Activated CD8+ T-effector/memory cells eliminate CD4+ CD25+ Foxp3+ T-suppressor cells from tumors via FasL mediated apoptosis.
Tumor-resident CD8(+) T cells display a quiescent effector/memory phenotype that is maintained in part by infiltrating CD4(+) CD25(+) Foxp3(+) T-suppressor cells. Intratumoral delivery of IL-12, in contrast, can restore cytotoxic function to tumor-associated CD8(+) T cells and induce the apoptotic death of T-suppressor cells. Depletion of CD8(+) T cells from tumors before IL-12 treatment resulted in the abrogation of treatment-mediated T-suppressor cell apoptosis revealing a link between CD8(+) T cell activation and T-suppressor elimination. Furthermore, IL-12 failed to induce T-suppressor cell loss in IFN-gamma- or FasL-deficient mice demonstrating a requirement for IFN-gamma and FasL in this process. Adoptive transfer of wild-type CD8(+) T cells to FasL-knockout mice restored posttherapy T-suppressor cell elimination from tumors establishing that expression of FasL on CD8(+) T cells was sufficient to promote T-suppressor cell death. IL-12 failed to induce FasL on T-effectors in IFN-gamma-knockout mice demonstrating a requirement for IFN-gamma in FasL up-regulation. Adoptive transfer of wild-type CD8(+) T cells induced T-suppressor cell death in IFN-gamma-knockout mice confirming that autocrine IFN-gamma was sufficient for CD8(+) T cell FasL expression. These findings reveal a mechanism by which cytotoxic T cells can abrogate regulatory cell activity.
Kilinc
Mehmet O
MO
Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA.
Rowswell-Turner
Rachael B
RB
Gu
Tao
T
Virtuoso
Lauren P
LP
Egilmez
Nejat K
NK
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D053222:Fas Ligand Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007156:Immunologic Memory / Q000235:genetics; D018664:Interleukin-12 / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
D015704:CD4 Antigens; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D018664:Interleukin-12