The Potency of Allospecific Tregs Cells Appears to Correlate With T Cell Receptor Functional Avidity

TY - JOUR

T1 - The Potency of Allospecific Tregs Cells Appears to Correlate With T Cell Receptor Functional Avidity

AU - Tsang, J. Y. S.

AU - Ratnasothy, K.

AU - Li, D.

AU - Chen, Y.

AU - Bucy, R. P.

AU - Lau, K. F.

AU - Smyth, L.

AU - Lombardi, G.

AU - Lechler, R.

AU - Tam, P. K. H.

PY - 2011/8

Y1 - 2011/8

N2 - CD4(+)CD25(+) regulatory T cells (T-reg cells) are an attractive adoptive cell therapy in mediating transplantation tolerance. T-cell receptor (TcR) activation is critical for T-reg function, suggesting that the TcR avidity of T-reg cells used in therapy may affect the therapeutic outcome. To address this, we compared the regulatory capacity of T-reg lines expressing TcRs derived from two TcR transgenic mice shown to have the same specificity but different functional avidities. T-reg lines generated from CD4(+)CD25(+) T cells from C57BL/6 mice were transduced with one of either of these TcRs. The antigen specificity of the transduced T-reg lines was confirmed in vitro. T-reg lines expressing the TcR with higher functional avidity showed stronger suppressive capacity in a linked suppression model in vitro. Furthermore, the same T-reg lines demonstrated a stronger proliferation in vivo following antigen exposure. Pretreatment of recipient BL/6 mice with these T-reg cells, together with anti-CD8 antibody and Rapamycin therapies, prolonged survival of BALB/c skins, as compared with mice that received T-reg lines with lower TcR avidity. Taken together, these data suggest that the TcR functional avidity may be important for T-reg function. It highlights the fact that strategies to select T-reg with higher functional avidity might be beneficial for immunotherapy in transplantation.

AB - CD4(+)CD25(+) regulatory T cells (T-reg cells) are an attractive adoptive cell therapy in mediating transplantation tolerance. T-cell receptor (TcR) activation is critical for T-reg function, suggesting that the TcR avidity of T-reg cells used in therapy may affect the therapeutic outcome. To address this, we compared the regulatory capacity of T-reg lines expressing TcRs derived from two TcR transgenic mice shown to have the same specificity but different functional avidities. T-reg lines generated from CD4(+)CD25(+) T cells from C57BL/6 mice were transduced with one of either of these TcRs. The antigen specificity of the transduced T-reg lines was confirmed in vitro. T-reg lines expressing the TcR with higher functional avidity showed stronger suppressive capacity in a linked suppression model in vitro. Furthermore, the same T-reg lines demonstrated a stronger proliferation in vivo following antigen exposure. Pretreatment of recipient BL/6 mice with these T-reg cells, together with anti-CD8 antibody and Rapamycin therapies, prolonged survival of BALB/c skins, as compared with mice that received T-reg lines with lower TcR avidity. Taken together, these data suggest that the TcR functional avidity may be important for T-reg function. It highlights the fact that strategies to select T-reg with higher functional avidity might be beneficial for immunotherapy in transplantation.

U2 - 10.1111/j.1600-6143.2011.03650.x

DO - 10.1111/j.1600-6143.2011.03650.x

M3 - Article

SN - 1600-6135

VL - 11

SP - 1610

EP - 1620

JO - American Journal of Transplantation

JF - American Journal of Transplantation

IS - 8

ER -