Enhanced efficacy of regulatory T cell transfer against increasing resistance, by elevated Foxp3 expression induced in arthritic murine hosts.
OBJECTIVE
To investigate the efficacy of type II collagen-reactive Foxp3-expressing T cell transfer in suppressing collagen-induced arthritis (CIA) in relation to disease progression.


METHODS
CD3-activated CD4 T cells were retrovirally transduced with the Foxp3 gene, and their in vitro suppressive activity on T cell proliferation was assessed for correlation with Foxp3 levels. To suppress CIA, Foxp3-transduced T cells generated with type II collagen- or ovalbumin (OVA)-pulsed dendritic cells (DCs), which were fractionated by Foxp3 levels, were adoptively transferred to mice at various time points.


RESULTS
The in vitro suppressive activity of Foxp3-transduced cells correlated positively with Foxp3 levels. Type II collagen-reactive, but not OVA-reactive, Foxp3-transduced cells significantly suppressed CIA when they were transferred before immunization, and this suppression was accompanied by decreased anti-type II collagen antibody production. Larger cell numbers were required to suppress CIA when transfer occurred 20 days after immunization, indicating that hosts became resistant to suppression. Transfer of 1 x 10(5) Foxp3(low) cells had only a marginal effect on CIA suppression in immunized hosts, while transfer of Foxp3(high) cells at smaller doses significantly suppressed CIA. Transfer of 1 x 10(5) Foxp3(high) cells after establishment of arthritis attenuated disease progression but did not reverse joint swelling.


CONCLUSIONS
Resistance to Foxp3-transduced T cells proceeded as CIA progressed, suggesting that late-stage aggressive arthritis is more resistant to regulatory T cell transfer. An elevated expression level of Foxp3 in type II collagen-specific T cells improved their suppressive function in CIA. Thus, transfer of T cells expressing high levels of Foxp3 could be a strategy to overcome the induced resistance to regulatory T cell therapy.
Ohata
Junko
J
Research Center for Allergy and Immunology, Riken, Yokohama, Japan. johata@rcai.riken.jp
Miura
Tomoko
T
Johnson
Todd A
TA
Hori
Shohei
S
Ziegler
Steven F
SF
Kohsaka
Hitoshi
H
D019264:Adoptive Transfer; D000818:Animals; D001168:Arthritis / Q000209:etiology / Q000276:immunology* / Q000628:therapy*; D002478:Cells, Cultured; D003094:Collagen / Q000008:administration & dosage; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D051379:Mice; D008811:Mice, Inbred DBA; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D003094:Collagen