Proinflammatory IFNγ Is Produced by but Not Required for the Generation of Eomes+ Thymic Innate CD8 T Cells

Abstract

Innate CD8 T cells are proinflammatory effector T cells that achieve functional maturation in the thymus prior to their export into and maturation in peripheral tissues. Innate CD8 T cells produce the Th1 cytokine IFNγ but depend on the Th2 cytokine IL-4 for their generation. Thus, innate CD8 T cells can permute the intrathymic cytokine milieu by consuming a Th2 cytokine but driving a Th1 cytokine response. The cellular source of IL-4 is the NKT2 subset of invariant NKT (iNKT) cells. Consequently, NKT2 deficiency results in the lack of innate CD8 T cells. Whether NKT2 is the only iNKT subset and whether IL-4 is the only cytokine required for innate CD8 T cell generation, however, remains unclear. Here, we employed a mouse model of NKT1 deficiency, which is achieved by overexpression of the cytokine receptor IL-2Rβ, and assessed the role of other iNKT subsets and cytokines in innate CD8 T cell differentiation. Because IL-2Rβ-transgenic mice failed to generate both NKT1 and innate CD8 T cells, we postulated an in vivo requirement for IFNγ-producing NKT1 cells for innate CD8 T cell development. In-depth analyses of IL-2Rβ-transgenic mice and IFNγ-deficient mice, however, demonstrated that neither NKT1 nor IFNγ was required to induce Eomes or to drive innate CD8 T cell generation. Instead, in vivo administration of recombinant IL-4 sufficed to restore the development of innate CD8 T cells in NKT1-deficient mice, affirming that intrathymic IL-4, and not IFNγ, is the limiting factor and key regulator of innate CD8 T cell generation in the thymus.

Harnessing the Power of IL-7 to Boost T Cell Immunity in Experimental and Clinical Immunotherapies

“…The γc family cytokine receptors also share the JAK/STAT pathway for signal transduction so that all γc cytokines signal through activation of the tyrosine kinases JAK1 and JAK3, followed by the phosphorylation, nuclear translocation, and transcriptional activation of STAT5 and other STAT molecules ( 2 3 ). Despite the common signaling pathways, however, the individual members within the γc cytokine family are distinct in their roles and requirements, so that, for example, IL-2 is critical for Foxp3 + Treg cell generation ( 4 ), IL-4 is non-redundant in the generation of IFNγ-producing thymic innate CD8 T cells ( 5 ), and IL-15 plays an important role in the development of invariant NKT ( i NKT) cells ( 6 ). Strikingly, IL-7 is unique among γc cytokines as its requirement is not limited to a specific T cell subset but essential for all T cells, regardless of their lineage and functional identities.…”