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Differential recognition of peptide analogs by naive verses activated PLP 139-151-specific CD4+ T cells
B L McRae1, K M Nikcevich, W J Karpus
1Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611, USA.
Abstract:
CD4+ T cells specific for PLP 139-151 induce a relapsing-remitting form of EAE which is similar to the human demyelinating disease multiple sclerosis (MS) in both clinical course and histopathology. Conservative and nonconservative amino acid substitutions were introduced at three TcR or MHC contact residues within PLP 139-151 to identify fine specificity requirements, at the polyclonal level, for stimulating naive encephalitogenic T cells and for reactivating pre-primed autoreactive T cells as measured by T cell proliferation, cytokine induction, and functional encephalitogenic potential. The results indicate that peptides with substitutions at position 145 exhibited a significantly diminished ability to induce active disease, but these substitutions had little or no effect on the ability to activate PLP 139-151-primed T cells for proliferation or disease transfer. A conservative or a nonconservative substitution at position 144 ablated both encephalitogenic potential in active and adoptive EAE models and the ability to induce proliferative responses in T cells primed to the native peptide. A nonconservative lysine for glycine, but not a conservative serine substitution, at position 146 had similar effects. In contrast to their inability to induce active EAE and stimulate in vitro proliferation of PLP 139-151-primed T cells, the Y144 and the 146 analog peptides were able to suboptimally reactivate these cells for transfer of adoptive EAE. Furthermore, the nonencephalitogenic K146 peptide was found to exacerbate in vivo induction of EAE induced by priming with a suboptimal dose of PLP 139-151. These data support the hypothesis that naive neuroantigen-specific CD4+ T cells have more stringent activation requirements than do PLP 139-151-specific T cells which have previously encountered antigen. The finding that the analog peptides induced differential patterns of cytokine production, with LT/TNF-alpha production but not IFN-gamma production correlating with full encephalitogenic potential, suggests different functional outcomes may result from differential levels of signal transduction triggered by the substituted peptides. The significance of these results to the potential development of autoimmune disease via molecular mimicry and for the development of new strategies for preventing and treating T cell-mediated autoimmune diseases is discussed.
Insights
Modifying specific amino acids in the PLP 139-151 peptide altered its ability to trigger experimental autoimmune encephalomyelitis (EAE). Naive T cells require more stringent activation than pre-primed T cells for EAE induction.
Area of Science:
- Immunology
- Neuroscience
- Autoimmunity
Background:
- Experimental autoimmune encephalomyelitis (EAE) in rodents serves as a model for human multiple sclerosis (MS).
- CD4+ T cells recognizing the myelin proteolipid protein (PLP) 139-151 peptide are key drivers of EAE.
- Understanding T cell receptor (TCR) and MHC contact residue requirements is crucial for dissecting autoimmune responses.
Purpose of the Study:
- To investigate the fine specificity of T cell activation by the PLP 139-151 peptide.
- To determine how amino acid substitutions at critical contact points affect encephalitogenic T cell responses.
- To compare the activation requirements of naive versus pre-primed autoreactive T cells.
Main Methods:
- Synthesis of PLP 139-151 analogs with conservative and nonconservative amino acid substitutions at positions 144, 145, and 146.
- Assessing T cell proliferation and cytokine induction in response to native and analog peptides.
- Evaluating the encephalitogenic potential of T cells activated by these peptides in active and adoptive EAE models.
- Investigating the effect of analog peptides on EAE induction and exacerbation.
Main Results:
- Substitutions at position 145 diminished active EAE induction but minimally affected primed T cell proliferation.
- Substitutions at position 144 abrogated both encephalitogenic potential and T cell proliferation.
- Analog peptides at positions 144 and 146 could suboptimally reactivate primed T cells for adoptive EAE transfer.
- Naive T cells demonstrated more stringent activation requirements than pre-primed T cells.
- Differential cytokine production (LT/TNF-alpha vs. IFN-gamma) correlated with encephalitogenic potential.
Conclusions:
- Amino acid substitutions at specific residues of PLP 139-151 differentially impact T cell activation and encephalitogenicity.
- Naive and primed T cells exhibit distinct activation thresholds, suggesting differential signaling pathways.
- Findings have implications for understanding molecular mimicry in autoimmune disease and developing targeted therapies for T cell-mediated autoimmune disorders.