Cutting Edge: OX40 agonists can drive regulatory T cell expansion if the cytokine milieu is right.
We report that OX40 stimulation drives all lineages of CD4 T cell development, including regulatory T cells (Tregs), and the plasticity of the response is dependant on local cytokines. In TGF-beta1-treated cultures, an OX40 agonist increased IFN-gamma and IL-4 production and diverted T cells from the Treg lineage. However, cytokine blockade in the context of OX40 stimulation promoted enhanced Treg accumulation. This observation was evident in naive mice, as OX40 engagement enhanced Treg proliferation and accumulation in vivo. Lastly, OX40 agonist administration influenced experimental autoimmune encephalomyelitis disease severity in opposing directions, depending on the timing of administration. Given during Ag priming, the OX40 agonist drove Treg expansion and inhibited disease, whereas given later it enhanced T cell effector cytokine production in the CNS and exacerbated disease. Hence, OX40 signaling can augment the accumulation of all CD4 T cell lineages; however, its accentuation of immune responses may have vastly different biologic outcomes depending upon the local cytokine milieu.
Earle A Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213, USA.
Carl E
CE
Ruby
Melissa A
MA
Yates
Daniel
D
Hirschhorn-Cymerman
Peter
P
Chlebeck
Jedd D
JD
Wolchok
Alan N
AN
Houghton
Halina
H
Offner
Andrew D
AD
Weinberg
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D018106:CD28 Antigens / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053262:Receptors, OX40 / Q000819:agonists* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D000906:Antibodies; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D053262:Receptors, OX40; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4; D007371:Interferon-gamma