Biology subjects

Hiwa, R.

Publications and source records attributed to Hiwa, R..

4 recordsLinked to original sources

bioRxiv2024

Transcriptional control of central T cell tolerance by NR4A family nuclear receptors

Although deletion of self-reactive thymocytes and their diversion into regulatory T cell (Treg) lineage are critical for immune tolerance and homeostasis, the molecular pathways that link antigen recognition to these fates are incompletely understood. The Nr4a nuclear hormone receptors are transcriptionally upregulated in response to TCR signaling in the thymus and are implicated in both deletion and diversion, but the mechanisms by which they operate are not clear. Redundancy among the family members and their requirement for Treg generation and maintenance have obscured their role in negative selection. Here we take advantage of competitive bone marrow chimeras and the OT-II/RIPmOVA model to demonstrate that Nr4a1 and Nr4a3 are essential for upregulation of Bcl2l11/BIM and negative selection by tissue-restricted model self-antigen (TRA). Moreover, we reveal that the Nr4a family is absolutely required for full induction of a broad transcriptional program triggered in self-reactive thymocytes by TRA recognition, and conserved across model systems and the natural repertoire. Importantly, both model self antigen-specific TCR Tg and polyclonal thymocytes lacking Nr4a1/3 that escape negative selection acquire an anergy-like program that persists in the periphery and is also evident among wild-type recent thymic emigrants (RTEs). We propose that the Nr4a family transduces TCR signals during thymic development to enforce the fates of highly self-reactive clones, mediating not only deletion and Treg diversion, but also contributing to a cell-intrinsic, persistent anergy-like program that may operate at the margins of canonical thymic tolerance mechanisms to restrain self-reactive T cells after thymic egress.

immunology↗

bioRxiv2021

Regulation of layered T cell tolerance mechanisms by the NR4A family is essential to preserve immune homeostasis and suppress autoimmunity

The NR4A family of orphan nuclear receptors (Nr4a1-3) plays redundant roles upstream of Foxp3 to establish and maintain Treg identity; deletion of multiple family members in the thymus results in Treg deficiency and a severe inflammatory disease. Consequently, it has been challenging to isolate the functions of this family in other immune cells. Here we take advantage of a competitive bone marrow chimera strategy, coupled with conditional genetic tools, to rescue Treg homeostasis and unmask such functions. Unexpectedly, chimeras harboring Nr4a1-/- Nr4a3-/- (DKO) bone marrow develop autoantibodies and a systemic inflammatory disease despite a replete Treg compartment of largely wild-type origin. This disease differs qualitatively from that seen with Treg-deficiency and is B cell-extrinsic. Negative selection of DKO thymocytes is profoundly impaired in a cell-intrinsic manner. Consistent with escape of self-reactive T cells into the periphery, DKO T cells with functional and phenotypic features of anergy accumulate in chimeric mice. Despite this, DKO T cells exhibit enhanced IL-2 production, implying a cell-intrinsic role for the NR4A family in peripheral T cell tolerance. These studies reveal roles for the NR4A family in multiple layered T cell tolerance mechanisms and demonstrate that each is essential to preserve immune homeostasis.

immunology↗

bioRxiv2020

Negative feedback by NUR77/Nr4a1 restrains B cell clonal dominance during early T-dependent immune responses

B cell clones compete for entry into and dominance within germinal centers (GC), where the highest affinity BCRs are selected. However, diverse and low affinity B cells can enter and reside in GCs for extended periods. To reconcile these observations, we hypothesized that a negative feedback loop may operate within B cells to preferentially restrain high affinity clones from monopolizing the early GC niche. Here we report a role for the nuclear receptor NUR77/Nr4a1 in this process. We previously showed that NUR77 expression scales with antigen stimulation and restrains B cell expansion when T cell help is limiting. Here we show that, although NUR77 is dispensable for regulating GC size when GC are elicited in a largely clonal manner, it serves to curb immunodominance under conditions where diverse clonal populations must compete for a constrained niche. Moreover, this is independent of B cell precursor frequency and reflects, at least in part, a B cell-intrinsic role for NUR77. We propose that this is important to preserve early B cell clonal diversity in order to limit holes in the post-immune repertoire and to optimize GC selection.

immunology↗

bioRxiv2020

A negative feedback loop mediated by the NR4A family of nuclear hormone receptors restrains expansion of B cells that receive signal one in the absence of signal two

Ag stimulation (signal 1) triggers B cell activation and proliferation, and primes B cells to recruit, engage, and respond to T cell help (signal 2). However, failure to receive signal 2 within a defined window of time results in an abortive round of proliferation, followed by anergy or apoptosis. Although the molecular basis of T cell help has been extensively dissected, the mechanisms that restrain Ag-stimulated B cells, and enforce dependence upon co-stimulation, are incompletely understood. Nr4a1-3 encode a small family of orphan nuclear receptors that are rapidly induced by B cell receptor (BCR) stimulation, yet little is known about their function in humoral immune responses. Here we use germline and conditional loss-of-function mouse models to show that Nr4a1 and Nr4a3 play partially redundant roles to restrain both the survival and proliferation of B cells that receive signal 1 in the absence of co-stimulatory signals, and do so in part by repressing expression of BATF and consequently c-MYC. Correspondingly, Ab responses to TI-2 immunogens are enhanced in the absence of Nr4a1, but are unaltered in response to immunogens that incorporate co-stimulatory signals. Unexpectedly, we also identify a role for the NR4A family in restraining B cell access to T cell help by repressing expression of the T cell chemokines CCL3/4, as well as CD86 and ICAM1, and show that this is relevant under conditions of competition for limiting T cell help. Our studies collectively reveal a novel negative feedback loop mediated by the NR4A family that increases B cell dependence upon T cell help and restrains strongly Ag-activated B cell clones from monopolizing limiting amounts of T cell help. We speculate that this imposes B cell tolerance and dampens immunodominance to facilitate preservation of clonal diversity during an immune response.

immunology↗