Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production

Abstract

While Th17 cells can protect against colonization by pathogenic organisms, they also have the potential to become pathogenic and promote autoimmune and inflammatory diseases. Mechanisms that control their pathogenic potential remain poorly understood. Here we show that Ndfip1, a co-activator of the E3 ubiquitin ligase Itch, restricts the frequency and pathogenicity of Th17 cells. Mice lacking Ndfip1 have increased numbers of Th17 cells, and this increase is cell intrinsic. We found that Ndfip1 restricts production of the proinflammatory cytokines in Th17 cells. Increased cytokine production correlated with reduced degradation and accumulation of RORγT. When transferred in vivo, Th17 cells lacking Ndfip1 were more likely to maintain their ability to make IL-17, were more potent proinflammatory cytokine producers, and were powerful inducers of colitis. Together our data support an essential role for Ndfip1 in degrading RORγT and suppressing Th17 lineage stability, proinflammatory cytokine production, and pathogenicity.

The Ubiquitin Ligase Adaptor NDFIP1 Selectively Enforces a CD8+ T Cell Tolerance Checkpoint to High-Dose Antigen

“…By contrast, IL-2 production and JUNB were not increased in Ndfip1-defi cient OT-I cells, and augmented expansion was via more rapid proliferation and diminished death rather than cell-cycle exit deficiencies. Elevated GzmB expression in Ndfip1 -deficient CD8 + T cells demonstrates that NDFIP1 can inhibit type 1 immune responses, in contrast to CD4 + T cells, in which NDFIP1 loss has little effect on Th1 differentiation (Layman et al, 2017b; Oliver et al, 2006). …”

“…NDFIP1 binds to and activates HECT-type E3 ubiquitin ligases (Mund and Pelham, 2009; Riling et al, 2015), thereby triggering ubiquitin-medi- ated degradation of key T cell differentiation regulators, including JUNB, RORγt, and JAK1 (Layman et al, 2017b; O’Leary et al, 2016; Oliver et al, 2006). In T cells, NDFIP1 primarily recruits and activates the HECT-type E3 ligase ITCH (Oliver et al, 2006).…”

“…In T cells, NDFIP1 primarily recruits and activates the HECT-type E3 ligase ITCH (Oliver et al, 2006). Ndfip1 -deficient CD4 + T cells resist both in vitro anti- CD3 induced anergy and in vivo tolerance to low or high antigen levels because of excessive interleukin (IL)-2 production, a failure to exit the cell cycle, and aberrant differentiation into T helper (Th) 2 or Th17 cells (Altin et al, 2014; Layman et al, 2017b; Oliver et al, 2006; Ramos-Hernández et al, 2013). Mice lacking NDFIP1 develop a fatal T cell-mediated inflammatory disease associated with T cell activation, regulatory T cell dysfunction, and Th2-mediated organ pathology (Altin et al, 2014; Beal et al, 2011; Layman et al, 2017a; Oliver et al, 2006).…”

Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease

“…These animals do not show the overt signs of inflammation such as dermatitis2526 observed in age-matched Ndfip1 fl/fl Foxp3- Cre animals. We observed increased frequencies of T reg cells (Supplementary Fig.…”

Immune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch

“…Itch might negatively control Th17 differentiation through ubiquitination mediated by lysine 48 (K48) linkage and degradation of RORγt, which is the master regulator of Th17 differentiation. Consistent with this, Nedd4 family interacting protein 1 (NDFIP1), which activates the catalytic activity of Itch, also promoted RORγt degradation and reduced IL-17 production in Th17 cells (Layman et al, 2017 ).…”