In allogeneic-hematopoietic stem cell transplantation for acute myeloid leukemia (AML), donor T cells combat leukemia through the graft-versus-leukemia (GVL) effect, while they also pose a risk of triggering life-threatening graft-versus-host disease (GVHD) by interacting with recipient cells. The onset of GVHD hinges on the interplay between donor T cells and recipient antigen-presenting cells (APCs), sparking T-cell activation. However, effective methods to balance GVHD and GVL are lacking.
In our study, we crafted nanocapsules by layering polycationic aminated gelatin and polyanionic alginate onto the surface of T cells, examining potential alterations in their fundamental physiological functions. Subsequently, we established an AML mouse model and treated it with transplantation of bone marrow cells (BMCs) combined with encapsulated T cells to investigate the GVL and anti-GVHD effects of encapsulated T cells. In vitro co-culture was employed to probe the effects of encapsulation on immune synapses, co-stimulatory molecules, and tumor-killing pathways.
Transplantation of BMCs combined with donor T cells selectively encapsulated onto AML mice significantly alleviates GVHD symptoms while preserving essential GVL effects. Encapsulated T cells exerted their immunomodulatory effects by impeding the formation of immune synapses with recipient APCs, thereby downregulating co-stimulatory signals such as CD28-CD80, ICOS-ICOSL, and CD40L-CD40. Recipient mice receiving encapsulated T-cell transplantation exhibited a marked increase in donor Ly-5.1-BMC cell numbers, accompanied by unaltered in vivo expression levels of perforin and granzyme B. While transient inhibition of donor T-cell cytotoxicity in the tumor microenvironment was observed in vitro following single-cell nanoencapsulation, subsequent restoration to normal antitumor activity ensued, attributed to selective permeability of encapsulated vesicle shells and material degradation. Moreover, the expression of apoptotic proteins and FAS-FAS ligand pathway at normal levels was still observed in leukemia tumor cells.
Encapsulated donor T cells effectively mitigate GVHD while preserving the GVL effect by minimizing co-stimulatory signaling with APCs through early immune isolation. Subsequent degradation of nanocapsules restores T-cell cytotoxic efficacy against AML cells, mediated by cytotoxic pathways. Using transplant-encapsulated T cells offers a promising strategy to suppress GVHD while preserving the GVL effect.
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Early-life establishment of tolerance to commensal bacteria at barrier surfaces carries enduring implications for immune health but remains poorly understood. Here, we showed that tolerance in skin was controlled by microbial interaction with a specialized subset of antigen-presenting cells. More particularly, CD301b+ type 2 conventional dendritic cells (DCs) in neonatal skin were specifically capable of uptake and presentation of commensal antigens for the generation of regulatory T (Treg) cells. CD301b+ DC2 were enriched for phagocytosis and maturation programs, while also expressing tolerogenic markers. In both human and murine skin, these signatures were reinforced by microbial uptake. In contrast to their adult counterparts or other early-life DC subsets, neonatal CD301b+ DC2 highly expressed the retinoic-acid-producing enzyme, RALDH2, the deletion of which limited commensal-specific Treg cell generation. Thus, synergistic interactions between bacteria and a specialized DC subset critically support early-life tolerance at the cutaneous interface.
Copyright © 2023 Elsevier Inc. All rights reserved.

Protective immune responses against respiratory pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus, are initiated by the mucosal immune system. However, most licensed vaccines are administered parenterally and are largely ineffective at inducing mucosal immunity. The development of safe and effective mucosal vaccines has been hampered by the lack of a suitable mucosal adjuvant. In this study we explore a class of adjuvant that harnesses mucosal-associated invariant T (MAIT) cells. We show evidence that intranasal immunization of MAIT cell agonists co-administered with protein, including the spike receptor binding domain from SARS-CoV-2 virus and hemagglutinin from influenza virus, induce protective humoral immunity and immunoglobulin A production. MAIT cell adjuvant activity is mediated by CD40L-dependent activation of dendritic cells and subsequent priming of T follicular helper cells. In summary, we show that MAIT cells are promising vaccine targets that can be utilized as cellular adjuvants in mucosal vaccines.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

There is an increasing appreciation for the heterogeneity of myeloid lineages in the lung, but relatively little is known about populations specifically associated with the conducting airways. We use single-cell RNA sequencing, flow cytometry, and immunofluorescence to characterize myeloid cells of the mouse trachea during homeostasis and epithelial injury/repair. We identify submucosal macrophages, similar to lung interstitial macrophages, and intraepithelial macrophages. Following injury, there are early increases in neutrophils and submucosal macrophages, including M2-like macrophages. Intraepithelial macrophages are lost after injury and later restored by CCR2+ monocytes. We show that repair of the tracheal epithelium is impaired in Ccr2-deficient mice. Mast cells and group 2 innate lymphoid cells are sources of interleukin-13 (IL-13) that polarize macrophages and directly influence basal cell behaviors. Their proximity to the airway epithelium establishes these myeloid populations as potential therapeutic targets for airway disease.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation1-3. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells4-6. Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72. Dendritic cells isolated from C9orf72-/- mice show marked early activation of the type I interferon response, and C9orf72-/- myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72-/- myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72-/- immune cells as well as splenomegaly and inflammation in C9orf72-/- mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.