Human and murine CD4 T cell reactivity to a complex antigen: recognition of the synthetic random polypeptide glatiramer acetate.
The capacity of glatiramer acetate (GA), a random copolymer of alanine, lysine, glutamic acid, and tyrosine to stimulate primary in vitro human and murine T cell proliferation was examined. PBMCs isolated from healthy humans and relapsing remitting multiple sclerosis patients and spleen cells from inbred strains of mice, expressing different H-2 haplotypes, were used as sources of non-GA-primed lymphocytes. GA functioned as a universal Ag, inducing dose-dependent proliferation of all non-GA-primed human and murine T cell populations tested. Moreover, GA stimulated PBMCs derived ex vivo from human cord blood, strongly suggesting that GA can activate both naive and memory T cells. The human T cell proliferative responses to GA were HLA class II DR-restricted by virtue of the ability of anti-class II Ab to inhibit T cell proliferation, and the demonstration that individual GA specific human T cell clones were HLA class II DR-restricted by either restriction element but not both. Furthermore, GA-reactive T cells secreted Th0 cytokines and expressed a diverse repertoire of TCR. Limiting dilution analysis indicated that the T cell precursor frequency among the healthy human adults tested ranged from 1:5,000 to 1:125,000. Given that all of the T cell populations tested were isolated from non-GA-primed donors, it appears that virtually all humans and murine strains contain significant numbers of T cell populations cross-reactive with GA. These findings may explain the recent clinical finding that daily s.c. administration of GA ameliorates the progression of multiple sclerosis.
Duda
P W
PW
Laboratory of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Krieger
J I
JI
Schmied
M C
MC
Balentine
C
C
Hafler
D A
DA
D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002461:Cell Line, Transformed; D002469:Cell Separation; D002999:Clone Cells; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D000068717:Glatiramer Acetate; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory / Q000235:genetics; D018189:Immunomagnetic Separation; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism* / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D006684:HLA-DR Antigens; D010455:Peptides; D000068717:Glatiramer Acetate