GM-CSF producing autoreactive CD4 ⁺ T cells in type 1 diabetes

The phenotype of autoreactive T cells in type 1 diabetes is described as Th1, Th17 and/or Th21, but is largely uncharacterized. We combined multi-parameter cytokine profiling and proliferation, and identified GM-CSF producing cells as a component of the response to beta cell autoantigens proinsulin and GAD65. Overall cytokine profiles of CD4 ⁺ T cell were not altered in type 1 diabetes. In contrast, patients with recent onset type 1 diabetes had increased frequencies of proinsulin-responsive CD4 ⁺ CD45RA ⁻ T cells producing GM-CSF (p = 0.002), IFNγ (p = 0.004), IL-17A (p = 0.008), IL-21 (p = 0.011), and IL-22 (p = 0.007), and GAD65-responsive CD4 ⁺ CD45RA ⁻ T cells producing IL-21 (p = 0.039). CD4 ⁺ T cells with a GM-CSF ⁺ IFNγ ⁻ IL-17A ⁻ IL-21 ⁻ IL-22 ⁻ phenotype were increased in patients for responses to both proinsulin (p = 0.006) and GAD65 (p = 0.037). GM-CSF producing T cells are a novel phenotype in the repertoire of T helper cells in type 1 diabetes and consolidate a Th1/Th17 pro-inflammatory pathogenesis in the disease.