The concept that activation of lymphocytes requires two signals was first proposed by Bretcher and Cohn in an attempt to explain how mature B cells become activated and differentiate into antibody secreting cells on the one hand, or enter into a state of anergy on the other (Bretscher and Cohn, 1970). In a broader sense, the model addresses the capacity of the immune system to discriminate between self and non-self, and mechanisms that control lymphocyte activation versus tolerance. In 1975 Lafferty and Cunningham extended the two signal hypothesis to include T cell activation (Lafferty and Cunningham, 1975). This model now forms the basis for our current perception of how T cells become activated, immunocompetent, and develop memory. It also explains how peripheral tolerance to self-antigens can be maintained, and why lymphocytes having received activation signals through their antigen receptors can become anergic, or enter a pathway leading to apoptotic cell death.

The decision between immune activation and immune silencing is often based on whether the T cell receives an additional signal, known as a costimulatory signal, following antigen recognition. This "second signal" is typically provided by an APC that expresses the ligand for a costimulatory receptor expressed on the T cell. Some of costimulatory receptors and their ligands are constitutively expressed on the cell surface while others are activation inducible. Our review focuses on the function of the CD137 T cell costimulatory pathway as it broadly relates to the regulation of T cell-dependent B cell mediated immunity. B cells, however, do not express CD137, and therefore, CD137-mediated regulation of B cell function must be indirect. In addition to T cells, a number of cell lineages, including DC, macrophages, and NK cells express CD137. It remains to be seen how these cells regulate T cell or B cell-mediated immune responses following CD137 crosslinking. To study T-dependent humoral immunity following CD137 signaling we vaccinated or virus infected normal mice and treated them with agonistic (for T cells) anti-CD137 mAbs. In addition, we treated autoimmune-prone and tumor-bearing mice with these antibodies.

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