OX40 controls functionally different T cell subsets and their resistance to depletion therapy.
T cell depletion is a widely used approach in clinical transplantation. However, not all T cells are equally sensitive to depletion therapies and a significant fraction of T cells persists even after aggressive treatment. The functional attributes of such T cells and the mechanisms responsible for their resistance to depletion are poorly studied. In the present study, we showed that CD4(+) T cells that are resistant to polyclonal anti-lymphocyte serum (ALS) mediated depletion exhibit phenotypic features of memory cells and uniformly express OX40 on the cell surface. Studies using the foxp3gfp knockin mice revealed that the remaining CD4(+)OX40(+) cells consist of Foxp3(+) Tregs and Foxp3(-) T effector/memory cells. The ALS-resistant CD4(+)OX40(+) cells failed to mediate skin allograft rejection upon adoptive transferring into congenic Rag(-/-) mice, but removal of Foxp3(+) Tregs from the OX40(+) cells resulted in prompt skin allograft rejection. Importantly, OX40 is critical to survival of both Foxp3(+) Tregs and T effector/memory cells. However, OX40 exhibits opposing effects on the functional status of Foxp3(+) Tregs and T effector/memory cells, as stimulation of OX40 on T effector cells induced amplified cell proliferation but stimulation of OX40 on the Foxp3(+) Tregs impaired their suppressor functions. Our study demonstrates that OX40 is a critical molecule in regulating survival and functions of depletion-resistant T cells; and these findings may have important clinical implications.
Kroemer
Alexander
A
Harvard Medical School, Transplant Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Xiao
Xiang
X
Vu
Minh Diem
MD
Gao
Wenda
W
Minamimura
Keisuke
K
Chen
Ming
M
Maki
Takashi
T
Li
Xian Chang
XC
D000818:Animals; D000961:Antilymphocyte Serum / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D017930:Genes, Reporter; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics; D016130:Immunophenotyping; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053262:Receptors, OX40 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016038:Skin Transplantation / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000961:Antilymphocyte Serum; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse