Altered T-cell subset repertoire affects treatment outcome of patients with myelofibrosis

Phenotypic characterization of T cells in myelofibrosis is intriguing because of increased inflammation, markedly elevated pro-inflammatory cytokines, and altered distribution of T-cell subsets. Constitutive activation of Janus kinase-2 (JAK2) in the majority of patients with myelofibrosis contributes to the expression of the programmed cell death protein-1 (PD1) and T-cell exhaustion. We wondered whether T-cell activation affects treatment outcome of patients with myelofibrosis and sought to determine whether the JAK1/2 inhibitor ruxolitinib affects the activation of T-cell subsets. T cells from 47 myelofibrosis patients were analyzed and the percentages of either helper (CD4⁺) or cytotoxic (CD8⁺) naïve, central memory, effector memory, or effector T cells; and fractions of PD1-expressing cells in each subset were assessed. Higher numbers of T cells co-expressing CD4/PD1 and CD8/PD1 were found in myelofibrosis patients than in healthy controls (n=28), and the T cells were significantly skewed toward an effector phenotype in both CD4⁺ and CD8⁺ subsets, consistent with a shift from a quiescent to an activated state. Over the course of ruxolitinib treatment, the distribution of aberrant T-cell subsets significantly reversed towards resting cell phenotypes. CD4⁺ and CD8⁺ subsets at baseline correlated with monocyte and platelet counts, and their PD1⁺ fractions correlated with leukocyte counts and spleen size. Low numbers of PD1⁺/CD4⁺ and PD1⁺/CD8⁺ cells were associated with complete resolution of palpable splenomegaly and improved survival rate, suggesting that low levels of exhausted T cells confer a favorable response to ruxolitinib treatment.