors, Antigen, T-Cell
  • Mutation
  • Molecular Sequence Data
  • Mice
  • Ligands
  • L Cells
  • Interleukin-3
  • Interleukin-2
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Racioppi, L., Ronchese, F., Matis, L. A., & Germain, R. N. (1993). Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling. J Exp Med, 177(4), 1047–1060. https://doi.org/10.1084/jem.177.4.1047
Racioppi, L., F. Ronchese, L. A. Matis, and R. N. Germain. “Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling.J Exp Med 177, no. 4 (April 1, 1993): 1047–60. https://doi.org/10.1084/jem.177.4.1047.

Published In

J Exp Med

DOI

ISSN

0022-1007

Publication Date

April 1, 1993

Volume

177

Issue

4

Start / End Page

1047 / 1060

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Signal Transduction
  • Receptors, Antigen, T-Cell
  • Mutation
  • Molecular Sequence Data
  • Mice
  • Ligands
  • L Cells
  • Interleukin-3
  • Interleukin-2