Toll-Like Receptor 8-Mediated Reversal of CD4⁺ Regulatory T Cell Function

Science 309, 1380-4 (2005)

Speaker : 林嬿琳                        Date :15:10-16:00, Nov. 02, 2005

Commentator : 凌斌 老師                Place: Room 601

Abstract :

CD4⁺ regulatory T (Treg) cells can prevent autoimmune diseases by suppressing the activation of CD4⁺ T cells. Yet they also can hamper antitumor responses and the efficiency of cancer immunotherapy. Therefore, the authors tested whether their suppressive function could be reversed. The Tregs used in this paper were tumor-specific CD4⁺ Treg cell lines (Treg102) generated from the tumor-infiltrating lymphocytes of cancer patients and naturally occurring CD4⁺CD25⁺ T cells from normal PBMCs. They found CpG-A could directly reverse the Treg-mediated suppressive effect on naïve CD4⁺ T cells to anti-CD3 antibody stimulation independent of dendritic cells. Interestingly, sequence elements in CpG-A responsible for the direct reversal of Treg cell suppressive function were poly-G oligonucleotides, not CpG motif. They suggested poly-G oligonucleotides mediated this reversalphenomenon through TLR receptor signaling. Knockdown the expression of IRAK4 and MyD88 essential for TLR signaling on Treg cells, the reversal effect could no longer be observed. Furthermore, they found that only TLR8 was expressed on Treg cells. Consistent with this, only the knockdown of TLR8 caused the loss of the reversibility. The authors clarified the TLR8-MyD88-IRAK4 pathway was required to reverse the suppressive function of Treg cells. In vivo, adoptive transfer of poly-G10-treated Treg102 cells into 586mel tumor-bearing mice restored the anti-tumor immunity and the growth of the tumors was controlled. In the future, poly-G oligonucleotides might be used in clinical trials to enhance the efficiency of cancer immunotherapy.

References:

1. Peng, G.G. et al. Toll-Like Receptor 8-Mediated Reversal of CD4⁺ Regulatory T Cell Function. Science 309, 1380-1384 (2005)

2. Curiel, T.J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942 (2004)