CD4+CD25- T cells transduced to express MHC class I-restricted epitope-specific TCR synthesize Th1 cytokines and exhibit MHC class I-restricted cytolytic effector function in a human melanoma model.
Cytolytic T cell-centric active specific and adoptive immunotherapeutic approaches might benefit from the simultaneous engagement of CD4(+) T cells. Considering the difficulties in simultaneously engaging CD4(+) and CD8(+) T cells in tumor immunotherapy, especially in an Ag-specific manner, redirecting CD4(+) T cells to MHC class I-restricted epitopes through engineered expression of MHC class I-restricted epitope-specific TCRs in CD4(+) T cells has emerged as a strategic consideration. Such TCR-engineered CD4(+) T cells have been shown to be capable of synthesizing cytokines as well as lysing target cells. We have conducted a critical examination of functional characteristics of CD4(+) T cells engineered to express the alpha- and beta-chains of a high functional avidity TCR specific for the melanoma epitope, MART-1(27-35), as a prototypic human tumor Ag system. We found that unpolarized CD4(+)CD25(-) T cells engineered to express the MART-1(27-35) TCR selectively synthesize Th1 cytokines and exhibit a potent Ag-specific lytic granule exocytosis-mediated cytolytic effector function of comparable efficacy to that of CD8(+) CTL. Such TCR engineered CD4(+) T cells, therefore, might be useful in clinical immunotherapy.
Chhabra
Arvind
A
Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA. arvindac@yahoo.com
Yang
Lili
L
Wang
Pin
P
Comin-Anduix
Begoña
B
Das
Raja
R
Chakraborty
Nitya G
NG
Ray
Swagatam
S
Mehrotra
Shikhar
S
Yang
Haiguang
H
Hardee
Cinnamon L
CL
Hollis
Roger
R
Dorsky
David I
DI
Koya
Richard
R
Kohn
Donald B
DB
Ribas
Antoni
A
Economou
James S
JS
Baltimore
David
D
Mukherji
Bijay
B
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D005822:Genetic Vectors; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes
D016207:Cytokines; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; C105787:MART-1-Melan-A(27-35) epitope; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell