CD4+ T cells classically recognize antigens that are endocytosed and processed in lysosomes for presentation on major histocompatibility complex (MHC) class II molecules. Here, endogenous Epstein-Barr virus nuclear antigen 1 (EBNA1) was found to gain access to this pathway by autophagy. On inhibition of lysosomal acidification, EBNA1, the dominant CD4+ T cell antigen of latent Epstein-Barr virus infection, slowly accumulated in cytosolic autophagosomes. In addition, inhibition of autophagy decreased recognition by EBNA1-specific CD4+ T cell clones. Thus, lysosomal processing after autophagy may contribute to MHC class II-restricted surveillance of long-lived endogenous antigens including nuclear proteins relevant to disease.

IntroductionHodgkin disease (HD) is characterized by a disruption of the lymph node architecture with low numbers of Hodgkin and Reed-Sternberg (H-RS) cells surrounded by an abundance of reactive nonmalignant cells. 1,2 This histologic pattern of HD may be due to the production and release of cytokines from H-RS cells that are involved in the growth of the lymphoma cells and the interactions with bystander cells. [3][4][5] Recently it has been shown that HD cell lines and primary H-RS cells express interleukin-6 (IL-6) and the ␣-chain of the IL-6 receptor (IL-6R; gp80). 3,4,6 IL-6 is synthesized by a variety of cells on stimulation and acts on a wide range of different target cells to regulate cell growth, differentiation, or gene expression. 7,8 IL-6 may act as an autocrine or paracrine growth factor for multiple myeloma, Epstein Barr virus (EBV)-immortalized B cells, and perhaps for H-RS cells, although this has not been proven yet for HD. 3,7,9-13 IL-6 exerts its action via a cell surface receptor complex consisting of at least 2 subunits: the IL-6R gp80 and the signal transducer gp130. 8,14 It has been shown that gp80 is not expressed on normal resting B cells and most Burkitt lymphoma (BL) cell lines 15 ; gp130 is shared by a number of cytokines as a signal transducing receptor component that does not bind IL-6 by itself. 7,8,16 The binding of IL-6 to gp80 leads to an association and dimerization of gp130, followed by the rapid activation of tyrosine kinases of the Janus family (Jak) and a subsequent activation of transcription factors of the signal transducers and activators of transcription (STAT) family. [17][18][19] STAT proteins are latent cytoplasmic transcription factors that become activated by tyrosine phosphorylation in response to a number of cytokines. STATs become phosphorylated and translocate as homodimers and heterodimers to the nucleus, where they bind to defined DNA elements within the promoter region of target genes and activate their transcription. [19][20][21] The activation by IL-6 is mainly associated with the tyrosine phosphorylation of STAT3. 19,22 Besides this extracellular mechanism of STAT activation by cytokines evidence also suggests that intracellular events may influence the activation state of STAT proteins and render them independent of extracellular stimuli. Constitutive STAT activation has been reported by several authors for acute leukemias, multiple myeloma, or breast cancer. 13,[23][24][25][26][27][28][29] To further explore the putative role of IL-6 in HD, the expression of gp130 and the influence on the activation of STAT proteins in HD cell lines was analyzed. Neutralizing monoclonal antibodies against IL-6, gp80, gp130, or both receptor subunits did not affect the proliferation of the HD cells or the constitutive activation of STAT molecules. However, the tyrosine kinase inhibitor AG490 inhibited both the constitutive activation of STAT3 and the growth of Hodgkin cell lines in vitro. Materials and methods Cell linesThe HD cell lines L1236, L428, L540, HDLM2, Dev, a...

Since the discovery in 1964 of the Epstein-Barr virus (EBV) in African Burkitt lymphoma, this virus has been associated with a remarkably diverse range of cancer types. Because EBV persists in the B cells of the asymptomatic host, it can easily be envisaged how it contributes to the development of B-cell lymphomas. However, EBV is also found in other cancers, including T-cell/natural killer cell lymphomas and several epithelial malignancies. Explaining the aetiological role of EBV is challenging, partly because the virus probably contributes differently to each tumour and partly because the available disease models cannot adequately recapitulate the subtle variations in the virus-host balance that exist between the different EBV-associated cancers. A further challenge is to identify the co-factors involved; because most persistently infected individuals will never develop an EBV-associated cancer, the virus cannot be working alone. This article will review what is known about the contribution of EBV to lymphoma development.

Although the latent membrane protein-1 (LMP1) of the Epstein-Barr virus (EBV) is believed to be important for the transformation of germinal centre (GC) B cells, the precise contribution of this viral oncogene to lymphoma development is poorly understood. In this study, we used a non-viral vector-based method to express LMP1 in primary human GC B cells. Gene expression profiling revealed that LMP1 induced in GC B cells transcriptional changes characteristic of Hodgkin's lymphoma cell lines. Strikingly, LMP1 down-regulated the expression of B-cell-specific genes including B-cell receptor components such as CD79A, CD79B, CD19, CD20, CD22, and BLNK. LMP1 also induced the expression of ID2, a negative regulator of B-cell differentiation. Our data suggest that in EBV-positive cases, LMP1 is likely to be a major contributor to the altered transcriptional pattern characteristic of Hodgkin/Reed-Sternberg cells, including the loss of B-cell identity.