OR.78. Breast Cancer Microenvironment InducesOX40L Expression on Dendritic Cells, which PrimePro-inflammatory Th2 CellsAlexander Pedroza-Gonzalez, Mike Gallegos, MarkMichnevitz, Sasha Tindle, Florentina Marches, JacquesBanchereau, A. Karolina Palucka. Baylor Institute forImmunology Research, Dallas, TX

We have shown that breast cancer tumors are infiltratedwith mature dendritic cells (DCs), which cluster with CD4+ Tcells. CD4+ T cells infiltrating breast cancer tumors secretetype 1 (IFN-γ), as well as high levels of type 2 (IL-4 and IL-13)cytokines. By implanting human breast cancer cell lines inNOD/SCID β2m-/- mice engrafted with human CD34+ hema-topoietic progenitor cells (HPCs) and autologous T cells, wefound that CD4+ T cells promote early tumor development.This can be prevented by administration of IL-13 antagonistsand is dependent on DCs. Now we show that CD4+ T cellsinfiltrating breast cancer tumors can also secrete TNFα.Immunofluorescence staining of breast cancer tissue sectionsfrom patients shows expression of OX40 ligand (OX40L) onDCs. OX40L expression on DCs can be induced by breastcancer cell-derived soluble factors. OX40L+ DCs induce invitro the production of IL-13 and TNFα in addition to type 1cytokines on naïve CD4+ T cells after 6 days of activation.Accordingly, in our model of breast tumor-bearing humanizedmice, DCs isolated from breast tumor and its draining lymphnodes induce the production of high level of IL4, IL13 andTNFα by naive CD4 T cells. Blocking in vitro OX40L preventsgeneration of the IL-13 secreting CD4+ T cells and decreasesthe production of TNFα. Thus, breast cancer targets DCs topromote its development by inducing type 2 immunity viaOX40L.

doi:10.1016/j.clim.2008.03.085

OR.79. Identification in Mouse and Human of a NewBlood-derived Dermal Langerin+ Dendritic CellsPopulation that Survey the Skin in the Steady StateFlorent Ginhoux,1 Matthew Collin,1 Keisuke Nagao,2 MarkUdey,2 Miriam Merad.1 1Mount Sinai School of Medicine, NewYork, NY; 2National Cancer Institute, Center for CancerResearch, National Institutes of Health, Bethesda, MD

Langerin is a C-type lectin receptor that recognizes gly-cosylated patterns on pathogens. Langerin is used to identifyhuman and mouse epidermal Langerhans cells (LC), as well asmigratory LC in the dermis and the skin draining lymph nodes(DLN). Using a mouse model that allows conditional ablationof langerin+ cells in vivo, together with congenic bone mar-row chimeras and parabiotic mice as tools to differentiateLC- and blood-derived dendritic cells (DC), we show that incontrast to the current view, langerin+CD8- DC in the skinDLN do not derive exclusively from migratory LC. We iden-tified a new population of blood-derived langerin+ DC thattransit through the dermis in the steady state beforereaching the DLN charged with skin antigens in a CCR7dependent mechanism. Dermal langerin+ DC can be distin-guished from LC by the absence of expression of the

Epithelial cell adhesion molecule (EpCAM), allowing us toshow that EpCAM-langerin+ dermal DC are present in thedermis and skin DLN of Rag2-/-TGFβ1-/- mice, whereasEpCAM+langerin+LC are absent. Moreover, we found anequivalent DC population in the human dermis that doesnot express EpCAM, expresses langerin and CD1a, however atlower levels than epidermal LC. Further experiments withhuman hematopoietic transplants will determine whetherthis newly identified DC population has a distinct home-ostasis compared with epidermal LC. Altogether, theseresults provide new insights into the heterogeneity ofcutaneous DC populations, defining new DC subpopulationsfrom different lineages likely to play different functionalroles in skin immunity.

doi:10.1016/j.clim.2008.03.086

OR.80. Respiratory Syncytial Virus Blocks MHCClass-II Surface Translocation in Human DendriticCellsJohn Connolly,1 Chuang Xu,1 Haisu Guo,1 Michelle Gill,2

Gagan Bajwa,2 Yaming Xue,1 Jacques Banchereau.1 1TaylorInstitute for Immunology Research, Dallas, TX; 2Universityof Texas Southwestern Medical Center, Dallas, TX

Respiratory syncytial virus (RSV) is the leading cause oflower respiratory tract infection in infants and youngchildren. Antigen presentation by dendritic cells (DCs) iscritical for the establishment of antiviral immunity and DCsare frequent target of viral immune evasion. Here we showthat primary blood mDCs exposed in vitro to RSV failed toupregulate MHC Class-II. Similar results were observed inmDCs isolated from the nasal mucosa of RSV infected infants.MHC Class-II levels remained low despite the apparentupregulation of other markers of DC maturation such asMHC Class-I, CD83, CD86 and CD40. This inhibition could notbe explained by the reduced bio-synthesis of MHC Class-II asclass II transactivator (CIITA) level remained unchanged andthe total cellular HLA-DR was comparable to flu exposedmDC. Furthermore, SDS stability assay showed similar level ofMHC Class-II peptide complex between the two viral treat-ments, indicating RSVexposure did not block Class-II loading.Consistent with the reduced surface expression, confocalmicroscopy demonstrated a selective blockade of MHC Class-II surface translocation by RSV. Blockade of Class-II sufacetraslocation was dependent on viral protein expression.These results demonstrate that RSV blocks DC antigenpresentation by inhibiting Class-II peptide complex transportto the surface and suggest a mechanism of viral immuneevasion.

doi:10.1016/j.clim.2008.03.087

OR.81. CD8+ T Cells are Required for theTherapeutic Effects of Glatiramer Acetate(Copaxone) on Autoimmune DemyelinationJason Mendoza, Nathan York, Andrew Benagh, Mihail Firan,Nitin Karandikar. UT-Southwestern Medical Center, Dallas,TX

S33Abstracts