The Leishmania major LACK Antigen with an Immunodominant Epitope at Amino Acids 156 to 173 Is Not Required for Early Th2 Development in BALB/c Mice

摘要

The Leishmania major LACK antigen contains an immunodominant epitope at amino acids 156 to 173 (LACK156-173) that is believed to nucleate the pathological Th2 immune response in susceptible BALB/c mice. To test this hypothesis, we generated L. major parasites that express a mutated LACK that fails to activate Vβ4/Vα8 T-cell receptor transgenic T cells specific for this epitope. Although mutant parasites attenuated the expansion of endogenous LACK-specific, interleukin-4 (IL-4)-expressing, CD4 T cells compared to wild-type parasites in vivo, the overall frequency of IL-4 and gamma interferon-secreting lymphocytes was similar to that elicited by wild-type L. major. Mutant parasites demonstrated diminished amastigote viability and delayed lesion development in mice, although parasites could be recovered over 200 days after infection. Complementation with a wild-type lack fusion construct partially rescued these defects, indicating a role for endogenous LACK in parasitism. Mice inoculated with mutant parasites were not protected against subsequent infection with wild-type L. major.