CD2-mediated IL-12-dependent signals render human gamma delta-T cells resistant to mitogen-induced apoptosis, permitting the large-scale ex vivo expansion of functionally distinct lymphocytes: implications for the development of adoptive immunotherapy strategies.
The ability of human gamma delta-T cells to mediate a number of in vitro functions, including innate antitumor and antiviral activity, suggests these cells can be exploited in selected examples of adoptive immunotherapy. To date, however, studies to examine such issues on a clinical scale have not been possible, owing in large measure to the difficulty of obtaining sufficient numbers of viable human gamma delta-T cells given their relative infrequency in readily available tissues. Standard methods used to expand human T cells often use a combination of mitogens, such as anti-T-cell receptor antibody OKT3 and interleukin (IL)-2. These stimuli, though promoting the expansion of alpha beta-T cells, usually do not promote the efficient expansion of gamma delta-T cells. CD2-mediated, IL-12-dependent signals that result in the selective expansion of human gamma delta-T cells from cultures of mitogen-stimulated human peripheral blood mononuclear cells are identified. It is first established that human gamma delta-T cells are exquisitely sensitive to apoptosis induced by T-cell mitogens OKT3 and IL-2. Next it is shown that the CD2-mediated IL-12-dependent signals, which lead to the expansion of gamma delta-T cells, do so by selectively protecting subsets of human gamma delta-T cells from mitogen-induced apoptosis. Finally, it is demonstrated that apoptosis-resistant gamma delta-T cells are capable of mediating significant antitumor cytotoxicity against a panel of human-derived tumor cell lines in vitro. Both the biologic and the practical implications of induced resistance to apoptosis in gamma delta-T cells are considered and discussed because these findings may play a role in the development of new forms of adoptive cellular immunotherapy. (Blood. 2000;96:3827-3837)
Lopez
R D
RD
Division of Bone Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, USA. richard.lopez@ccc.uab.edu
Xu
S
S
Guo
B
B
Negrin
R S
RS
Waller
E K
EK
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018801:CD2 Antigens / Q000276:immunology / Q000494:pharmacology*; D018929:Cell Culture Techniques / Q000379:methods*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008934:Mitogens / Q000494:pharmacology; D016853:Muromonab-CD3 / Q000494:pharmacology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D007376:Interleukin-2; D008934:Mitogens; D016853:Muromonab-CD3; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta