In 2022, a global mpox outbreak occurred, and remains a concern today. The T cell memory response to MPXV (monkeypox virus) infection has not been fully investigated. In this study, we evaluate this response in convalescent and MVA-BN (Modified Vaccinia Ankara - Bavarian Nordic) vaccinated individuals using VACV-infected cells. Strong CD8+ and CD4+ T cell responses are observed, and T cell responses are biased towards viral early expressed proteins. We identify seven immunodominant HLA-A*02:01 restricted MPXV-specific epitopes and focus our detailed phenotypic and scRNAseq analysis on the immunodominant HLA-A*02:01-G5R18-26-specific CD8+ T cell response. While tetramer+CD8+ T cells share similar differentiation and activation phenotypes, T cells from convalescent individuals show greater cytotoxicity, migratory potential to site of infection and TCR clonal expansion. Our data suggest that effective functional profiles of MPXV-specific memory T cells induced by Mpox infection may have an implication on the long-term protective responses to future infection.
© 2025. The Author(s).

Variant-adapted vaccines are recommended in vulnerable populations to address the waning immunity and the emergence of immune-escaping SARS-CoV-2 variants, yet data about immune responses to such vaccines in people living with HIV (PLWH) are limited. We therefore aimed to assess long-term immune responses to an original-BA.4/5 mRNA booster in this population.
In this prospective longitudinal study, PLWH receiving either an original-BA.4/5 bivalent booster or an original monovalent booster and HIV-negative healthcare workers (HCWs) receiving a bivalent booster were enrolled and sampled before (T0), 1 month (T1), and 4-9 months (T2) after the vaccine administration. SARS-CoV-2-specific T and B cells, RBD-binding antibodies, and RBD-blocking antibodies against both wild type (WT) and omicron BA.4/5 virus were determined.
The bivalent booster is able to transiently increase both humoral and polyfunctional T cell responses in PLWH, with humoral responses comparable to those observed in HCWs. While T cell responses are cross-reactive against viral variants and stable over time, humoral immunity is imprinted to the ancestral virus and wanes quickly. Furthermore, whilst previous SARS-CoV-2 infection does not affect the trajectory of vaccine-elicited immune responses, markers of HIV-related T cell dysfunction are associated with lower antibody peak responses and higher antibody waning. Lastly, the bivalent booster was superior to the monovalent one in inducing BA.4/5-reactive RBD-blocking antibodies.
The original-BA.4/5 bivalent booster is highly immunogenic in PLWH and superior to the monovalent one in inducing humoral responses against the BA.4/5 virus, although HIV-related T cell dysfunction markers are associated with blunted and less durable antibody immunity.
© 2025. The Author(s).

Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor involved in innate immunity, but its role in adaptive immunity, specifically in the context of CD8+ T-cell antitumour immunity, remains unclear. Here, we demonstrate that RIG-I is upregulated in tumour-infiltrating CD8+ T cells, where it functions as an intracellular checkpoint to negatively regulate CD8+ T-cell function and limit antitumour immunity. Mechanistically, the upregulation of RIG-I in CD8+ T cells is induced by activated T cells, and directly inhibits the AKT/glycolysis signalling pathway. In addition, knocking out RIG-I enhances the efficacy of adoptively transferred T cells against solid tumours, and inhibiting RIG-I enhances the response to PD-1 blockade. Overall, our study identifies RIG-I as an intracellular checkpoint and a potential target for alleviating inhibitory constraints on T cells in cancer immunotherapy, either alone or in combination with an immune checkpoint inhibitor.
© 2024. The Author(s).

T cell immune dysfunction is a prominent feature of chronic HIV infection. To evaluate non-specific dysfunction, a method involving both generic activation and T cell receptor (TCR) stimulation is necessary. We created a tunable artificial antigen-presenting cell (aAPC) system. This system consists of lipid bilayers on cytometry-compatible silica microbeads (5 μm). When only anti-CD3 is incorporated, T cell activation is limited. Introducing anti-CD28 agonists significantly elevates the cytokine expression and upregulation of activation-induced markers. CD28 co-stimulation modulates the response profile, preferentially promoting IL-2 expression relative to other cytokines. aAPCs-stimulated CD4+ and CD8+ T cells from untreated HIV-infected individuals exhibit altered effector functions and diminished CD28 dependence. These functions are skewed toward TNFα, IFNγ and CD107a, with reduced IL-2. Antiretroviral therapy partially normalizes this distorted profile in CD4+ T cells, but not in CD8+ T cells. Our findings show T cell intrinsic biases that may contribute to persistent systemic T cell dysfunction associated with HIV pathogenesis.
© 2024 The Author(s).

NK cells are dysfunctional in myasthenia gravis (MG), but the mechanism is unclear. This study aims to measure associations and underlying mechanisms between the NK cells and the development of MG.
Twenty healthy controls (HCs) and 53 MG patients who did not receive glucocorticoids and immunosuppressants were collected. According to the Myasthenia Gravis Foundation of America (MGFA) classification, MG patients were categorized into MGFA I group (n = 18) and MGFA II-IV group (n = 35). Flow cytometry, cell sorting, ELISA, mRNA-sequencing, RT-qPCR, western blot, and cell culture experiments were performed to evaluate the regulatory mechanism of exhausted NK cells.
Peripheral NK cells in MGFA II-IV patients exhibit exhausted phenotypes than HCs, marked by the dramatic loss of total NK cells, CD56dimCD16- NK cells, elevated PD1 expression, reduced NKG2D expression, impaired cytotoxic activity (perforin, granzyme B, CD107a) and cytokine secretion (IFN-γ). Plasma IL-6 and IL-21 are elevated in MG patients and mainly derived from the aberrant expansion of monocytes and Tfh cells, respectively. IL-6/IL-21 cooperatively induced NK-cell exhausted signature via upregulating SOCS2 and inhibiting the phosphorylation of STAT5. SOCS2 siRNA and IL-2 supplement attenuated the IL-6/IL-21-mediated alteration of NK-cell phenotypes and function.
Inhibition of IL-6/IL-21/SOCS2/STAT5 pathway and recovery of NK-cell ability to inhibit autoimmunity may be a new direction in the treatment of MG.
Copyright © 2024 Zhang, Han, Bi, Yang, Lin, Li, Zhang and Bu.