Immunoregulatory effects of CD4+ T helper subsets in human melanoma.
BACKGROUND
The elucidation of CD4+ T helper (Th) cell traits is important for the understanding of immunoregulatory mechanisms in patients with cancer, in particular the Th-cell effect on cytotoxic CD8+ tumor-specific lymphocytes (CTL).


METHODS
Sixty-six T-cell receptor alpha beta+/CD4+ clones were generated from tumor-infiltrating lymphocytes of five patients with melanoma and classified into subsets by cytokine production. Transwell experiments were performed to test how the soluble factors of each Th-clone subset affected the cytotoxicity of the tumor-specific CTL against autologous tumor.


RESULTS
Th0 clones enhanced cytotoxicity of the CD8+ CTL compared with control CTL cultured in cytokine-free medium. Th1-clone supernatant also enhanced cytotoxicity by CD8+ CTL. In contrast, Th2 clones decreased killing compared with control CTL. Replacement of the Th clones by exogenous interleukin (IL)-2 in concentrations similar to that produced by Th0 and Th1 clones enhanced cytotoxicity. However, suppression of cytotoxicity was observed when similar concentrations of IL-4 were added instead. The helper effect of Th0-soluble factors could be inhibited by anti-IL-2 antibody, whereas anti-IL-4 antibody did not show a significant enhancement.


CONCLUSIONS
The majority of the CD4+ tumor-infiltrating lymphocytes (Th0) in patients with melanoma enhance the CTL response to autologous tumor by their soluble factors, whereas Th2 cells suppress the CTL response.
Lee
K Y
KY
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Goedegebuure
P S
PS
Linehan
D C
DC
Eberlein
T J
TJ
D015703:Antigens, CD / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002999:Clone Cells; D046508:Culture Techniques / Q000379:methods; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D015703:Antigens, CD; D016207:Cytokines; D006684:HLA-DR Antigens; D007378:Interleukins; D007371:Interferon-gamma