JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms

Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT‐signalling is known to be involved in the regulation of CD4+ T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4+ T cell responses, we undertook an in‐depth analysis of CD4+ T cell function upon ruxolitinib exposure. We observed a decrease in total CD3+ cells after 3 weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro‐inflammatory T‐helper cell types 1 (Th1) and Th17 were reduced, which were validated by in vitro studies. In line with our in vitro data, we found that inflammatory cytokines [tumour necrosis factor‐α (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P < 0·05). Finally, we showed that ruxolitinib does not interfere with the T cell receptor signalling pathway, but impacts IL2‐dependent STAT5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD4+ T cells, such as autoimmune diseases. In addition, they also provide a potential explanation for the increased infection rates (i.e. viral reactivation and urinary tract infection) seen in ruxolitinib‐treated patients.