Use of interleukin-7, interleukin-2, and interferon-gamma to propagate CD4+ T cells in culture with maintained antigen specificity.
In contrast to CD8+ T cells, it has been difficult to establish consistently satisfactory conditions for the bulk culture of antitumor CD4+ T cells in either mice or humans. This difficulty is not limited to tumor antigen, since similar problems are encountered growing CD4+ T cells that recognize alloantigen, tetanus, or candida. Four basic findings are reviewed in this article, stemming from work with identical results in both human and mouse. (a) Although CD4+ T cells initially proliferate after exposure to appropriate antigen-presenting cells (APCs), such proliferation is not sustained; however, expansion of CD4+ T cells can be achieved with the addition of recombinant interleukin-2 (rIL2) or rIL-7. (b) Specific CD4+ responses to antigens are often better sustained with exogenous IL-7 than with exogenous IL-2. (c) Adding rIL-7 or rIL-2 permits sustained CD4+ T-cell proliferation, but subsequent culture restimulation is complicated by high background reactivity to APCs whether APCs are antigen pulsed or not; this problem can be overcome by addition of exogenous interferon-gamma (IFN-gamma) to the CD4+ cultures. (d) In certain instances proliferation is paradoxically impaired by reexposure to specific antigen, possibly reflecting apoptosis; this problem is also overcome by addition of rIFN-gamma to culture. We conclude that combinations of exogenous IL-7, IL-2, and IFN-gamma with APC restimulation can be used to sustain antigen-specific CD4+ T cells in culture. Using these techniques, antitumor CD4+ T cells were propagated from the peripheral blood of two tumor-bearing patients.
Cohen
P A
PA
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Kim
H
H
Fowler
D H
DH
Gress
R E
RE
Jakobsen
M K
MK
Alexander
R B
RB
Mulé
J J
JJ
Carter
C
C
Rosenberg
S A
SA
D000818:Animals; D000937:Antigen-Antibody Reactions; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D000939:Epitopes; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology
D000951:Antigens, Neoplasm; D000939:Epitopes; D007376:Interleukin-2; D015851:Interleukin-7; D007371:Interferon-gamma