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).
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.
Jensen
Kirk D C
KD
Laboratory of Vaccine Research, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
Sercarz
Eli E
EE
Gabaglia
Claudia Raja
CR
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000953:Antigens, Protozoan / Q000737:chemistry / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D045142:Cross-Priming / Q000276:immunology; D016207:Cytokines; D007114:Immunization; D016056:Immunodominant Epitopes / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D018320:Leishmania major / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D015800:Protozoan Proteins / Q000737:chemistry / Q000276:immunology*; D016052:Protozoan Vaccines / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
D000953:Antigens, Protozoan; D016207:Cytokines; D016056:Immunodominant Epitopes; D008024:Ligands; D010455:Peptides; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D011948:Receptors, Antigen, T-Cell; C093139:LACK antigen, Leishmania; D015847:Interleukin-4; D007371:Interferon-gamma