Generation and immunosuppressive functions of p53-induced human adaptive regulatory T cells.
Inducible regulatory T cells (iTregs, also called Tr1 cells) are generated in the periphery (circulation or tissue) of cancer patients upon the encounter of naïve CD4+T cells with tumor-associated antigens. As p53 is often inactivated by genetic or epigenetic events during oncogenesis, p53-induced Tr1 cells might play a key role in establishing immunosuppressive networks in cancer patients. Tr1 cells were generated by co-culturing circulating CD4+CD25-T cells with autologous immature dendritic cells pulsed with a wild-type (WT) p53-derived peptide or an unrelated peptide derived from mucin 1 (MUC1). The Tr1 phenotype and the specificity for p53 of these cells were confirmed by multicolor flow cytometry. Moreover, the Tr1 cell-mediated suppression of T-cell proliferation was evaluated by CFSE-based flow cytometry, while their ability to alter the T-cell cytokine profile by ELISA and Luminex assays. The capacity of p53-induced Tr1 cells to suppress the generation and function of cytotoxic T lymphcoytes (CTLs) was assessed by flow cytometry and ELISPOT. Of note, low doses of the p53-derived peptide (p53low) induced greater numbers of Tr1 cells than the same peptide employed at high doses (p53high). Moreover, Tr1/p53lowcells not secreted higher levels of interleukin-10 and transforming growth factor β1, but also mediated more robust suppressive effects on CTL proliferation than Tr1/p53highcells. Tr1/p53lowcells, Tr1/p53highcells, as well as Tr1 cells generated with low doses of an unrelated MUC1-derived peptide were equally effective in suppressing the expansion and antitumor activity of p53-reactive CTLs. p53lowinduced the expansion of highly suppressive p53-reactive Tr1 cells. However, the capacity of these Tr1 cells to suppress the generation and function of p53-reactive CTLs was independent of their antigen-specificity.
Department of Otorhinolaryngology; University of Giessen-Marburg; Marburg, Germany.
Magis
M
Mandapathil
Carmen
C
Visus
Olivera J
OJ
Finn
Stephan
S
Lang
Theresa L
TL
Whiteside
adaptive Treg; antigen-specific Treg; immunosuppression; p53-induced Treg; wild-type p53 peptide