A subset of dendritic cells induces CD4+ T cells to produce IFN-gamma by an IL-12-independent but CD70-dependent mechanism in vivo.
Interferon (IFN)-gamma, a cytokine critical for resistance to infection and tumors, is produced by CD4(+) helper T lymphocytes after stimulation by cultured dendritic cells (DCs) that secrete a cofactor, interleukin (IL)-12. We have identified a major IL-12-independent pathway whereby DCs induce IFN-gamma-secreting T helper (Th)1 CD4(+) T cells in vivo. This pathway requires the membrane-associated tumor necrosis family member CD70 and was identified by targeting the LACK antigen from Leishmania major within an antibody to CD205 (DEC-205), an uptake receptor on a subset of DCs. Another major DC subset, targeted with 33D1 anti-DCIR2 antibody, also induced IFN-gamma in vivo but required IL-12, not CD70. Isolated CD205(+) DCs expressed cell surface CD70 when presenting antigen to T cell receptor transgenic T cells, and this distinction was independent of maturation stimuli. CD70 was also essential for CD205(+) DC function in vivo. Detection of the IL-12-independent IFN-gamma pathway was obscured with nontargeted LACK, which was presented by both DC subsets. This in situ analysis points to CD70 as a decision maker for Th1 differentiation by CD205(+) DCs, even in Th2-prone BALB/c animals and potentially in vaccine design. The results indicate that two DC subsets have innate propensities to differentially affect the Th1/Th2 balance in vivo and by distinct mechanisms.
Soares
Helena
H
Laboratory of Cellular Physiology and Immunology and Chris Browne Center, The Rockefeller University, New York, NY 10021, USA.
Waechter
HaeNa
H
Glaichenhaus
Nicholas
N
Mougneau
Evelyne
E
Yagita
Hideo
H
Mizenina
Olga
O
Dudziak
Diana
D
Nussenzweig
Michel C
MC
Steinman
Ralph M
RM
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology; D053282:CD27 Ligand / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
D015703:Antigens, CD; D000953:Antigens, Protozoan; D053282:CD27 Ligand; C093569:DEC-205 receptor; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; C093139:LACK antigen, Leishmania; D018664:Interleukin-12; D007371:Interferon-gamma