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As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic α4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of α4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFNγ + CD8 + T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (T RM ) CD8 + T cells (CD103 + CD49a + CD69 + ). The combination treatment also led to increased infiltration of CD39 + CD103 + tumor-specific CD8 + T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic α4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.

Current influenza A virus (IAV) vaccines stimulate antibody responses that are directed against variable regions of the virus, and are therefore ineffective against divergent strains. As CD8+ T cells target the highly conserved, internal IAV proteins, they have the potential to increase heterosubtypic immunity. Early T‐cell priming events influence lasting memory, which is required for long‐term protection. However, the early responding, IAV‐specific cells are difficult to monitor because of their low frequencies. Here, we tracked the dissemination of endogenous IAV‐specific CD8+ T cells during the initial phases of the immune response following IAV infection. We exposed a significant population of recently activated, CD25+CD43+ IAV‐specific T cells that were not detected by tetramer staining. By tracking this population, we found that initial T‐cell priming occurred in the mediastinal lymph nodes, which gave rise to the most expansive IAV‐specific CD8+ T‐cell population. Subsequently, IAV‐specific CD8+ T cells dispersed to the bronchoalveolar lavage and blood, followed by spleen and liver, and finally to the lung. These data provide important insight into the priming and tissue dispersion of an endogenous CD8+ T‐cell response. Importantly, the CD25+CD43+ phenotype identifies an inclusive population of early responding CD8+ T cells, which may provide insight into TCR repertoire selection and expansion. A better understanding of this response is critical for designing improved vaccines that target CD8+ T cells. We tracked the dissemination of endogenous IAV‐specific CD8+ T cells during the initial phases of the immune response following IAV infection. We exposed a significant population of recently activated CD25+CD43+ IAV‐specific T cells that were not detected by tetramer staining. Identification of this subset provides a method to investigate factors that impact early T‐cell priming, which is critical for understanding how to generate durable memory to infections and vaccines.

Tumor-specific CD8 + T cells are exposed to persistent antigenic stimulation which induces a dysfunctional state called “exhaustion.” Though functioning to limit damage caused by immune response, T cell exhaustion leads to attenuated effector function whereby cytotoxic CD8 + T cells fail to control tumor progression in the late stage. This pathway is a dynamic process from activation to “progenitor exhaustion” through to “terminally exhaustion” with distinct properties. With the rapid development of immunotherapy via enhancing T cell function, new studies are dissecting the mechanisms and identifying specific biomarkers of dynamic differentiation during the process of exhaustion. Further, although immune checkpoint inhibitors (ICIs) have achieved great success in clinical practice, most patients still show limited efficacy to ICIs. The expansion and differentiation of progenitor exhausted T cells explained the success of ICIs while the depletion of the progenitor T cell pool and the transient effector function of terminally exhausted T cells accounted for the failure of immune monotherapy in the context of exorbitant tumor burden. Thus, combination strategies are urgent to be utilized based on the reduction of tumor burden or the expansion of the progenitor T cell pool. In this review, we aim to introduce the concept of homeostasis of the activated and exhausted status of CD8 + T cells in the tumor immune microenvironment, and present recent findings on dynamic differentiation process during T cell exhaustion and the implications for combination strategies in immune therapy.

Immunosuppressive therapy prevents graft rejection but increases the risk of non-melanoma skin cancer (NMSC), especially in elderly kidney transplant recipients (KTR). In this study, we separately investigated the differentiation of CD8 regulatory T cells (Tregs) and responder T cells (Tresps) between healthy KTR without NMSC, KTR developing NMSC within two years after the enrolment, and KTR with NMSC at the time of enrolment. Antigen-unexperienced CCR7 CD45RA CD31 recent thymic emigrant (RTE) cells differentiate CD45RA CD31 memory (CD31 memory) cells, resting mature naïve (MN) cells or direct proliferation into CD45RA CD31 memory (CD31 memory) cells, consisting of both CCR7 CD45RA central memory (CM) and CCR7 CD45RA effector memory (EM) cells. We found that both RTE Treg and Tresp differentiation CD31 memory Tregs/Tresps was age-independently increased in KTR, who developed NMSC during the follow-up period, causing abundant CM Treg/Tresp production, which may be crucial for cancer immunity. These changes favored a strongly increased CD8 Treg/Tresp ratio, suggesting this ratio as a reliable marker for NMSC development in KTR. However, with age, this differentiation was replaced by increased conversion of resting MN Tregs/Tresps into CM Tregs/Tresps, which exhausted for Tresps but not for Tregs. In KTR with already existing NMSC at enrolment, differentiation was maintained conversion and proliferation of resting MN Tregs/Tresps, which however increasingly exhausted with age, especially for Tresps. This resulted in a strong accumulation of terminally differentiated effector memory (TEMRA) Tresps in elderly individuals. Patients with NMSC recurrence showed increased proliferation of resting MN Tregs/Tresps into EM Tregs/Tresps, which tended to exhaust more rapidly, particularly for Tresps, than in patients without NMSC recurrence. In conclusion, we provide evidence that immunosuppressive therapy inhibits differentiation of CD8 Tregs more than that of CD8 Tresps, resulting in an exhausted Tresp profile, thus providing a possible therapeutic approach to improve poor cancer immunity in elderly KTR.

Exosomes are representative extracellular vesicles (EV) derived from multivesicular endosomes (MVE) and have been described as new particles in the communication of neighborhood and/or distant cells by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and nucleotides including micro (mi) RNAs. Exosomes from immune cells and tumor cells act in part as a regulator in tumor immunology. CD8+ T cells that show potent cytotoxic activity against tumor cells reside as an inactive naïve form in the T‐cell zone of secondary lymphoid organs. Once receiving tumor‐specific antigenic stimulation by dendritic cells (DC), CD8+ T cells are activated and differentiated into effector CTL. Subsequently, CTL circulate systemically, infiltrate into tumor lesions through the stromal neovasculature where mesenchymal stromal cells, for example, mesenchymal stem cells (MSC) and cancer‐associated fibroblasts (CAF), abundantly exist, destroy mesenchymal tumor stroma in an exosome‐mediated way, go into tumor parenchyma, and attack tumor cells by specific interaction. DC‐derived and regulatory T (Treg) cell‐derived exosomes, respectively, promote and inhibit CTL generation in this setting. In this review, we describe the roles of exosomes from immune cells and tumor cells on the regulation of tumor progression. Tumor progression is regulated by immune cell‐released exosomes. CD8+ T‐cell exosomes prevent tumor invasion and metastasis by depletion of mesenchymal tumor stromal cells.

Background Previous research in FMS-like tyrosine kinase 3 ligands (FLT3L) has primarily focused on their potential to generate dendritic cells (DCs) from bone marrow progenitors, with a limited understanding of how these cells affect CD8 T cell function. In this study, we further investigated the in vivo role of FLT3L for the immunomodulatory capabilities of CD8 T cells. Methods Albumin-conjugated FLT3L (Alb-FLT3L) was generated and applied for translational medicine purposes; here it was used to treat naïve C57BL/6 and OT1 mice for CD8 T cell response analysis. Syngeneic B16ova and E.G7ova mouse models were employed for adoptive cell transfer to evaluate the effects of Alb-FLT3L preconditioning of CD8 T cells on tumor progression. To uncover the underlying mechanisms of Alb-FLT3L modulation, we conducted bulk RNA-seq analysis of the CD44 high CD8 T cells. STAT1-deficient mice were used to elucidate the functional roles of Alb-FLT3L in the modulation of T cells. Finally, antibody blockade of type one interferon signaling and in vitro coculture of plasmacytoid DCs (pDCs) with naive CD8 T cells was performed to determine the role of pDCs in mediating regulation of CD44 high CD8 T cells. Results CD44 high CD8 T cells were enhanced in C57BL/6 mice administrated with Alb-FLT3L. These CD8 T cells exhibited virtual memory features and had greater proliferative and effective functions. Notably, the adoptive transfer of CD44 high naïve CD8 T cells into C57BL/6 mice with B16ova tumors led to significant tumor regression. RNA-seq analysis of the CD44 high naïve CD8 T cells revealed FLT3L to induce CD44 high CD8 T cells in a JAK-STAT1 signaling pathway-dependent manner, as supported by results indicating a decreased ability of FLT3L to enhance CD8 T cell proliferation in STAT1-deficient mice as compared to wild-type control mice. Moreover, antibody blockade of type one interferon signaling restricted the generation of FLT3L-induced CD44 high CD8 T cells, while CD44 expression was able to be induced in naïve CD8 T cells cocultured with pDCs derived from FLT3L-treated mice. This suggests the crucial role of pDCs in mediating FLT3L regulation of CD44 high CD8 T cells. Conclusions These findings provide critical insight and support the therapeutic potential of Alb-FLT3L as an immune modulator in preconditioning of naïve CD8 T cells for cancer immunotherapy.

OBJECTIVES: Recurrent miscarriage is a multifactorial condition, with immune dysregulation proposed as a potential contributing factor. This study investigates the causal relationship between immune cell phenotypes and miscarriage risk using Mendelian randomization (MR). MATERIAL AND METHODS: We performed a two-sample MR analysis using genome-wide association study (GWAS) summary statistics from publicly available datasets. The exposure data for immune cell phenotypes were obtained from the ebi-a-GCST90001599 dataset in the IEU GWAS database, which included over 3,000 individuals of predominantly European ancestry from multiple cohorts within the UK Biobank. The outcome data for miscarriage risk were sourced from the UKB-B-419 dataset in the MRC-IEU GWAS database, which analysed the number of spontaneous miscarriages in 78,700 individuals of predominantly European ancestry from the United Kingdom. The primary MR analysis was conducted using inverse-variance weighted (IVW) regression, complemented by Wald ratio and MR-Egger regression methods to assess robustness. MR-PRESSO was used to test for pleiotropy, while sensitivity analyses evaluated instrument validity and heterogeneity. RESULTS: MR-Egger regression did not provide statistically significant evidence for a causal association between immune cell phenotypes and miscarriage risk. However, IVW and Wald ratio analyses identified statistically significant associations between specific immune cell profiles and miscarriage risk. A higher proportion of HLA DR+ CD4+ and CD8+ T cells was associated with an increased risk of miscarriage (p < 0.005), while a higher absolute lymphocyte count was linked to a decreased risk (p = 0.011). Additionally, elevated levels of TCRgd T cells and FSC-A on CD4+ T cells were potentially protective against miscarriage (p < 0.01). Conversely, lower proportions of granulocytes and FSC-A on myeloid dendritic cells were associated with an increased miscarriage risk (p < 0.05). MR-PRESSO detected significant pleiotropy (global test p < 0.001), suggesting that some genetic variants may influence other traits, potentially biasing the initial MR estimates. CONCLUSIONS: Our findings suggest a complex interplay between immune cell composition and miscarriage risk, providing new insights into the immunological mechanisms contributing to pregnancy loss. These results highlight the need for further research to confirm these associations and explore potential therapeutic targets for immune-related pregnancy complications.

Older adults often show signs of impaired CD8+ T‐cell immunity, reflected by weaker responses against new infections and vaccinations, and decreased protection against reinfection. This immune impairment is in part thought to be the consequence of a decrease in both T‐cell numbers and repertoire diversity. If this is indeed the case, a strategy to prevent infectious diseases in older adults could be the induction of protective memory responses through vaccination at a younger age. However, this requires that the induced immune responses are maintained until old age. It is therefore important to obtain insights into the long‐term maintenance of the antigen‐specific T‐cell repertoire. Here, we review the literature on the maintenance of antigen‐experienced CD8+ T‐cell repertoires against acute and chronic infections. We describe the complex interactions that play a role in shaping the memory T‐cell repertoire, and the effects of age, infection history, and T‐cell avidity. We discuss the implications of these findings for the development of new vaccination strategies to protect older adults. In this review, we aim to provide insight in the maintenance of antigen‐experienced CD8+ T‐cell clones during life. We describe what is already known on the effect of age on the virus‐specific T‐cell repertoire and discuss the contribution of infection history in shaping the repertoire. Insight in factors shaping the T‐cell repertoire will help to improve the protective memory response against infectious diseases in older adults.

We previously demonstrated in the Chinese macaque model that an oral vaccine made of inactivated SIV and Lactobacillus plantarum induced CD8(+) regulatory T-cells, which suppressed the activation of SIV(+)CD4(+) T-cells, prevented SIV replication, and protected macaques from SIV challenges. Here, we sought whether a similar population of CD8(+) T-regs would induce the suppression of HIV replication in elite controllers (ECs), a small population (3‰) of HIV-infected patients with undetectable HIV replication. For that purpose, we investigated the in vitro antiviral activity of fresh CD8(+) T-cells on HIV-infected CD4(+) T-cells taken from 10 ECs. The 10 ECs had a classical genomic profile: all of them carried the KIR3DL1 gene and 9 carried at least 1 allele of HLA-B:Bw4-80Ile (i.e., with an isoleucine residue at position 80). In the nine HLA-B:Bw4-80Ile-positive patients, we demonstrated a strong viral suppression by KIR3DL1-expressing CD8(+) T-cells that required cell-to-cell contact to switch off the activation signals in infected CD4(+) T-cells. KIR3DL1-expressing CD8(+) T-cells withdrawal and KIR3DL1 neutralization by a specific anti-killer cell immunoglobulin-like receptor (KIR) antibody inhibited the suppression of viral replication. Our findings provide the first evidence for an instrumental role of KIR-expressing CD8(+) regulatory T-cells in the natural control of HIV-1 infection.

Tissue-resident memory CD8 T (T ) cells that develop in the epithelia at portals of pathogen entry are important for improved protection against re-infection. CD8 T cells within the skin and the small intestine are long-lived and maintained independently of circulating memory CD8 T cells. In contrast to CD8 T cells at these sites, CD8 T cells that arise after influenza virus infection within the lungs display high turnover and require constant recruitment from the circulating memory pool for long-term persistence. The distinct characteristics of CD8 T cell maintenance within the lungs may suggest a unique program of transcriptional regulation of influenza-specific CD8 T cells. We have previously demonstrated that the transcription factors Hobit and Blimp-1 are essential for the formation of CD8 T cells across several tissues, including skin, liver, kidneys, and the small intestine. Here, we addressed the roles of Hobit and Blimp-1 in CD8 T cell differentiation in the lungs after influenza infection using mice deficient for these transcription factors. Hobit was not required for the formation of influenza-specific CD8 T cells in the lungs. In contrast, Blimp-1 was essential for the differentiation of lung CD8 T cells and inhibited the differentiation of central memory CD8 T (T ) cells. We conclude that Blimp-1 rather than Hobit mediates the formation of CD8 T cells in the lungs, potentially through control of the lineage choice between T and T cells during the differentiation of influenza-specific CD8 T cells.