Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo.
Lymphocyte differentiation from naive CD4(+) T cells into mature Th1, Th2, Th17, or T regulatory cell (Treg) phenotypes has been considered end stage in character. In this study, we demonstrate that dendritic cells (DCs) activated with a novel immune modulator B7-DC XAb (DC(XAb)) can reprogram Tregs into T effector cells. Down-regulation of FoxP3 expression after either in vitro or in vivo Treg-DC(XAb) interaction is Ag-specific, IL-6-dependent, and results in the functional reprogramming of the mature T cell phenotype. The reprogrammed Tregs cease to express IL-10 and TGFbeta, fail to suppress T cell responses, and gain the ability to produce IFN-gamma, IL-17, and TNF-alpha. The ability of IL-6(+) DC(XAb) and the inability of IL-6(-/-) DC(XAb) vaccines to protect animals from lethal melanoma suggest that exogenously modulated DC can reprogram host Tregs. In support of this hypothesis and as a test for Ag specificity, transfer of DC(XAb) into RIP-OVA mice causes a break in immune tolerance, inducing diabetes. Conversely, adoptive transfer of reprogrammed Tregs but not similarly treated CD25(-) T cells into naive RIP-OVA mice is also sufficient to cause autoimmune diabetes. Yet, treatment of normal mice with B7-DC XAb fails to elicit generalized autoimmunity. The finding that mature Tregs can be reprogrammed into competent effector cells provides new insights into the plasticity of T cell lineage, underscores the importance of DC-T cell interaction in balancing immunity with tolerance, points to Tregs as a reservoir of autoimmune effectors, and defines a new approach for breaking tolerance to self Ags as a strategy for cancer immunotherapy.
Radhakrishnan
Suresh
S
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Cabrera
Rosalyn
R
Schenk
Erin L
EL
Nava-Parada
Pilar
P
Bell
Michael P
MP
Van Keulen
Virginia P
VP
Marler
Ronald J
RJ
Felts
Sara J
SJ
Pease
Larry R
LR
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D015551:Autoimmunity / Q000187:drug effects*; D018122:B7-1 Antigen / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D051858:Forkhead Transcription Factors; D007108:Immune Tolerance; D020381:Interleukin-17 / Q000096:biosynthesis*; D051379:Mice; D009101:Multiple Myeloma / Q000628:therapy; D061027:Programmed Cell Death 1 Ligand 2 Protein; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D014612:Vaccines
D000906:Antibodies; D018122:B7-1 Antigen; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D014612:Vaccines