Genetic and environmental interactions contribute to immune variation in rewilded mice
Oyesola, Oyebola et al.
Nat Immunol. 2024
An individual’s immune phenotype is shaped by some combination of genetic, maternal and epigenetic factors, and nonheritable influences. In this paper, the authors studied the relative and interactive contributions of genetic and environmental influences on immune profiles. They introduced female laboratory mice of different genotypes-C57BL/6, 129S1 and PWK/PhJ-into a natural environment, in a process termed ‘rewilding’. They then have tracked behavior outdoors, challenged the mice with Trichuris muris embryonated eggs 2 weeks after release and recovered the mice for analysis. MDMR analysis on PBMC cellular composition showed that genotype and environment had a notable effect on variation in cellular composition. They also observed a trend towards more neutrophils in the rewilded PWK/PhJ mice, indicating a genotype effect on neutrophil abundance in the rewilding environment. They focused on the immune response of mesenteric lymph nodes (MLNs). An interactive effect of genotype, environment and infection (Gen × Env × Inf) contributed to the variation in immune composition in the MLN. It’s indicated that CD4 T and B cell populations in the MLNs showed differential effects of environment versus genotype in driving immune variation. Rewilded T. muris-exposed mice of all genotypes had more CD44-expressing B cells than their counterparts in the vivarium. And central memory CD4 and CD8 T cells also expanded following rewilding. They found that Gen × Env similarly contributed to the variation in the T cell population. They further analyzed the multiplex plasma cytokine data of systemic and circulating levels of IL-5, IL-17a, IL-22, IL-6, TNF and IFNγ. The data showed that the circulating IFNγ levels were especially high in infected C57BL/6 mice in both laboratory and rewilded settings. They observed that Gen × Env interaction has a bigger effect on supernatant cytokine responses. Then they used scRNA-seq to examine effects of Gen × Env × Inf interactions on immune composition and cytokine responses in the MLN cells. Genotype and environment (Gen × Env) interactions also contributed to significant variation in immune composition as assessed by scRNA-seq. Collectively, they indicated that interactions between environment and genotype are an important source of variation in immune phenotypes.DOI:10.1038/s41590-024-01862-5.
02
Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome
Vinnakota, Janaki Manoja et al.
Nat Cancer. 2024
CAR T cells targeting CD19 induce high remission rates in B cell malignancies, but their transfer is frequently associated with cytokine release syndrome (CRS) and neurotoxicity1, also known as immune effector cell-associated neurotoxicity syndrome (ICANS). In this paper, the scientists examined the role of microglia using mouse models and cohorts of individuals with ICANS. They used a B cell lymphoma (NHL) model and a B-ALL model and treated tumor-bearing mice with CAR19 T cells. They observed major changes with respect to dendrite length, dendrite segments, number of dendrite terminal points and branch points after CAR19 T cell transfer, indicating that microglia activation was induced after CAR19 T cell transfer. CAR19 T cell-treated mice exhibited increased numbers of Iba-1+ cells in the cortex of those bearing B-NHL and B-ALL. They then used mRNA sequencing analysis on microglia. Gene expression in the microglia cluster was fundamentally different in the CAR19 T cell group and seven clusters were identified. They also observed significantly increased expression of multiple genes related to the TNF signaling pathway in microglia derived from mice that received CAR19 T cells. In addition, they performed behavior tests in mice after CAR19 T cell transfer. They discovered that B-ALL-bearing mice treated with mouse CAR19 T cells exhibited neurocognitive deficits compared to untreated B-ALL-bearing mice. Expression of multiple genes related to postsynaptic neurotransmitter receptor activity was decreased, consistent with the neurocognitive deficiency in mice treated with CAR19 T cells. And depletion of microglia, starting from 1 week before tumor injection, improved neurocognitive function in B-ALL-bearing mice treated with CAR19 T cells. Next, they analyzed serine-threonine kinase activity on microglia from B-NHL-bearing mice with CAR19 T cells treatment and observed increased phosphorylation of multiple kinases at the phospho-protein level. They then deleted Tak1 in microglia and showed that Tak1 deletion improved neurocognitive function. In conclusion, they identified a functional role for microglia in mediating CAR19 T cell-induced neurotoxicity.
DOI: 10.1038/s43018-024-00764-7.Editor & Reviewer: Congci Yu
