CD40 ligand and CTLA-4 are reciprocally regulated in the Th1 cell proliferative response sustained by CD8(+) dendritic cells.
Subsets of murine dendritic cells (DCs) from the spleen differ in their ability to induce proliferative responses in both primary and secondary CD4(+) T cells. Recent evidence indicates that lymphoid-related CD8(+) DCs fail to provide appropriate signals to freshly isolated secondary CD4(+) T cells to sustain their proliferation in vitro. In the present study, we examined peptide-pulsed CD8(-) and CD8(+) DCs for ability to stimulate Th1 and Th2 cell clones with the same Ag specificity. Defective ability to induce proliferation was selectively shown by CD8(+) DCs presenting Ag to the Th1 clone. The deficiency in CD8(+) DCs was overcome by CD40 triggering before peptide pulsing. When exposed to CD8(+) DCs in the absence of CD40 activation, the Th1 clone expressed low levels of CD40 ligand and high levels of surface CTLA-4. Neutralization of CTLA-4 during the DC/T cell coculture resulted in increased CD40 ligand expression and proliferation of T cells. Remarkably, the activation of CD40 on DCs under conditions that would increase Th1 cell proliferation, also resulted in down-regulation of surface CTLA-4. These results confirm differential effects of CD8(+) and CD8(-) DCs in the stimulation of Ag-primed Th cells. In addition, they suggest that reciprocal regulation of CD40 ligand and CTLA-4 expression occurs in Th1 cells exposed to CD8(+) DCs.
Department of Experimental Medicine, University of Perugia, Perugia, Italy.
Francesca
F
Fallarino
Ursula
U
Grohmann
Carmine
C
Vacca
Roberta
R
Bianchi
Maria C
MC
Fioretti
Paolo
P
Puccetti
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000032:analysis*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D018796:Immunoconjugates; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008811:Mice, Inbred DBA; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology; D015854:Up-Regulation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D016827:CD8 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D023201:CD40 Ligand; D018664:Interleukin-12; D000069594:Abatacept; D007371:Interferon-gamma