MEK Inhibition Results In Selective Immunosuppression Of Human T Cells And Decreases Cytokine Production In A Memory Stage-Dependent Manner
Year: 2010
Type: article
Abstract: Although allogeneic stem cell transplantation is a treatment of choice for many hematologic malignancies, a key complication is graft-versus-host disease (GVHD). Although currently used immunosuppressive medications may successfully inhibit GVHD, none are selective enough to spare pathogen-specific T cells, leading to an increased risk of life-threatening infections (e.g., CMV reactivation). Recent studies suggest that naive and early memory T cells may be relatively more potent at inducing GVHD, whereas we and others have shown that most CMV-specific T cells exist as relatively differentiated cells. Therefore, we reasoned that differences in signaling could be used to selectively inhibit certain maturation stages of human T cells. Since the MAPK pathway has been demonstrated to be important for cytokine production in T cells, we measured phospho-Erk1/2 (p-Erk) in PMA:Ionomycin-treated or SEB-stimulated CD4+ and CD8+T cell maturation subsets by flow cytometry. Naive (CD27+CD45RA+) and early memory (M1, CD27+CD45RA-) T cells expressed three-fold higher p-Erk than intermediate (M2, CD27-CD45RA-) and late memory (M3, CD27-CD45RA+) T cells (P<0.05). To test the hypothesis that the effects of MEK inhibition depend on p-Erk expression, we stimulated T cells from healthy donors using allogeneic dendritic cells (DC) and assessed alloactivation in the presence or absence of the MEK inhibitor U0126. U0126-treated CD4+ and CD8+T cells were 60-70% less activated than DMSO-treated cells, as assessed both by CD38 upregulation and CFSE dilution. Next we determined whether U0126 selectively suppresses cytokine production in a stage-dependent manner. We stimulated PBMC from healthy subjects (n=7) with SEB in the presence of U0126 and measured IL-2, IFNγ and TNFα production in T cell maturation subsets. In CD4+T cells, both IL-2 and TNFα production were significantly more suppressed in naive and early memory cells (Table 1). In CD8+ cells, we similarly saw reductions in IFNγ and TNFα production following MEK inhibition (Table 1). Preliminary experiments also suggest that U0126 only minimally suppresses of CMV pp65-specific T cells from healthy subjects (n=3), although additional confirmation is needed. These data demonstrate that MEK inhibition preferentially inhibits naive and early memory cells critical for GVHD initiation while sparing late-memory CMV-specific cells, providing the basis for more selective clinical strategies for GVHD inhibition.Tabled 1Mean percent reduction in cytokine production in response to U0126 (n=7)CellCytokineNM1M2M3CD4+IL-279%56%50%∗∗CD4+TNFα87%62%48%∗∗CD8+IFNγ58%30%15%0%CD8+TNFα70%55%38%5%∗all P<0.05 for CD4: N vs. M1, M1 vs. M2, CD8: N vs. M1, M1 vs. M2, M2 vs. M3.∗∗M3 cells are not significantly present in CD4+ cells. Open table in a new tab ∗all P<0.05 for CD4: N vs. M1, M1 vs. M2, CD8: N vs. M1, M1 vs. M2, M2 vs. M3. ∗∗M3 cells are not significantly present in CD4+ cells.
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W1967893907