Journal of Experimental Medicine最新文献

In the tumor microenvironment (TME), "exhausted" CD8+ T cells are classified into progenitor (Tpex) and terminally exhausted (Ttex) populations. Tpex cells, critically regulated by zinc finger and BTB domain containing 27 (Zbtb27)/Bcl6 transcription factor, could be reinvigorated during immune checkpoint blockade (ICB) therapy, while Ttex cells, characterized by stronger proliferation and cytotoxicity, play an indispensable role in tumor control. However, the mechanisms governing the differentiation into Ttex and their function remain not well understood. In this study, we identified that Zbtb32, highly expressed in CD8+ Ttex subset, is crucial for CD8+ T cells within tumors. Zbtb32, regulated by CD28 signaling, promotes the differentiation of CD8+ T cells into Ttex subset, enhancing their cytotoxicity, proliferation, and anti-tumor capability. Importantly, we found a competitive DNA binding between Zbtb32 and Bcl6, especially in regulation of Id2 expression. Thus, our findings demonstrate the pivotal role of Zbtb32 in CD8+ T cell anti-tumor function, with implications in cancer immunotherapy.

Many cancer patients do not benefit from current immunotherapies. This lack of efficacy may be, in part, due to insufficient priming and activation of T cells. Here, we show that activation of liver-X-receptors (LXRs) promotes adaptive anti-tumor immunity by enhancing priming of T cells. Genetic LXR deletion in the host and depletion of dendritic and CD8+ T cells, but not of macrophages, abrogated anti-tumor effects of LXR-agonistic therapy. In cross-presentation assays, LXR agonism promoted T cell activation upon DC/T cell cross talk. Genetic deletion of LXRs in T cells, but not in dendritic cells, blunted this effect. Dissection of the temporal dynamics of LXR-enhanced T cell effector function showed that LXR agonism rendered T cells more receptive to adopting effector states upon stimulation. Consistently, LXR agonist therapy elicited T cell expansion in cancer patients enrolled in a phase I trial. Our findings establish LXR activation as an effective approach for enhancing T cell priming.

Antibody-mediated immune responses in mucosal tissues are critical for defending against pathogens while maintaining homeostasis with commensals. Nasal vaccination aims to induce local protection in the upper airway mucosa. Although B cell-driven immunity is well characterized in gut-associated lymphoid tissues such as Peyer's patches and mesenteric LNs, much less is known about analogous processes in the upper airways. Here, we show that B cell receptor (BCR) affinity and CCR6 regulate germinal center (GC) seeding and class-switch recombination (CSR) to IgA in nasal-associated lymphoid tissue (NALT) following nasal vaccination. B cells bearing low-affinity BCRs failed to upregulate CCR6 and did not support T follicular helper cell differentiation or seed GCs in the NALT. CCR6-deficient B cells were unable to migrate to the NALT subepithelial dome or undergo IgA CSR and seed GC effectively in response to nasal vaccination or commensal bacteria signals. Thus, effective targeting of B cell clones to induce CCR6 expression is essential for nasal vaccine design.

Cancer immunotherapy has mostly relied on conventional T cells to achieve success in a limited set of tumor types. A promising avenue to expand the repertoire of cancers effectively treated through immune intervention is to mobilize other anti-tumor effectors, such as γδ T cells. Among these, the Vδ1+ subset commonly predominates within peripheral tissues and within tumors, typically associating with good prognosis. In this Found in Translation, we discuss how to leverage the biological properties of Vδ1+ γδ T cells for cancer immunotherapy, with special focus on the delta one T (DOT) cell approach.

The germinal center (GC) is a specialized structure that ensures the production of high-quality antibodies. Although recent studies have pinpointed the existence of a pre-plasma cell (prePC) population within mouse GC B cells, it remains unclear how these prePCs mechanistically differentiate into PCs. Additionally, there is a lack of validation of these findings in human cells. Here, we demonstrate CD205 is highly expressed in prePCs both in mouse and in human. The histone H3 lysine 27 demethylase Kdm6b, not Kdm6a, potently enhances the differentiation of prePCs into bona fide PCs by removing repressive H3K27me3 marks at the Irf4 locus. Interestingly, prePCs favor glutamine metabolism, which provides α-ketoglutarate as a substrate for the demethylation reaction of Kdm6b. Thus, prePCs require metabolic and epigenetic reprogramming to differentiate into PCs in the GC.

Patients with loss-of-function DOCK8 or dominant-negative STAT3 variants have hyper-IgE syndrome, although only DOCK8 deficiency consistently presents with elevated food-specific IgE and symptomatic allergy. We previously found in mice that DOCK8 restricts the differentiation of IL-13+ T follicular helper (Tfh13) cells that drive anaphylactic IgE, although the mechanisms were unclear. Here, we show that DOCK8 promotes STAT3 activity, which inhibits GATA3 in T cells. However, only patients with DOCK8, but not STAT3, deficiency had elevated Tfh13 cells. Cell-specific deletion of either Dock8 (T-Dock8-/-) or Stat3 (T-Stat3-/-) augmented peanut-specific IgE and Tfh13s when oral sensitization was promoted by adjuvants. However, the phenotypes diverged during adjuvant-free oral peanut exposure: only T-Dock8-/- mice developed Tfh13 cells and peanut-specific IgE, accompanied by reduced Foxp3+ Tregs. Treg depletion in T-Stat3-/- mice unmasked Tfh13 induction to oral antigen alone. Thus, DOCK8 and STAT3 cooperate to restrain Tfh13 differentiation to food allergens, and additional Treg impairment in DOCK8 deficiency allows for Tfh13 cell induction and allergy.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the highest rates of recurrence, metastasis, and patient mortality due to the absence of effective therapies. Hypoxia-inducible factor 1 (HIF-1) regulates the expression of thousands of RNAs in TNBC. Here, we demonstrate that transcription of the ISG20 gene, which encodes an RNA exonuclease, is activated by HIF-1 in TNBC cells. ISG20-mediated degradation of RHOBTB3 mRNA increases HIF-1α protein expression and activates NANOG signaling, which increases breast cancer stem cell specification and lung metastasis. ISG20 also degrades STAT1 and IRF1 mRNAs, leading to decreased expression of CXCL10 and impaired recruitment of CD8+ T cells and natural killer cells, thereby promoting breast cancer immune evasion. Silencing ISG20 increases the sensitivity of mouse TNBC cells to anti-PD1 antibody immune checkpoint blockade. Our data suggest that targeting ISG20, in combination with immunotherapy, could be an effective therapeutic strategy for TNBC.

Fulminant viral hepatitis (FVH) is a devastating condition caused by hepatotropic viruses such as hepatitis A virus (HAV), hepatitis B virus (HBV), and HSV-1/2. We studied 149 FVH patients (73 males and 76 females, aged 1-76) for blood autoantibodies (auto-Abs) neutralizing type I interferons (IFNs; IFN-α2, -β, -ω). Six of 16 (37.5%) HSV-triggered FVH patients carried such auto-Abs on admission, including three with a previously known autoimmune disease. These patients contrasted with 133 HAV- (n = 46) or HBV-triggered (n = 87) patients, none of whom had such detectable auto-Abs. Odds ratios for HSV-triggered FVH in individuals with auto-Abs ranged from 35.3 (95% CI: 13.0-96.2; P < 10-7) for those neutralizing only 100 pg/ml IFN-α/ω to 1,895 (CI: 448.5-8,002; P < 10-12) for those neutralizing both IFN-α and IFN-ω at 10 ng/ml. Over one third of HSV-triggered FVH cases in this international cohort were due to preexisting auto-Abs. This finding highlights auto-Abs against type I IFNs as a major determinant of HSV-FVH and paves the way for targeted preventive or therapeutic interventions.

Avian influenza A virus (IAV) H5N1 is an emerging threat of human pandemic. We describe a 71-year-old man who died of H5N1 pneumonia in Louisiana and whose blood contained autoantibodies neutralizing type I IFNs (AAN-I-IFNs), including the 12 IFN-α subtypes (1-10 ng/ml) and IFN-ω (100 pg/ml). Causality between these AAN-I-IFN and lethal outcome of avian influenza in this patient is based on (1) our previous report that AA-I-IFN underlie about 5% of cases of critical pneumonia triggered by seasonal influenza viruses in three cohorts, (2) the rarity of this combination of AAN-I-FNs in individuals over 70 years old (<1%), and (3) the rarity of lethal avian influenza among infected individuals (<1%). AAN-I-IFNs underlie a growing number of severe viral diseases, from arboviral encephalitis to viral pneumonia, particularly in the elderly. This case suggests they can also underlie life-threatening avian H5N1 influenza. The presence of AAN-I-IFN may facilitate infection, replication, and adaptation of zoonotic IAVs to humans and, therefore, human-to-human transmission.