Altered peptide ligands can modify the Th2 T cell response to the immunodominant 161-175 peptide of LACK (Leishmania homolog for the receptor of activated C kinase).

Abstract

Following Leishmania major infection, the early LACK (Leishmania homolog of receptors for activated C kinase)-induced IL-4 response appears to determine disease susceptibility in BALB/c mice. Therefore, we sought to manipulate the pathogenic T cell responses to the immunodominant epitope with the use of altered peptide ligands (APLs). Conservative and non-conservative substitutions for each amino acid of the LACK 161-175 peptide determinant were tested for their stimulatory capacity in four different LACK-reactive T cell systems. From these results, we propose a likely LACK 163-171/I-A(d) core peptide register and show that APLs with changes at putative T cell receptor (TCR) contacts provide the greatest potential for immune deviation. In particular, the TCR-contact H164V APL expanded Th1 cells upon in vitro recall of naïve splenocytes from LACK-specific BV4 T cell receptor transgenic mice and stimulated IFN-gamma secretion from a Th2-committed LACK-reactive T cell line. We also observed that non-conservative substitutions flanking the core determinant had strong agonistic effects for proliferation and Th1/Th2 modulation. However, upon immunization, the H164V APL considerably downregulated proliferation and cytokine responses to the wild type LACK 161-175 peptide, while immunization with the weak agonist, MHC contact APL S171K, increased the IFN-gamma/IL-4 ratio to the wild type peptide. In these instances, a hyporesponsive T cell response to the wild-type peptide was achieved by immunizing with an APL possessing non-conservative substitutions at TCR contact sites, while immune deviation was accomplished using a weak-agonist APL that retained the core determinant. Thus, certain LACK-APLs are able to induce T cell responses with a protective phenotype in an infectious disease such as leishmaniasis.

• Authors: Kirk D C Jensen, Eli E Sercarz, Claudia Raja Gabaglia
• Journal: Molecular immunology (Mol Immunol) Vol. 46 Issue 3 Pg. 366-74 (Jan 2009) ISSN: 0161-5890 [Print] England
• PMID: 19042022 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, Protozoan
• Cytokines
• Immunodominant Epitopes
• Ligands
• Peptides
• Protozoan Proteins
• Protozoan Vaccines
• Receptors, Antigen, T-Cell
• LACK antigen, Leishmania
• Interleukin-4
• Interferon-gamma

Topics

• Amino Acid Sequence
• Amino Acid Substitution
• Animals
• Antigens, Protozoan (chemistry, immunology)
• Cell Line
• Cell Proliferation
• Cross-Priming (immunology)
• Cytokines
• Immunization
• Immunodominant Epitopes (immunology)
• Interferon-gamma (immunology)
• Interleukin-4 (immunology)
• Leishmania major (immunology)
• Ligands
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Molecular Sequence Data
• Peptides (chemistry, immunology)
• Protozoan Proteins (chemistry, immunology)
• Protozoan Vaccines (immunology)
• Receptors, Antigen, T-Cell (immunology)
• Th2 Cells (cytology, immunology)