Selective loss of c-Rel compromises dendritic cell activation of T lymphocytes Daniel J. Boffa, a Biao Feng, b Vijay Sharma, a Ronald Dematteo, c George Miller, c M. Suthanthiran, a Rafael Nunez, c,d,1 and Hsiou-Chi Liou b, * a The Department of Medicine, The New York Presbyterian Hospital, Weill Medical College of Cornell University, 515 East 71 Street, S-210, New York, NY 10021, USA b The Division of Immunology, Weill Medical College of Cornell University, USA c Memorial Sloan Kettering Research Center, USA d Department of Medicine, Hematology–Oncology Section, University of Illinois at Chicago, USA Received 18 November 2002; accepted 23 April 2003 Abstract Dendritic cells initiate the immune response by presenting antigen in the context of varying levels of costimulation. The maturation state of the dendritic cell determines the quantity and quality (Th1, Th2) of the subsequent T cell response. Members of the NF-jB family of transcription factors have previously been implicated in dendritic cell development. Here, we used a mouse with a homozygous c-Rel deletion to investigate the role of c-Rel in the function of bone marrow derived dendritic cells. When direct presentation was evaluated, we found c-Rel = dendritic cells induce less allogeneic T cell stimulation than c-Rel þ=þ dendritic cells. In addition, T cell encounters with c-Rel = dendritic cells generate less IFN-c and IL-4 when compared to those with c-Rel þ=þ DCs. A similar degree of functional compromise was observed in antigen-specific T cells that were stimulated by c-Rel = dendritic cells. Functional deficits were not linked to differences in the ability to undergo maturation per se, as LPS exposure induced similar morphologic and cell surface changes in both c-Rel þ=þ and cRel = DCs. Although LPS induced a compensatory increase in the nuclear activity of fellow NF-jB family members, RelB and p65, LPS exposure was unable to negate the deficiencies in au- tologous T cell proliferation and cytokine production associated with the loss of c-Rel in dendritic cells. Taken together, our study supports a unique and non-redundant role for c-Rel in dendritic cell costimulatory capacity. Ó 2003 Elsevier Science (USA). All rights reserved. Keywords: NF-jB; c-Rel; Cytokines; Dendritic cells; T lymphocytes; Costimulation 1. Introduction Dendritic cells (DCs) are critical mediators of the immune response. They are uniquely suited to both present antigens and deliver costimulatory signals to na € ıve T cells [1]. In addition to introducing antigen to the host immune system, dendritic cells influence the type of response that is generated. One mechanism by which DCs control the quality of the response involves IL-12. Increased IL-12 secretion by dendritic cells drives the cell-mediated Th1 pathway while reduced levels fa- vor the Th2 pathway or humeral response [2]. In order to perform such varied tasks, the dendritic cell must be armed with a battery of surface and trans- port proteins as well as cytokines and other secretory stores. Transcriptional regulation ensures adequate and appropriately timed production of the specific peptides. Members of the NF-jB family of transcription factors p50, p52, p65 (RelA), c-Rel, and RelB are expressed at relatively high levels in dendritic cells [3]. To varying degrees, the NF-jB transcription factors are associated with dendritic cell development, maturation, and func- tion [4–6]. For example, lipopolysaccharide (LPS), a bacterial wall component, leads to DC maturation with a corresponding elevation in nuclear NF-jB [7,8]. Sev- Cellular Immunology 222 (2003) 105–115 www.elsevier.com/locate/ycimm * Corresponding author. Fax: 1-212-746-8167. E-mail addresses: rafaelnr@uic.edu (R. Nunez), hcliou@med.cor- nell.edu (H.-C. Liou). 1 Also corresponding author. 0008-8749/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0008-8749(03)00114-X