Background:Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma(MM)progression.Simultaneously,previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upo...Background:Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma(MM)progression.Simultaneously,previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with commonγ-chain family cytokines in vitro and during homeostatic proliferation.The aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets upregulating PD-1 and TIM-3 checkpoint molecules.Methods:The expression of CD25,CD122,CD127 commonγ-chain cytokine receptors,phosphorylated signal transducer and activator of transcription-5(pSTAT5)and eomesodermin(EOMES)was comparatively assessed with flow cytometry in PD-1-and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM patients.Results:Substantial proportions of PD-1-and TIM-3-positive T lymphocytes expressed commonγ-chain cytokine receptors and pSTAT5.Frequencies of cytokine receptor expressing cells were significantly higher within TIM-3+T cells compared to PD-1+TIM-3−subsets.Considerable proportions of both PD-1-/TIM-3-negative and positive CD8+T cells express EOMES,while only moderate frequencies of CD4+PD-1+/TIM-3+T cells up-regulate this transcription factor.Besides,the surface presence of CD25 and intranuclear expression of EOMES in CD4+T cells were mutually exclusive regardless of PD-1 and TIM-3 expression.The stimulation with commonγ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+and TIM-3+T cell subsets in vitro.Conclusions:Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine stimulation.Differences in commonγ-chain cytokine receptor expression between PD-1+and TIM-3+T cells may reflect functional dissimilarity of these cell subsets.Checkpoint blockade appears to alleviate lymphopenia-induced proliferation of PD-1+T cells but may raise the possibility of immune-mediated adverse events.展开更多
文摘Background:Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma(MM)progression.Simultaneously,previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with commonγ-chain family cytokines in vitro and during homeostatic proliferation.The aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets upregulating PD-1 and TIM-3 checkpoint molecules.Methods:The expression of CD25,CD122,CD127 commonγ-chain cytokine receptors,phosphorylated signal transducer and activator of transcription-5(pSTAT5)and eomesodermin(EOMES)was comparatively assessed with flow cytometry in PD-1-and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM patients.Results:Substantial proportions of PD-1-and TIM-3-positive T lymphocytes expressed commonγ-chain cytokine receptors and pSTAT5.Frequencies of cytokine receptor expressing cells were significantly higher within TIM-3+T cells compared to PD-1+TIM-3−subsets.Considerable proportions of both PD-1-/TIM-3-negative and positive CD8+T cells express EOMES,while only moderate frequencies of CD4+PD-1+/TIM-3+T cells up-regulate this transcription factor.Besides,the surface presence of CD25 and intranuclear expression of EOMES in CD4+T cells were mutually exclusive regardless of PD-1 and TIM-3 expression.The stimulation with commonγ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+and TIM-3+T cell subsets in vitro.Conclusions:Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine stimulation.Differences in commonγ-chain cytokine receptor expression between PD-1+and TIM-3+T cells may reflect functional dissimilarity of these cell subsets.Checkpoint blockade appears to alleviate lymphopenia-induced proliferation of PD-1+T cells but may raise the possibility of immune-mediated adverse events.
