ABSTRACT
The costimulatory receptor OX40 has recently been shown to be involved in primary CD4 responses to several defined Ags. However, to date there has been little information regarding the mechanism of action of OX40, such as whether it regulates T cell numbers, reactivity, or both, and whether it contributes to induction of long-term T cell responses. With an agonist Ab to OX40, and by tracking Ag-specific TCR transgenic T cells in vivo, we show that ligation of OX40 induces clonal expansion and survival of CD4 cells during primary responses, and results in the accumulation of greater numbers of memory cells with time. Significantly, OX40-deficient T cells, from mice generated by gene targeting, secrete IL-2 and proliferate normally during the initial period of activation, but cannot sustain this during the latter phases of the primary response, exhibiting decreased survival over time. Mice lacking OX40 develop only low frequencies of Ag-specific CD4 cells late in primary responses in vivo and generate dramatically lower frequencies of surviving memory cells. These results demonstrate that OX40-OX40L interactions control primary T cell expansion and the ability to retain high numbers of Ag-specific T cells. In this way, OX40 signals promote survival of greater numbers of T cells with time and control the size of the memory T cell pool.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Immunologic Memory/immunology , Lymphocyte Activation/immunology , Receptors, Immunologic/physiology , Receptors, Tumor Necrosis Factor , T-Lymphocyte Subsets/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 7/physiology , Animals , CD4-Positive T-Lymphocytes/cytology , Cell Differentiation/genetics , Cell Differentiation/immunology , Cell Division/genetics , Cell Division/immunology , Cell Survival/genetics , Cell Survival/immunology , Cells, Cultured , Clone Cells , Immune Sera/pharmacology , Immunologic Memory/genetics , Lymphocyte Activation/genetics , Lymphocyte Count , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , Receptors, OX40 , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocyte Subsets/cytology , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunologyABSTRACT
CD134 (OX40) is a member of the TNF receptor family that is expressed on activated T lymphocytes. T cells from mice that lack expression of CD134 made strong responses to a range of challenges, but they showed impaired proliferation in response to direct stimulation through the TCR with monoclonal anti-CD3epsilon Ab. CD134-deficient mice controlled infection with Leishmania major, Nippostrongylus brasiliensis, and Theiler's murine encephalomyelitis virus, and they made overtly normal Ab responses to a variety of antigens. Thus, CD134 is not essential for many T cell responses in vivo, nor is it required for the provision of help to B cells. Nonetheless, a subtle role in the regulation of T cell reactivity is suggested by the effect of CD134 deficiency on in vitro T cell responses.
