An examination of MHC class II and costimulatory molecule expression in B cell lymphomas
Cycon, Kelly A.
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Major histocompatibility complex class II (MHCII) molecules present antigenic peptides to CD4 + T cells, and therefore occupy a primary role in the activation of immune responses. MHCII expression is directly correlated with immunogenicity, and inversely correlated with tumorigenicity, in clones of the L1210 murine B lymphoma. Moreover, decreases in MHCII expression on diffuse large B cell lymphoma (DLBCL) correlate directly with significant decreases in patient survival. Thus, the consequential role that MHCII antigen expression plays in B cell lymphomas is clinically important. In this thesis, we investigated (1) the immunogenic characteristics of MHCII + L1210 clones, (2) the mechanisms responsible for the loss of MHCII expression in DLBCL cell lines, and (3) whether MHCII expression can be up-regulated therapeutically in DLBCL. Our results suggest that the immunogenicity of MHCII + L1210 clones directly correlates with the ability to act as APC to stimulate naïve T cells through the concomitant expression of the costimulatory molecules B7-1, B7-2, and CD40. Additionally, in DLBCL cells, our studies indicate that the down-regulation of MHCII expression occurs through multiple distinct mechanisms, with decreased expression of CIITA, the "master regulator" of MHCII transcription, being the most common mechanism. In DB, a MHCII-negative DLBCL cell line, specific histone modifications associated with open chromatin conformation and active transcription were significantly reduced at the CIITA promoters, relative to MHCII+ B cells. Importantly, histone deacetylase inhibitor (HDACi) treatment resulted in the activation of CIITA transcription and MHCII expression in DB cells. These collective results suggest that epigenetic mechanisms involving histone modifications and histone deacetylase (HDAC) activity contribute to the silencing of CIITA transcription in DB DLBCL cells. Furthermore, the silencing of CIITA transcription can be alleviated with HDACi treatment.