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

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.

NF-κB–inducing kinase plays an essential T cell–intrinsic role in graft-versus-host disease and lethal autoimmunity in mice

“…Without irradiation of recipients and without anti-OX40, donor CD4 + T cells proliferate and accumulate, but are rendered anergic and do not acquire effector function (24), because in the absence of irradiation damage and inflammation, costimulatory molecules are not upregulated (22). The OX40 stimulus causes alloreactive donor T cells to differentiate to IFN-γ producers.…”

“…The OX40 stimulus causes alloreactive donor T cells to differentiate to IFN-γ producers. It acts directly on donor cells, as shown by lack of a response by Ox40 -/-donor T cells transferred alone into in WT (H-2 bm12 ×CD45.1)F1 recipients (24). We tested naive aly/aly or littermate control donor CD4 + T cells in this model to assess whether NIK is essential for OX40-mediated costimulation.…”

IL-12 Is Required for Anti-OX40-Mediated CD4 T Cell Survival

“…OX40 expression is induced 16 -24 h after Ag and CD28 stimulation of T cells and maintained for up to 120 h (1). OX40 interaction with OX40L, its cognate ligand found on mature DCs and other activated APCs, increases proliferation and differentiation of effector cells, induces greater migration of T cells, and enhances their survival (2)(3)(4)(5)(6)(7). It is the ability of OX40 to enhance survival of CD4 T cells, in some cases 34-fold, that is of particular interest, as this property could aid in the development of effective immunotherapeutic strategies against tumors and/or chronic pathogens (8 -10).…”

Development and characterization of recombinant human Fc:OX40L fusion protein linked via a coiled-coil trimerization domain

“…Analysis of CD4 + T-cell responses following in vivo OX40 engagement showed an increase in antigen-specific T-cell expansion, enhanced cytokine production and an increase in the generation and stability of a memory T cells (Evans et al, 2001;Huddleston et al, 2006;Kaleeba et al, 1998;Weinberg et al, 1998). In mouse tumor models, OX40 engagement, with an agonist antibody or soluble ligand in the absence of immunization, produced antitumor effects against breast and colon cancers, melanoma, sarcoma and glioma (Kjaergaard et al, 2001;Kjaergaard et al, 2000;Morris et al, 2001;Pan et al, 2002;Weinberg et al, 2000).…”