Endogenous Retroviral Superantigen Driven Germinal Center Derived Lymphomagenesis
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Many human non-Hodgkin's B cell lymphomas (B-NHL) are thought to be derived from germinal-center (GC) cells, including follicular small and large center cell lymphoma (FCC), diffuse large cell lymphoma (DLCL), and Burkitt's lymphoma (BL). For the generation of normal GCs, antigen-specific T cells are needed as helpers. B-NHL frequently contain CD4 as well as CD8 T cells. Unlike most solid tumors, they express HLA class II molecules and are capable of presenting antigens to CD4+ T lymphocytes. Whether these CD4 T cells interact with, and/or respond antigen to the malignant lymphoma B cells remains obscure. Such interactions are difficult to explore in humans and studies addressing such issues are rare.
Studies with inbred mouse strains are, therefore, crucial for the understanding of host- lymphoma cell relationships. Analysis of the SJL mouse model for human GC-derived lymphomas has provided the most insight into the significance of normal host CD4 T cells frequently found in GC-derived B cell lymphomas. Transplantable lymphoma growth and/or primary lymphoma incidence are greatly diminished in gamma-irradiated and anti-CD4-treated normal mice. This dependence of SJL lymphoma growth on host CD4 T cells, in responsive to the lymphoma cells, is the hallmark of the phenomenon that has been dubbed “revers immunological surveillance”. The stimulatory moiety on the lymphoma cells proved to be a viral superantigen, vSAg29 (Mtv29-LTR) that stimulates host CD4+BV16+ T cells. The responding T cells elaborate cytokines (notably IL-5 and IL-4) upon which the lymphoma cells depend for their growth. This phenomenon has now also been described for lymphomas from other mouse strains of mice harboring Mtv29, and for Mtv7-encoded vSAgs. Other cellular interactions are important for lymphomagenesis, including those between CD30 (present on the lymphoma B cells and its ligand, CD30L (present on activated host T cells); as well as interactions between lymphotoxin (LT) beta bearing lymphoma B cells and LT-beta receptor bearing follicular dendritic cells (FDC). Blocking such interactions with antibodies or with other blocking reagents drastically reduce lymphoma growth.
We are now extending our studies on the mouse model into human lymphomas- looking at the repertoire of lymphoma-infiltrating T cells as well as seeking potential retrovirus-encoded superantigens or nominal antigens. Such a venture is not far-fetched, since the human genome in known to be laden with retroviral sequences (~0.6% of the genome), some of which have the potential to code for superantigens. Knowledge gained from deciphering the characteristics of CD4 T cells found in human B lymphomas, as well as the stimulating moieties on the lymphoma cells could be of great value in understanding the lymphoma process, as well as in formulation of therapeutic strategies.
VINCENT K. TSIAGBE, PH.D.
Assistant Professor of Pathology
Department of Pathology
New York University School of medicine
New York, NY 10016
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