Volume 23 Issue 8, August 2022

Wherry and colleagues describe how anti-PD-1 immunotherapy impacts outcomes of influenza vaccination in patients with cancer, and specifically, how it increases seroconversion and affects quantitative and qualitative aspects of antibodies and follicular T helper cell responses.

Specific brain circuits recruited during stress contribute to differential immune responses and affect how the immune system handles viral and autoimmune challenges.

Multistep mechanosensing of lymphocyte infiltration and proliferation by the remodeling stroma and matrix underlies the immensely rapid and massive tissue expansion by lymph nodes in response to immune challenge.

Immune checkpoint blocking therapies do not always work and come with some risks, but identifying non-responders and patients at risk of adverse events is becoming easier and more accurate.

Deacetylation of specific lysine residues in the DNA-binding domain of the transcription factors IRF3 and IRF7 by SIRT1 is necessary for liquid–liquid phase separation and transactivation of type I interferons. SIRT1 agonists partially restored the impaired innate immune responses in senescent cells and aged mice, suggestive of a possible strategy for preventing innate immunosenescence.

The response of circulating effector CD4 T cells to type I interferons (IFN-I) correlates with the overall survival of patients with cancer receiving immune checkpoint inhibition. IFN-I responsiveness is already epigenetically encoded before treatment initiation, highlighting a deterministic, clinically relevant feature that can predict therapeutic efficacy.

Boussiotis and colleagues review the hallmarks of tumor-associated macrophages and discuss the mechanisms that contribute to their pathophysiological adaptations to the tumor microenvironment.

Yu et al. review the roles played by follicular helper T cells in sustaining germinal center B cell responses and vaccination strategies, as well as potential pathogenic autoimmune responses.

Acton and colleagues examine the mechanics of lymph node swelling during the course of an immune response. They find tissue tension regulates fibroblastic reticular cell (FRC) proliferation during lymph node expansion and that podoplanin (PDPN)–CLEC-2 signaling in FRCs regulates this process, which in turn regulates T cell activation.

Patients with cancer undergoing anti-PD-1 immune checkpoint blockade can experience immune-related adverse effects. Wherry and colleagues examined the immunity elicited upon immunization of patients with cancer and report that anti-PD-1 immunotherapy dynamically affects influenza vaccine-induced immune responses.

The deacetylase SIRT1 regulates IRF3/IRF7-mediated antiviral interferon signaling. Here the authors show that SIRT1 deactylates the DNA-binding domain resulting in liquid–liquid phase separation of IRF3/IRF7 and that this signaling is inhibited in aging, an effect that can be reversed with a SIRT1 agonist to restore antiviral response.

Heissmeyer and colleagues show that TCR stimulation-induced cell death is controlled by N⁶-methyladenosine (m⁶A) modification of Orai1 and Ripk1 mRNAs. m⁶A is deposited by a ‘writer’ complex of Wtap and the N⁶-methyltransferase and bound by the ‘reader’ protein Ythdf2. T cells lacking Wtap exhibit enhanced Ca²⁺ entry in response to TCR ligation and decreased survival due to activation-induced cell death.

Xue and colleagues show that Tcf1 and Lef1 recruit the genome organizer CTCF to promote chromatin interactions and form highly connected, dynamic interaction hubs in CD8⁺ T cells undergoing homeostatic proliferation.

Mackay and colleagues show that distinct programs of tissue residency are induced in CD8⁺ and CD4⁺ T_RM cell subsets, a difference attributable to the activity of the transcription factor Runx3.

Sixt and colleagues show that different fibroblast populations in the lymph node mechanically control its swelling in a multitier fashion.

Patients with partial recombination-activating gene (RAG) deficiency (pRD) present variable late-onset autoimmune clinical phenotypes. Walter and colleagues identified a restricted primary B cell antigen receptor repertoire enriched for autoreactivity and clonal persistence in pRD. They described dysregulated B cell maturation with expansion of T-bet⁺ B cells revealing how RAG impacts stringency of tolerance and B cell fate in the periphery.

Predicting which patients will respond to checkpoint blocking therapies is a major challenge. Here the authors score the epigenetic imprinting of T cell responsiveness to type 1 interferons and use this information to predict response to anti-PD1 therapy and long-term survival of cancer patients.