Differential Nr4a1 and Nr4a3 expression discriminates tonic from activated TCR signalling events in vivo

Abstract

Nr4a gene family members are activated by T cell receptor (TCR) signalling and play key roles in Regulatory T cell differentiation and have also been implicated in promoting T cell exhaustion in cancer. The precise signalling pathways that govern their transcription, however, remain unclear. Here we utilise Nr4a3-Tocky mice to elucidate the signalling pathways that govern Nr4a1, 2 and 3 expression in response to physiological stimulation of CD4 + and CD8 + T cells. Our findings reveal that Nr4a1-3 are Src family kinase-dependent. Moreover, Nr4a2 and Nr4a3 are abolished by calcineurin inhibitors and bind NFAT1, highlighting a necessary role for NFAT in the control of Nr4a2 and Nr4a3. Interestingly, the NFAT pathway is redundant for Nr4a1 activation, but all three Nr4a members require ERK signalling for optimal expression. Analysis of T cells expressing constitutively active NFAT1 reveals that NFAT1 alone is sufficient to induce expression of Nr4a2 and Nr4a3, but not Nr4a1.These findings further our understanding of Nr4a regulation, highlighting key differences in the sensitivity of Nr4a1 and Nr4a3 to distal TCR signalling pathways.

Early programming of CD8 + T cell response by the orphan nuclear receptor NR4A3

“…20). In addition, data suggest that in both T cells and B cells, NR4A3 is not induced following tonic signaling, contrary to what was observed for NR4A1 (50,51). This, coupled to our sequencing data obtained early following TCR stimulation support that the impact of NR4A3 on CD8 + T cell differentiation is not likely to be via a role in the response of memory T cells to tonic signaling.…”

Exhausted CD8+ T cells exhibit low and strongly inhibited TCR signaling during chronic LCMV infection

“…Altogether with the RNAseq data and previous studies 2 , this suggests that TCR signaling is strongly regulated in exhausted cells, as maximum signaling levels are not reached in vivo, despite the antigen being abundantly present. Additionally, recent work showed Nr4a1 transcription is not induced by NFAT alone 37 and there is evidence for ERK signaling mediated AP-1 induction being involved in Nr4a1 transcription 38 . In chronic LCMV infection, the formation of NFAT/AP-1 dimers is impaired 39 , implying that Nr4a1 does not report the full extent of TCR signaling in this setting.…”

T resident helper cells promote humoral responses in the lung

“…2, A to C, and fig. S2B) (28). Cells in cluster 1 were also enriched for Rora, which is reportedly induced by extrinsic signals in the microenvironment and plays a role in negatively regulating lung inflammation during infection (29).…”