4-1BB and OX40 dual costimulation synergistically stimulate primary specific CD8 T cells for robust effector function.
CD40, 4-1BB, and OX40 are costimulatory molecules belonging to the TNF/nerve growth factor superfamily of receptors. We examined whether simultaneous costimulation affected the responses of T cells using several different in vivo tracking models in mice. We show that enforced dual costimulation through 4-1BB and OX40, but not through CD40, induced profound specific CD8 T cell clonal expansion. In contrast, the response of specific CD4 T cells to dual costimulation was additive rather than synergistic. The synergistic response of the specific CD8 T cells persevered for several weeks, and the expanded effector cells resided throughout lymphoid and nonlymphoid tissue. Dual costimulation through 4-1BB and OX40 did not increase BrdU incorporation nor an increase in the number of rounds of T cell division in comparison to single costimulators, but rather enhanced accumulation in a cell-intrinsic manner. Mechanistically speaking, we show that CD8 T cell clonal expansion and effector function did not require T help, but accumulation in (non)lymphoid tissue was predominantly CD4 T cell dependent. To determine whether this approach would be useful in a physiological setting, we demonstrated that dual costimulation mediated rejection of an established murine sarcoma. Importantly, effector function directed toward established tumors was CD8 T cell dependent while being entirely CD4 T cell independent, and the timing of enforced dual costimulation was exquisitely regulated. Collectively, these data suggest that simultaneous dual costimulation through 4-1BB and OX40 induces a massive burst of CD8 T cell effector function sufficient to therapeutically treat established tumors even under immunocompromising conditions.
Division of Immunology, University of Connecticut Health Center, Farmington 06032, USA.
Seung-Joo
SJ
Lee
Lara
L
Myers
Guruprasaadh
G
Muralimohan
Jie
J
Dai
Yi
Y
Qiao
Zihai
Z
Li
Robert S
RS
Mittler
Anthony T
AT
Vella
D000818:Animals; D015703:Antigens, CD; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002455:Cell Division / Q000276:immunology / Q000502:physiology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use; D013997:Time Factors; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D015703:Antigens, CD; D015704:CD4 Antigens; D017475:Receptors, Nerve Growth Factor; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9