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)

作者：Jensen Kirk D C; Sercarz Eli E; Gabaglia Claudia Raja^*

来源：Molecular Immunology, 2009, 46(3): 366-374.

DOI：10.1016/j.molimm.2008.10.024

• LACK
• Leishmania
• Flanking residues
• Core determinant
• Altered peptide ligands
• Agonists
• I-A(d)
• T cell receptor
• Th1/Th2

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 immunnodominant 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 ill vitro recall of naive 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 all infectious disease such as leishmaniasis.

• 出版日期2009-1