PARENT SESSION
1:30 PM to 3:30 PM
Tuesday, April 23, 2002
Poster Session 19 Biological Response Modifiers and Immunology
Room: Nevada Exhibition Center

(P24-260) Radiation affects antigen presentation by dendritic cells.

Liao, Yu-Pei^*,1, McBride, William¹, ¹ Department of Radiation Oncology, Los Angeles, CA

ABSTRACT-
Dendritic cells (DCs) are professional antigen presenting cells involved in initiating immune responses. DCs capture, process, and load antigen on class I or II major histocompatibility complex (MHC) molecules to generate CD8+ or CD4+ T cells, respectively. Antigenic peptides presented on MHC class I molecules can be loaded by endogenous or exogenous pathways. The endogenous pathway in DC involves degradation of antigen through the proteasome. Peptides are then transported to the endoplasmic reticulum and loaded onto the MHC class I molecules. The exogenous pathway involves direct loading of peptides generated elsewhere onto the MHC class I molecules of DC. In this report, we investigated how proteasome activity affects DC function and how irradiation influences these pathways. DCs were generated by 7 days culture of murine bone marrow cells in GM-CSF and IL-4. PS-341 treatment of these cells inhibited proteasome activity (>90%), as measured by degradation of fluorogenic substrate. Irradiation (10 Gy) also inhibited activity by 20-50%. The effect of PS-341 and irradiation on the exogenous pathway of antigen presentation was examined using the human melanoma antigenic peptide MART-1 (27-35), which is immunodominant within the context of HLA-A2.1 MHC molecules. HLA-A2.1/K^b-transgenic mice were immunized with peptide pulsed DCs, with and without irradiation or PS-341 treatment. Both treatments resulted in a significant increase in MART specific T cells responses, as assessed by IFN- production in an ELISPOT assay. Neither radiation nor PS-341 changed MHC class I expression as assessed by flow cytometry analysis. These results suggest that inhibition of proteasome activity by irradiation can enhance exogenous presentation of antigenic peptides and immune responses, possibly by vacating sites on MHC molecules normally loaded through endogenous pathways. Thus, while the endogenous pathway of antigen presentation may be inhibited by irradiation, the exogenous pathway may be enhanced.

KEYWORDS: radiation, antigen presentation, dendritic cell, proteasome