OX40 (CD134) engagement drives differentiationof CD4+ T cells to effector cells

Authors

  • Cortny A. Huddleston,

    1. Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA
    Search for more papers by this author
  • Andrew D. Weinberg,

    1. Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR, USA
    Search for more papers by this author
  • David C. Parker Dr.

    Corresponding author
    1. Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA
    • Department of Molecular Microbiology and Immunology, 3181 SW Sam Jackson Park Road, L220, Portland OR 97239, USA, Fax: +1-503-494-6862
    Search for more papers by this author

Abstract

Naive, CD4+ T cells proliferate extensively but fail to differentiate when they are transferred into unirradiated recipients that express alloantigen or transgenic antigen on all MHC class II+ cells. Addition of an agonist antibody to OX40 (CD134), a costimulatory TNF receptor family member expressed on activated CD4+ T cells, enables the proliferating T cells to accumulate as differentiated effector cells and kill the host animals. The donor T cells from anti-OX40-treated animals express high levels of IL-2Rα (CD25) and acquire the ability to secrete IFN-γ when stimulated with IL-12 and IL-18. OX40 promotes differentiation by 48 h in T cell priming, before changes in Bcl-2 expression or cell recovery become apparent. We found that a Bcl-2 transgene or deficiency in Fas or TNFR1 failed to influence accumulation of differentiated donor cells, and found larger changes in expression of cytokine and cytokine receptor genes than in survival genes. Accumulation of differentiated CD4+ effector T cells is initiated directly through OX40, but some OX40-deficient donor cells can gain effector function as bystanders to OX40+/+ cells. Taken together, these data suggest that CD4+ T cell differentiation to effector function is an important effect of OX40 engagement under conditions of ubiquitous antigen presentation.

Ancillary