iNKT cell production of GM-CSF controls Mycobacterium tuberculosis

Invariant natural killer T (iNKT) cells are activated during infection, but how they limit microbial growth is unknown in most cases. We investigated how iNKT cells suppress intracellular Mycobacterium tuberculosis (Mtb) replication. When co-cultured with infected macrophages, iNKT cell activation, as measured by CD25 upregulation and IFNγ production, was primarily driven by IL-12 and IL-18. In contrast, iNKT cell control of Mtb growth was CD1d-dependent, and did not require IL-12, IL-18, or IFNγ. This demonstrated that conventional activation markers did not correlate with iNKT cell effector function during Mtb infection. iNKT cell control of Mtb replication was also independent of TNF and cell-mediated cytotoxicity. By dissociating cytokine-driven activation and CD1d-restricted effector function, we uncovered a novel mediator of iNKT cell antimicrobial activity: GM-CSF. iNKT cells produced GM-CSF in vitro and in vivo in a CD1d-dependent manner during Mtb infection, and GM-CSF was both necessary and sufficient to control Mtb growth. Here, we have identified GM-CSF production as a novel iNKT cell antimicrobial effector function and uncovered a potential role for GM-CSF in T cell immunity against Mtb.
Author Summary Mycobacterium tuberculosis (Mtb) is the cause of tuberculosis, a leading cause of sickness and death worldwide. Although much is known about CD4+ and CD8+ T cell responses to Mtb, the role of other T cell subsets is poorly understood. Invariant natural killer T (iNKT) cells are innate lymphocytes that express a semi-invariant T cell receptor and recognize lipid antigens presented by CD1d. Although iNKT cells participate in the immune response to many different pathogens, little is known about how iNKT cells directly kill microbes. We previously showed that when co-cultured with Mtb-infected macrophages, iNKT cells inhibit intracellular Mtb replication. Now, we used this model to dissociate the signals that induce iNKT cell activation markers including IFNγ production, from the signals that activate iNKT cell antimicrobial activity. This allowed us to uncover a novel antimicrobial effector function produced by iNKT cells: GM-CSF. GM-CSF is essential for immunity to Mtb, but its role has never been defined. This study is the first report to demonstrate a protective function of GM-CSF production by any T cell subset during Mtb infection. T cell production of GM-CSF should be considered as a potential mechanism of antimicrobial immunity.