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Changes in cytokine secretion induced by altered peptide ligands of myelin basic protein peptide 85-99
L J Ausubel1, J I Krieger, D A Hafler
1Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Myelin basic protein (MBP)-specific T cells were isolated directly from peripheral blood by stimulation either with native MBPp85-99 or altered peptide ligands (APLs) in which substitutions of the lysine were made at position 93, a TCR contact residue. We report here that the APL 93A could alter the cytokine profile of some autoreactive MBPp85-99 reactive T cell clones, switching them from a Th0 phenotype secreting high concentrations of IL-4, IL-5, and IFN-gamma into Th2 cells secreting significantly less IFN-gamma. However, in vitro stimulation with the 93A peptide, in some instances, induced T cells that responded better to the native MBPp85-99 peptide. Functionally, the APL 93A was shown to act as an antagonist for IFN-gamma secretion. Based on TCR sequencing and single cell cloning, this alteration in cytokine profile was determined to be the result of the differential activation of individual T cell clones. We discuss the implications of these data for the strength of signal model of T cell activation.
Insights
Altered peptide ligands (APLs) can modify T cell responses to myelin basic protein (MBP). Some APLs shifted T cell clones from a Th0 to a Th2 phenotype, reducing IFN-gamma secretion and acting as antagonists.
Area of Science:
- Immunology
- Autoimmunity
- T cell biology
Background:
- Myelin basic protein (MBP)-specific T cells are implicated in autoimmune responses.
- Altered peptide ligands (APLs) are modified peptides used to modulate T cell activity.
- Understanding T cell responses to MBP is crucial for autoimmune disease research.
Purpose of the Study:
- To investigate the effect of APLs on MBP-specific T cells.
- To characterize the cytokine profiles and functional responses of T cells stimulated with APLs.
- To explore the implications for T cell activation models.
Main Methods:
- Isolation of MBP-specific T cells from peripheral blood.
- Stimulation with native MBP peptide (MBPp85-99) and APLs (e.g., 93A).
- Cytokine profiling (IL-4, IL-5, IFN-gamma), TCR sequencing, and single-cell cloning.
Main Results:
- APL 93A altered cytokine profiles of some T cell clones, shifting them from Th0 to Th2 phenotypes.
- APL 93A induced T cells that responded better to native MBP peptide in some cases.
- APL 93A functioned as an antagonist for IFN-gamma secretion.
- Differential activation of individual T cell clones underlies the observed alterations.
Conclusions:
- APLs can modulate autoreactive T cell responses, including cytokine production and functional avidity.
- The observed effects are due to the differential activation of distinct T cell clones.
- These findings have implications for the strength of signal model of T cell activation in autoimmunity.