The role of T cells and myeloid-derived suppressor cells in refractory immune thrombocytopenia

Abstract

Immune thrombocytopenia (ITP) is characterized by a dysregulated immune response against platelets, affecting both their destruction and production. A role for an abnormal T-cell compartment has been established in ITP pathogenesis and treatments that increase platelet counts in patients with ITP have shown improvements in T-cell profiles. On the other hand, patients who were refractory to treatment appear to retain the T-cell abnormalities as before. Myeloid-derived suppressive cells (MDSCs) are also emerging as key contributors to the immune pathology of ITP and response to treatment. In this review, we will discuss how various treatments affect the T-cell and MDSC compartments in ITP. The review will focus on studies that have examined the underlying mechanisms and/or genetic basis responsible for refractoriness to a given treatment and highlight remaining challenges in identifying factors and mechanisms to predict response to treatment.

Keywords: T regulatory; myeloid-derived suppressive cells; refractory immune thrombocytopenia; responder/non-responder; role of T cells; thrombopoietin receptor agonists.

FIGURE 1

T-cell and MDSC compartments dictate outcome of remission/refractoriness to treatment ITP. An imbalance in effector T (T_H1 and T_H17) and regulatory (T_reg) cells is present in patients with ITP. The numbers of ITP MDSCs are lower than healthy controls and their suppressive activity weaker in part due to altered metabolic activity attributed to decrease in levels of LBK1, CPT-1 and Ets-1. Following treatment, if the immune homoeostasis is rebalanced such that the T_H1 and T_H17 numbers and effector functions are reined in part through an expansion of T_reg and metabolically reprogrammed MDSCs with improved immunosuppressive activity, the patients will go into remission. In those who are unable to reset the imbalance, patients will become refractory to treatment. Several genetic markers related to T cells such as CARD9, SIRT1, HMGB1, TCR clonality have been associated with response/non-response to treatment. CARD9, caspase recruitment domain-containing protein 9; CPT-1, carnitine palmitoyltransferase-1; Ets-1, E-twenty-six specific proto-oncogene 1 transcription factor; HMGB1, high-mobility group box 1 protein; ITP, immune thrombocytopenia; LBK1, liver Kinase B1; MDSC, myeloid-derived suppressive cell; SIRT, sirtuin 1; T_H, T helper cell; T_reg, T regulatory cell; TCR, T-cell receptor.