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The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4 Cre Satb1 f/f mice enriched for antigen-specific Tfh cells, and TGF-β-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1 -/- CD4 + T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4 Cre Satb1 f/f mice accumulated tumor antigen-specific, LIGHT + CXCL13 + IL-21 + Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4 + T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4 + T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-β-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors., Competing Interests: Declaration of interests J.R.C.-G. has stock options with Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics, receives honorarium from Anixa Biosciences, Alloy Therapeutics, and Leidos, and has sponsored research with Anixa Biosciences. R.L.: Clinical trial protocol committee–CG oncology; Scientific advisor/consultant–B.M.S., Ferring, Fergene, Arquer Diagnostics. B.A.P. has completed Advisory Board with AstraZeneca and has Research Support from B.M.S. J.R. is currently an employee of STEMCELL Technologies., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC→BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC→BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC→BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this routing of information is critically instructive for observational fear conditioning. VIDEO ABSTRACT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The basolateral amygdala (BLA) and ventral hippocampus (vHPC) have both been implicated in mediating anxiety-related behaviors, but the functional contribution of BLA inputs to the vHPC has never been directly investigated. Here we show that activation of BLA-vHPC synapses acutely and robustly increased anxiety-related behaviors, while inhibition of BLA-vHPC synapses decreased anxiety-related behaviors. We combined optogenetic approaches with in vivo pharmacological manipulations and ex vivo whole-cell patch-clamp recordings to dissect the local circuit mechanisms, demonstrating that activation of BLA terminals in the vHPC provided monosynaptic, glutamatergic inputs to vHPC pyramidal neurons. Furthermore, BLA inputs exerted polysynaptic, inhibitory effects mediated by local interneurons in the vHPC that may serve to balance the circuit locally. These data establish a role for BLA-vHPC synapses in bidirectionally controlling anxiety-related behaviors in an immediate, yet reversible, manner and a model for the local circuit mechanism of BLA inputs in the vHPC., (Copyright © 2013 Elsevier Inc. All rights reserved.)