Perinatal thymic-derived CD8αß-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R-STAT5B-driven neoplasms.

The contribution of γδ T cells to immune responses is associated with rapid secretion of interferon-γ (IFN-γ). Here, we show a perinatal thymic wave of innate IFN-γ-producing γδ T cells that express CD8αß heterodimers and expand in preclinical models of infection and cancer. Optimal CD8αß+ γδ T cell development is directed by low T cell receptor signaling and through provision of interleukin (IL)-4 and IL-7. This population is pathologically relevant as overactive, or constitutive, IL-7R-STAT5B signaling promotes a supraphysiological accumulation of CD8αß+ γδ T cells in the thymus and peripheral lymphoid organs in two mouse models of T cell neoplasia. Likewise, CD8αß+ γδ T cells define a distinct subset of human T cell acute lymphoblastic leukemia pediatric patients. This work characterizes the normal and malignant development of CD8αß+ γδ T cells that are enriched in early life and contribute to innate IFN-γ responses to infection and cancer.

Humoral Immune Response of SARS-CoV-2-Infected Patients with Cancer: Influencing Factors and Mechanisms.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients with cancer show worse outcomes compared with patients without cancer. The humoral immune response (HIR) of patients with cancer against SARS-CoV-2 is not well characterized. To better understand it, we conducted a serological study of hospitalized patients with cancer infected with SARS-CoV-2. MATERIALS AND METHODS: This was a unicentric, retrospective study enrolling adult patients with SARS-CoV-2 admitted to a central hospital from March 15 to June 17, 2020, whose serum samples were quantified for anti-SARS-CoV-2 receptor-binding domain or spike protein IgM, IgG, and IgA antibodies. The aims of the study were to assess the HIR to SARS-CoV-2; correlate it with different cancer types, stages, and treatments; clarify the interplay between the HIR and clinical outcomes of patients with cancer; and compare the HIR of SARS-CoV-2-infected patients with and without cancer. RESULTS: We included 72 SARS-CoV-2-positive subjects (19 with cancer, 53 controls). About 90% of controls revealed a robust serological response. Among patients with cancer, a strong response was verified in 57.9%, with 42.1% showing a persistently weak response. Treatment with chemotherapy within 14 days before positivity was the only factor statistically shown to be associated with persistently weak serological responses among patients with cancer. No significant differences in outcomes were observed between patients with strong and weak responses. All IgG, IgM, IgA, and total Ig antibody titers were significantly lower in patients with cancer compared with those without. CONCLUSION: A significant portion of patients with cancer develop a proper HIR. Recent chemotherapy treatment may be associated with weak serological responses among patients with cancer. Patients with cancer have a weaker SARS-CoV-2 antibody response compared with those without cancer. IMPLICATIONS FOR PRACTICE: These results place the spotlight on patients with cancer, particularly those actively treated with chemotherapy. These patients may potentially be more vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, so it is important to provide oncologists further theoretical support (with concrete examples and respective mechanistic correlations) for the decision of starting, maintaining, or stopping antineoplastic treatments (particularly chemotherapy) not only on noninfected but also on infected patients with cancer in accordance with cancer type, stage and prognosis, treatment agents, treatment setting, and SARS-CoV-2 infection risks.

M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity.

A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or ß-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or ß-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.

Type 1 Treg cells promote the generation of CD8+ tissue-resident memory T cells.

Tissue-resident memory T (TRM) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of TRM cells are incompletely understood. Here we show that type 1 regulatory T (Treg) cells, which express the transcription factor T-bet, promote the generation of CD8+ TRM cells. The absence of T-bet-expressing type 1 Treg cells reduces the presence of TRM cells in multiple tissues and increases pathogen burden upon infectious challenge. Using infection models, we show that type 1 Treg cells are specifically recruited to local inflammatory sites via the chemokine receptor CXCR3. Close proximity with effector CD8+ T cells and Treg cell expression of integrin-ß8 endows the bioavailability of transforming growth factor-ß in the microenvironment, thereby promoting the generation of CD8+ TRM cells.

Renal control of disease tolerance to malaria.

Malaria, the disease caused by Plasmodium spp. infection, remains a major global cause of morbidity and mortality. Host protection from malaria relies on immune-driven resistance mechanisms that kill Plasmodium However, these mechanisms are not sufficient per se to avoid the development of severe forms of disease. This is accomplished instead via the establishment of disease tolerance to malaria, a defense strategy that does not target Plasmodium directly. Here we demonstrate that the establishment of disease tolerance to malaria relies on a tissue damage-control mechanism that operates specifically in renal proximal tubule epithelial cells (RPTEC). This protective response relies on the induction of heme oxygenase-1 (HMOX1; HO-1) and ferritin H chain (FTH) via a mechanism that involves the transcription-factor nuclear-factor E2-related factor-2 (NRF2). As it accumulates in plasma and urine during the blood stage of Plasmodium infection, labile heme is detoxified in RPTEC by HO-1 and FTH, preventing the development of acute kidney injury, a clinical hallmark of severe malaria.

Cutting Edge: the BTLA-HVEM regulatory pathway interferes with protective immunity to intestinal Helminth infection.

Helminths exploit intrinsic regulatory pathways of the mammalian immune system to dampen the immune response directed against them. In this article, we show that infection with the parasitic nematode Strongyloides ratti induced upregulation of the coinhibitory receptor B and T lymphocyte attenuator (BTLA) predominantly on CD4(+) T cells but also on a small fraction of innate leukocytes. Deficiency of either BTLA or its ligand herpes virus entry mediator (HVEM) resulted in reduced numbers of parasitic adults in the small intestine and reduced larval output throughout infection. Reduced parasite burden in BTLA- and HVEM-deficient mice was accompanied by accelerated degranulation of mucosal mast cells and increased Ag-specific production of the mast cell-activating cytokine IL-9. Our combined results support a model whereby BTLA on CD4(+) T cells and additional innate leukocytes is triggered by HVEM and delivers negative signals into BTLA(+) cells, thereby interfering with the protective immune response to this intestinal parasite.