Cutaneous T cell lymphoma reactive CD4+ cytotoxic T lymphocyte clones display a Th1 cytokine profile and use a fas-independent pathway for specific tumor cell lysis.
We have previously described two cytotoxic T lymphocyte clones isolated from lymphocytes infiltrating a human major histocompatibility complex class II-/class I+, CD4+ cutaneous T cell lymphoma. These clones displayed a CD4+CD8dim+ (TC5) and CD4+ CD8- (TC7) phenotype and mediated a specific major histocompatibility complex class I-restricted cytotoxic activity toward Cou-LB autologous tumor cell line. Our studies were performed to elucidate the mechanism involved in T-cell-clone-mediated cytotoxicity and to determine the cytokine profile of both the lymphoma cell line and specific cytotoxic T lymphocyte clones. The results indicate that, despite surface expression of Fas receptor on Cou-LB and Fas ligand induction on TC5 and TC7 cell membranes, the CD4+ cytotoxic T lymphocyte clones do not use this cytotoxic mechanism to lyse their specific target. The TC7 clone uses instead a granzyme-perforin-dependent pathway. Furthermore, quantitative analysis of Th1 and Th2 cytokine mRNA expression in the cutaneous T cell lymphoma cell line as well as in TC5 and TC7 clones indicated that, whereas the tumor cells display a Th2-type profile (interleukin-4, interleukin-6, and interleukin-10), the cytotoxic T lymphocyte clones express Th1-type cytokines (interferon-gamma, granulocyte macrophage colony stimulating factor, and interleukin-2). In addition, preincubation of the tumor-infiltrating lymphocyte clones with autologous tumor cells induced their activation and subsequent amplification of the Th1-type response. These results indicate a direct contribution of the malignant cells in the Th1/Th2 imbalance observed frequently in cutaneous T cell lymphoma patients and suggest their potential role in depressed cell-mediated immunity. Identification of CD4+ Th1-type cytotoxic T lymphocyte clones, the tumor antigen they recognize, and optimization of their cytokine expression profile should be useful for the design of new immunotherapy protocols in cutaneous T cell lymphoma.
Echchakir
H
H
Laboratoire Cytokines et Immunologie des tumeurs humaines, INSERM U487, Institut Gustave Roussy, Villejuif, France.
Bagot
M
M
Dorothée
G
G
Martinvalet
D
D
Le Gouvello
S
S
Boumsell
L
L
Chouaib
S
S
Bensussan
A
A
Mami-Chouaib
F
F
D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D016207:Cytokines / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D016410:Lymphoma, T-Cell, Cutaneous / Q000473:pathology*; D008297:Male; D012878:Skin Neoplasms / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*; D018417:Th1 Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
D016207:Cytokines; D007376:Interleukin-2; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D019014:fas Receptor; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor