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Lymphoid tissues are an important HIV reservoir site that persists in the face of antiretroviral therapy and natural immunity. Targeting these reservoirs by harnessing the antiviral activity of local tissue-resident memory (T RM ) CD8 + T-cells is of great interest, but limited data exist on T RM -like cells within lymph nodes of people living with HIV (PLWH). Here, we studied tonsil CD8 + T-cells obtained from PLWH and uninfected controls from South Africa. We show that these cells are preferentially located outside the germinal centers (GCs), the main reservoir site for HIV, and display a low cytolytic and a transcriptionally T RM -like profile distinct from blood CD8 + T-cells. In PLWH, CD8 + T RM -like cells are expanded and adopt a more cytolytic, activated, and exhausted phenotype not reversed by antiretroviral therapy (ART). This phenotype was enhanced in HIV-specific CD8 + T-cells from tonsils compared to matched blood suggesting a higher antigen burden in tonsils. Single-cell transcriptional and clonotype resolution showed that these HIV-specific CD8 + T-cells in the tonsils express heterogeneous signatures of T-cell activation, clonal expansion, and exhaustion ex-vivo. Interestingly, this signature was absent in a natural HIV controller, who expressed lower PD-1 and CXCR5 levels and reduced transcriptional evidence of T-cell activation, exhaustion, and cytolytic activity. These data provide important insights into lymphoid tissue-derived HIV-specific CD8 + T RM -like phenotypes in settings of HIV remission and highlight their potential for immunotherapy and targeting of the HIV reservoirs.

Psoriasis is a chronic autoimmune skin disorder characterized by keratinocyte hyperproliferation, persistent inflammation, and frequent relapse. Tissue-resident memory T (TRM) cells, particularly IL-17– and phosphorylated STAT3 (pSTAT3)–expressing CD8 + subsets, have been established as central drivers of disease persistence and recurrence. These pathogenic TRM cells maintain local inflammatory circuits that are poorly targeted by current therapies, which helps to explain the limited durability of clinical remission in many patients. Therefore, strategies for selective suppression of these immune subsets are urgently needed. In this study, we investigated the therapeutic potential of nano-sized graphene oxide (NGO), a biocompatible material with emerging anti-inflammatory properties. NGO treatment significantly enhanced mitochondrial function in immune cells, reflected by improved oxygen consumption rate and reduced mitochondrial reactive oxygen species production. Restoration of mitochondrial homeostasis led to robust suppression of pSTAT3 and IL-17 signaling pathways. Importantly, NGO induced a dose-dependent reduction in the numbers of pathogenic CD8 + TRM17 cells in both murine models of psoriasis and human-patient-derived immune cells. Beyond its direct effects on pathogenic TRM cells, NGO treatment alleviated epidermal hyperplasia and inflammatory infiltration in psoriatic lesions and promoted the expansion of regulatory T cells, thereby fostering an immune environment more conducive to tissue resolution. Taken together, these findings show that NGO exerted potent therapeutic effects by coupling mitochondrial reprogramming with immune modulation. By attenuating pSTAT3–IL-17–driven TRM cell responses and enhancing regulatory T cell activity, NGO has emerged as a promising candidate for durable immunometabolic therapy in psoriasis. Graphical abstract

Background The accumulation of IL-17–producing CD8 + tissue-resident memory T (IL-17 + CD8 + TRM) cells contributes to chronic and recurrent psoriasis. Suppressor of cytokine signaling 3 (SOCS3) plays a critical role in limiting pSTAT3 and pNF-κB activity to restrain excessive IL-17–mediated inflammation. This study investigated how IL-1–induced activation of pSTAT3 and pNF-κB leads to SOCS3 downregulation in CD8 + TRM cells, facilitating the expansion of IL-17 + subsets in psoriasis. It also evaluated the therapeutic potential of restoring SOCS3 through targeted STAT3 inhibition and STAT5 activation. Methods Using both in vitro assays and an IL-1 receptor antagonist knockout mouse model of imiquimod-induced psoriasis, we examined hyperactive IL-1 signaling in CD8 + TRM cells isolated from ex vivo psoriatic samples. The STAT3 inhibitor STA-21 was used to assess its effect on SOCS3 expression and IL-17 + CD8 + TRM cells frequency. Results Hyperactivation of IL-1 signaling in chronic psoriasis established a pathogenic NF-κB-STAT3 feedback loop in CD8 + TRM cells, where elevated pSTAT3 and pNF-κB activity suppressed SOCS3 expression, promoting the expansion of IL-17 + CD8 + TRM cells and exacerbating disease severity. Therapeutic modulation via STA-21 restored SOCS3 levels, reduced IL-17 + CD8 + TRM numbers, and attenuated the pathogenic feedback loop. Dual regulation of STAT3 inhibition and STAT5 activation emerged as a promising approach to attenuate psoriatic inflammation. Conclusion Our findings demonstrate that the IL-1/pNF-κB/pSTAT3 axis in CD8 + TRM cells as a major contributor of psoriasis pathogenesis. Restoring SOCS3 expression through combined STAT3 inhibition and STAT5 activation represents a potential immunomodulatory approach that may contribute to treatment strategies for severe or recurrent psoriasis. However, further studies, including direct comparisons with current biological combination therapies, are needed to fully evaluate its efficacy and safety. Graphical Abstract

CD8+ tissue‐resident memory T cells (TRM) are strategically located in peripheral tissues, enabling a rapid response to local infections, which is different from circulating memory CD8+ T cells. Their unique positioning makes them promising targets for vaccines designed to enhance protection at barrier sites and other organs. Recent studies have shown a correlation between CD8+ TRM cells and favorable clinical outcomes in various types of cancer, indicating their potential role in immune checkpoint blockade (ICB) therapies. However, the dual nature of CD8+ TRM cells presents challenges, as their inappropriate activation may lead to autoimmunity and chronic inflammatory conditions. This review highlights significant advancements in the field, focusing on the differentiation pathways and phenotypic heterogeneity of CD8+ TRM cells across different tissues and disease states. We also review their protective roles in various contexts and the implications for vaccine development against infections and treatment strategies for tumors. Overall, this comprehensive review outlines the common features of CD8+ TRM cell differentiation and biological functions, emphasizing their specific characteristics across diverse tissues and disease states, which can guide the design of therapies against infections and tumors while minimizing the risk of autoimmune diseases. Xu et al. described the differentiation, biological function, and phenotype heterogeneity of CD8+TRM cells across various types of tissues and distinct disease settings, and discussed their potential roles in the designation of vaccines against infectious diseases and immune therapy of tumors .

The immune system, smartly and surprisingly, saves the exposure of a particular pathogen in its memory and reacts to the pathogen very rapidly, preventing serious diseases. Immunologists have long been fascinated by understanding the ability to recall and respond faster and more vigorously to a pathogen, known as “memory”. T-cell populations can be better described by using more sophisticated techniques to define phenotype, transcriptional and epigenetic signatures and metabolic pathways (single-cell resolution), which uncovered the heterogeneity of the memory T-compartment. Phenotype, effector functions, maintenance, and metabolic pathways help identify these different subsets. Here, we examine recent developments in the characterization of the heterogeneity of the memory T cell compartment. In particular, we focus on the emerging role of CD8 + T RM and T SCM cells, providing evidence on how their immunometabolism or modulation can play a vital role in their generation and maintenance in chronic conditions such as infections or autoimmune diseases.

Understanding CD8 tissue-resident memory T cells (TRM) spatial characteristics in hepatocellular carcinoma (HCC) is challenging, and clarifying the spatial feature changes following immunotherapy represents an urgent research gap. This study employs a multi-omics approach to analyze the spatial distribution and intercellular interactions of TRM cells in HCC tissues using radiomics, single-cell sequencing, and multiplex immunofluorescence histochemistry (m-IHC). Our results show that the number of CD8 TRM cells in HCC increases following immunotherapy. Furthermore, after dividing tumor tissues into the tumor core (TC), invasion margin (IM), and normal tissue (N), a increase in CD8 TRM cells from the IM to the TC can be observed. Consistent with the results of single-cell sequencing analysis, this change in spatial characteristics may be associated with the interactions between CD8 TRM cells and CD68 cells. Immunotherapy can modify the spatial characteristics of CD8 TRM cells via regulating their crosstalk with other immune cells, and the spatial distribution of CD8 TRM cells in the HCC tumor microenvironment (TME) correlates with immune checkpoint blockade (ICB) therapeutic efficacy. Clarifying the mechanisms of action of immunotherapeutic drugs and developing a non-invasive radiomics model to predict CD8⁺ TRM cell dynamics will facilitate the clinical management of HCC.

Irreversible electroporation (IRE) is a relatively new, non-thermal ablation technology for cancer treatment that requires further investigation to optimize its therapeutic efficacy. To improve IRE-ablation, we developed an IRE+Combo-treatment regimen that included the Combo adjuvants poly-I:C (pIC)/CpG, anti-PD-L1 antibody (PD-L1-Ab) and the 41BB-agonist, and investigated its anti-tumor immunity in a 3LL OVA lung cancer model. We demonstrated that inclusion of the 41BB-agonist in the IRE+Combo-ablation stimulated a more efficient CD8 + T cell response (5.3%) than that observed in the absence of 41BB-agonist (3.0%) or upon IRE ablation alone (0.4%), leading to eradication of subcutaneous 3LL OVA cancer in 75% of 3LL OVA -bearing mice. We further showed that the IRE+Combo-treatment regimen resulted in the eradication of both 3LL OVA cancer and lung tumor metastases. Interestingly, our flow cytometry analyses argued that addition of the 41BB-agonist to the IRE+Combo-ablation stimulated a higher frequency of novel CD8 + CD103 + conventional type-1 dendritic cells (cDC1) (14.4%) in tumor-drainage lymph-nodes (TDLNs) relative to control IRE+CpG/pIC/PD-L1-Ab- (7.5%) and IRE- (4.0%) treatment groups. This novel cDC1 subpopulation exhibited the most robust expression of DC maturation markers and costimulatory 41BBL and 41BB of all cDC1 subsets. The 41BB-agonist also stimulated a higher frequency of 41BB + CD103 + TCF-1 + tissue-resident memory T (T RM ) cells (14.5%) in TDLNs when compared with the two control (2.6% and 0.3%) treatment groups. Importantly, the IRE+Combo-treatment regimen was more efficient than the two control groups at converting the immunosuppressive tumor microenvironment (TME), an effect that was mitigated by reducing the frequency of inhibitory myeloid-derived suppressive cells while increasing that of immunogenic cDC1 and CD8 + T cells and rescuing T cell exhaustion. Taken together, our data establish that the 41BB-agonist potentiates the efficacy of IRE+Combo-therapy for lung cancer treatment by promoting unexpected cDC1 and T RM cell responses, and emphasize the importance of targeting this promising molecular signal to improve current cancer IRE-ablation protocols.

The maintenance of intestinal homeostasis depends on a complex interaction between the immune system, intestinal epithelial barrier, and microbiota. Alteration in one of these components could lead to the development of inflammatory bowel diseases (IBD). Variants within the autophagy gene have been implicated in susceptibility and severity of Crohn's disease (CD). Individuals carrying the risk T300A variant have higher caspase 3-dependent degradation of ATG16L1 resulting in impaired autophagy and increased cellular stress. ATG16L1-deficiency induces enhanced IL-1β secretion in dendritic cells in response to bacterial infection. Infection of ATG16L1-deficient mice with a persistent strain of murine norovirus renders these mice highly susceptible to dextran sulfate sodium colitis. Moreover, persistent norovirus infection leads to intestinal virus specific CD8 T cells responses. Both Toll-like receptor 7 (TLR7), which recognizes single-stranded RNA viruses, and ATG16L1, which facilitates the delivery of viral nucleic acids to the autolysosome endosome, are required for anti-viral immune responses. However, the role of the enteric virome in IBD is still poorly understood. Here, we investigate the role of TLR7 and ATG16L1 in intestinal homeostasis and inflammation. At steady state, mice have a significant increase in large intestinal lamina propria (LP) granzyme B tissue-resident memory CD8 T (T ) cells compared to WT mice, reminiscent of persistent norovirus infection. Deletion of in myeloid ( ) or dendritic cells ( ) leads to a similar increase of LP T . Furthermore, and mice were more susceptible to dextran sulfate sodium colitis with an increase in disease activity index, histoscore, and increased secretion of IFN-γ and TNF-α. Treatment of mice with the TLR7 agonist Imiquimod attenuated colonic inflammation in these mice. Our data demonstrate that ATG16L1-deficiency in myeloid and dendritic cells leads to an increase in LP T and consequently to increased susceptibility to colitis by impairing the recognition of enteric viruses by TLR7. In conclusion, the convergence of ATG16L1 and TLR7 signaling pathways plays an important role in the immune response to intestinal viruses. Our data suggest that activation of the TLR7 signaling pathway could be an attractive therapeutic target for CD patients with risk variants.

Immunotherapy has made breakthroughs in the treatment of non-small-cell lung cancer (NSCLC); however, only a subset of patients achieved long-term survival, so it is of great importance to find a biomarker of lung cancer thus guide immunotherapy. Studies have shown that the infiltration level of tissue resident memory CD8 T cells (CD8 TRMs) is positively correlated with lung cancer prognosis and can be an ideal biomarker for assessing the tumor local immune status. We screened the radiomic features associated with CD8 TRMs as targets in NSCLC surgical specimens by radiomic approaches, and established a radiomic predictive model to assess the local immune status, which may provide a scientific reference for lung cancer treatment strategies. We retrospectively analyzed the NSCLC surgical specimens immune cell database and extracted CD8 TRMs cell data, preoperative CT scan data were achieved. A total of 97 patients containing complete preoperative data were included, radiomic features were extracted from the preoperative CT image data. All the patients were divided into two groups, namely high-CD8 TRMs infiltrated group and low-CD8 TRMs infiltrated group, based on the proportion of CD8 TRMs cells subset in the immune cell population. The most valuable radiomic features and semantic features were extracted and selected, and a neural network model was established to predict the level of CD8 TRMs cell infiltration level to assess the tumor local immune status. The NSCLC tumor immune status predictive model was built to discriminate high- from low-CD8 TRMs with an area under the curve (AUC) of 0.788 (95% CI) in the training set and 0.753 (95% CI) in the validation set. The radiomic models using CT image data showed a good predictive performance for accessing NSCLC immune status thus has great potential for personalized therapeutic decision making.

Cancer immunotherapy is aimed at stimulating tumor-specific cytotoxic T lymphocytes and their subsequent trafficking so that they may reach, and persist in, the tumor microenvironment, recognizing and eliminating malignant target cells. Thus, characterization of the phenotype and effector functions of CD8 T lymphocytes infiltrating human solid tumors is essential for better understanding and manipulating the local antitumor immune response, and for defining their contribution to the success of current cancer immunotherapy approaches. Accumulating evidence indicates that a substantial subpopulation of CD3 CD8 tumor-infiltrating lymphocytes are tissue resident memory T (T ) cells, and is emerging as an activated tumor-specific T-cell subset. These T cells accumulate in various human cancer tissues, including non-small-cell lung carcinoma (NSCLC), ovarian and breast cancers, and are defined by expression of CD103 [α (CD103)β ] and/or CD49a [α1(CD49a)β1] integrins, along with C-type lectin CD69, which most likely contribute to their residency characteristic. CD103 binds to the epithelial cell marker E-cadherin, thereby promoting retention of T cells in epithelial tumor islets and maturation of cytotoxic immune synapse with specific cancer cells, resulting in T-cell receptor (TCR)-dependent target cell killing. Moreover, CD103 integrin triggers bidirectional signaling events that cooperate with TCR signals to enable T-cell migration and optimal cytokine production. Remarkably, T cells infiltrating human NSCLC tumors also express inhibitory receptors such as programmed cell death-1, the neutralization of which, with blocking antibodies, enhances CD103-dependent TCR-mediated cytotoxicity toward autologous cancer cells. Thus, accumulation of T cells at the tumor site explains the more favorable clinical outcome, and might be associated with the success of immune checkpoint blockade in a fraction of cancer patients.