Altered ligands reveal limited plasticity in the T cell response to a pathogenic epitope

Experimental leishmaniasis offers a well characterized model of T helper type 1 cell (Th1)-mediated control of infection by all intracellular organism. Susceptible BALB/c mice aberrantly develop Th2 cells ill response to infection and are unable to control parasite dissemination. The early CD4(+) T cell response in these mice is oligoclonal and reflects the expansion of V beta 4/V alpha 8-bearing T cells in response to a single epitope from the parasite Leishmania homologue of mammalian RACK1 (LACK) antigen. Interleukin 4 (IL-4) generated by these cells is believed to direct the subsequent Th2 response. We used T cells from T cell receptor-transgenic mice expressing such a V beta 4/V alpha 8 receptor to characterize altered peptide ligands with similar affinity for I-A(d). Such altered ligands failed to activate IL-4 production from transgenic LACK-specific T cells or following injection into BALB/c mice. Pretreatment of susceptible mice with altered peptide ligands substantially altered the course of subsequent infection. The ability to confer a healer phenotype on otherwise susceptible mice using altered peptides that differed by a single amino acid suggests limited diversity in the endogenous T cell repertoire recognizing this antigen.