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 an intracellular organism. Susceptible BALB/c mice aberrantly develop Th2 cells in 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 Vbeta4/ Valpha8-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 Vbeta4/Valpha8 receptor to characterize altered peptide ligands with similar affinity for I-Ad. 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.
Pingel
S
S
Departments of Medicine, Microbiology, and Immunology, University of California San Francisco, San Francisco, California 94143, USA.
Launois
P
P
Fowell
D J
DJ
Turck
C W
CW
Southwood
S
S
Sette
A
A
Glaichenhaus
N
N
Louis
J A
JA
Locksley
R M
RM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology*; D004198:Disease Susceptibility; D000939:Epitopes / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology*; D015800:Protozoan Proteins / Q000737:chemistry / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D018089:Superantigens / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D000953:Antigens, Protozoan; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D010446:Peptide Fragments; D015800:Protozoan Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D018089:Superantigens; C093139:LACK antigen, Leishmania; D015847:Interleukin-4; D007371:Interferon-gamma