biostudies-literatureTan CHoward Hughes Medical InstituteBurroughs Wellcome FundNIAID NIH HHSRheumatology Research FoundationU.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin DiseasesUehara Memorial FoundationNIAMS NIH HHSCancer Research InstituteChan–Zuckerberg Biohub; Innovative Genomics Institute; Parker Institute for Cancer ImmunotherapyDivision of Intramural Research, National Institute of Allergy and Infectious Diseases1267-1279https://www.ebi.ac.uk/biostudies/studies/S-EPMC8081071biostudies-literatureUnknown21(10)Antigen stimulation (signal 1) triggers B cell proliferation and primes B cells to recruit, engage and respond to T cell help (signal 2). Failure to receive signal 2 within a defined time window results in B cell apoptosis, yet the mechanisms that enforce dependence on co-stimulation are incompletely understood. Nr4a1-3 encode a small family of orphan nuclear receptors that are rapidly induced by B cell antigen receptor stimulation. Here, we show that Nr4a1 and Nr4a3 play partially redundant roles to restrain B cell responses to antigen in the absence of co-stimulation and do so, in part, by repressing the expression of BATF and, consequently, MYC. The NR4A family also restrains B cell access to T cell help by repressing expression of the T cell chemokines CCL3 and CCL4, as well as CD86 anNature immunologyNR4A nuclear receptors restrain B cell responses to antigen when second signals are absent or limiting.PMC8081071R01 AR069520R01AR0695205T32AI007334-28HHMI Medical Research Fellows programLloyd J. Old STAR grantInnovative Research AwardCareer Award for Medical ScientistsT32 AI007334R01 AI148487Hiwa RBrooks JFNoviski MHibiya KHuizar JTan CZikherman JGarcia JHeyn CLi ZVykunta VMueller JLMarson AfalseNR4A nuclear receptors restrain B cell responses to antigen when second signals are absent or limiting.Antigen stimulation (signal 1) triggers B cell proliferation and primes B cells to recruit, engage and respond to T cell help (signal 2). Failure to receive signal 2 within a defined time window results in B cell apoptosis, yet the mechanisms that enforce dependence on co-stimulation are incompletely understood. Nr4a1-3 encode a small family of orphan nuclear receptors that are rapidly induced by B cell antigen receptor stimulation. Here, we show that Nr4a1 and Nr4a3 play partially redundant roles to restrain B cell responses to antigen in the absence of co-stimulation and do so, in part, by repressing the expression of BATF and, consequently, MYC. The NR4A family also restrains B cell access to T cell help by repressing expression of the T cell chemokines CCL3 and CCL4, as well as CD86 an2020-01-01T00:00:00Z2020 Oct2026-04-30T03:08:59.466Z2022-02-10T08:17:36.494ZS-EPMC80810713286892810.1038/s41590-020-0765-7