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Tumor antigen-specific CD4 + T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy. However, activation of antigen-specific CD4 + T cells is restricted at local tumor sites where antigen-presenting cells (APCs) are frequently dysfunctional, which can cause rapid exhaustion of anti-tumor immune responses. Herein, we characterize anti-tumor effects of a unique human CD4 + helper T-cell subset that directly recognizes the cytoplasmic tumor antigen, NY-ESO-1, presented by MHC class II on cancer cells. Upon direct recognition of cancer cells, tumor-recognizing CD4 + T cells (TR-CD4) potently induced IFN-γ-dependent growth arrest in cancer cells. In addition, direct recognition of cancer cells triggers TR-CD4 to provide help to NY-ESO-1-specific CD8 + T cells by enhancing cytotoxic activity and improving viability and proliferation in the absence of APCs. Notably, the TR-CD4 either alone or in collaboration with CD8 + T cells significantly inhibited tumor growth in vivo in a xenograft model. Finally, retroviral gene-engineering with T cell receptor (TCR) derived from TR-CD4 produced large numbers of functional TR-CD4. These observations provide mechanistic insights into the role of TR-CD4 in tumor immunity and suggest that approaches to utilize TR-CD4 will augment anti-tumor immune responses for durable therapeutic efficacy in cancer patients.

Relapse after immunosuppression (IS) treatment withdrawal is frequent in patients with Autoimmune Hepatitis (AIH), and non-invasive biomarkers predictive of this risk are lacking. We assessed the frequency of circulating T cell subsets as potential biomarkers of disease activity and predictor of the risk of relapse after IS withdrawal. Serum levels of the cytokine B-cell Activating Factor (BAFF) were also investigated. Blood samples from 58 patients with active AIH, 56 AIH patients in remission, and 31 patients with NASH were analyzed. The frequency of activated CD4+ T peripheral helper (TPH) cells (CD4+CD45RA-CXCR5-PD1+CD38+) and of activated CD8+ T cells (CD8+CD45RA-PD1+CD38+) were assessed by flow cytometry. BAFF levels were determined by ELISA. Activated TPH and CD8+ T cell frequencies were significantly increased in patients with active AIH compared to remission AIH or NASH (TPH: 0.88% of total CD3+ vs. 0.42% and 0.39% respectively, p  < 0.0001; CD8+ subset: 1.42% vs. 0.09% and 0.11% p  < 0.0001). Among patients in remission undergoing treatment withdrawal ( n  = 18), those with increased frequencies of activated TPH (> 0.5% of total CD3+) and/or activated CD8+ T cells (> 0.18% total CD3+) had a higher risk of relapse (80% vs. 15% after 2 years, p  = 0.0071). High BAFF serum concentration (> 213pg/ml) was also associated to a higher risk of relapse (57% vs. 11%, p  = 0.0452). In conclusion, high frequency of activated TPH and of activated CD8+, as well as high levels of BAFF, before IS discontinuation, were significantly associated to a greater risk of relapse during the first two years. Thus, they represent promising biomarkers to provide personalized clinical follow-up for patients with AIH.

Human melanoma cells express various tumour antigens that are recognized by CD8 + cytotoxic T lymphocytes (CTLs) and elicit tumour-specific responses in vivo . However, natural and therapeutically enhanced CTL responses in melanoma patients are of limited efficacy. The mechanisms underlying CTL effector phase failure when facing melanomas are still largely elusive. Here we show that, on conjugation with CTL, human melanoma cells undergo an active late endosome/lysosome trafficking, which is intensified at the lytic synapse and is paralleled by cathepsin-mediated perforin degradation and deficient granzyme B penetration. Abortion of SNAP-23-dependent lysosomal trafficking, pH perturbation or impairment of lysosomal proteolytic activity restores susceptibility to CTL attack. Inside the arsenal of melanoma cell strategies to escape immune surveillance, we identify a self-defence mechanism based on exacerbated lysosome secretion and perforin degradation at the lytic synapse. Interfering with this synaptic self-defence mechanism might be useful in potentiating CTL-mediated therapies in melanoma patients. Cytotoxic T lymphocytes recognise and eliminate tumour cells. Here, the authors show that on contact with these immune cells melanoma cells can resist T cell cytotoxicity by modulating the trafficking of their lysosomal compartment, this results in the degradation of the T cell protein perforin by the protease cathepsin B.

Background Regulatory T cells (Treg) in diverse species include CD4 + and CD8 + T cells. In all species, CD8 + Treg have been only partially characterized and there is no rat model in which CD4 + and CD8 + FOXP3 + Treg are genetically tagged. Results We generated a Foxp3-EGFP rat transgenic line in which FOXP3 gene was expressed and controlled EGFP. CD4 + and CD8 + T cells were the only cells that expressed EGFP, in similar proportion as observed with anti-FOXP3 antibodies and co-labeled in the same cells. CD4 + EGFP + Treg were 5–10 times more frequent than CD8 + EGFP + Treg. The suppressive activity of CD4 + and CD8 + Treg was largely confined to EGFP + cells. RNAseq analyses showed similarities but also differences among CD4 + and CD8 + EGFP + cells and provided the first description of the natural FOXP3 + CD8 + Treg transcriptome. In vitro culture of CD4 + and CD8 + EGFP − cells with TGFbeta and IL-2 generated induced EGFP + Treg. CD4 + and CD8 + EGFP + Treg were expanded upon in vivo administration of a low dose of IL-2. Conclusions This new and unique rat line constitutes a useful model to identify and isolate viable CD4 + and CD8 + FOXP3 + Treg. Additionally, it allows to identify molecules expressed in CD8 + Treg that may allow to better define their phenotype and function not only in rats but also in other species.

The persistence of transcriptionally silent but replication-competent HIV-1 reservoirs in Highly Active Anti-Retroviral Therapy (HAART)-treated infected individuals, represents a major hurdle to virus eradication. Activation of HIV-1 gene expression in these cells together with an efficient HAART has been proposed as an adjuvant therapy aimed at decreasing the pool of latent viral reservoirs. Using the latently-infected U1 monocytic cell line and latently-infected J-Lat T-cell clones, we here demonstrated a strong synergistic activation of HIV-1 production by clinically used histone deacetylase inhibitors (HDACIs) combined with prostratin, a non-tumor-promoting nuclear factor (NF)- kappaB inducer. In J-Lat cells, we showed that this synergism was due, at least partially, to the synergistic recruitment of unresponsive cells into the expressing cell population. A combination of prostratin+HDACI synergistically activated the 5' Long Terminal Repeat (5'LTR) from HIV-1 Major group subtypes representing the most prevalent viral genetic forms, as shown by transient transfection reporter assays. Mechanistically, HDACIs increased prostratin-induced DNA-binding activity of nuclear NF-kappaB and degradation of cytoplasmic NF-kappaB inhibitor, IkappaBalpha . Moreover, the combined treatment prostratin+HDACI caused a more pronounced nucleosomal remodeling in the U1 viral promoter region than the treatments with the compounds alone. This more pronounced remodeling correlated with a synergistic reactivation of HIV-1 transcription following the combined treatment prostratin+HDACI, as demonstrated by measuring recruitment of RNA polymerase II to the 5'LTR and both initiated and elongated transcripts. The physiological relevance of the prostratin+HDACI synergism was shown in CD8(+)-depleted peripheral blood mononuclear cells from HAART-treated patients with undetectable viral load. Moreover, this combined treatment reactivated viral replication in resting CD4(+) T cells isolated from similar patients. Our results suggest that combinations of different kinds of proviral activators may have important implications for reducing the size of latent HIV-1 reservoirs in HAART-treated patients.

T cells could be engineered to overcome the aberrant metabolic milieu of solid tumors and tip the balance in favor of a long‐lasting clinical response. Here, we explored the therapeutic potential of stably overexpressing cystathionine‐gamma‐lyase (CTH, CSE, or cystathionase), a pivotal enzyme of the transsulfuration pathway, in antitumor CD8+ T cells with the initial aim to boost intrinsic cysteine metabolism. Using a mouse model of adoptive cell transfer (ACT), we found that CTH‐expressing T cells showed a superior control of tumor growth compared to control T cells. However, contrary to our hypothesis, this effect was not associated with increased T cell expansion in vivo or proliferation rescue in the absence of cysteine/cystine in vitro. Rather than impacting methionine or cysteine, ACT with CTH overexpression unexpectedly reduced glycine, serine, and proline concentration within the tumor interstitial fluid. Interestingly, in vitro tumor cell growth was mostly impacted by the combination of serine/proline or serine/glycine deprivation. These results suggest that metabolic gene engineering of T cells could be further investigated to locally modulate amino acid availability within the tumor environment while avoiding systemic toxicity. Gene engineering of T cells represents a promising approach for overcoming the aberrant metabolic milieu of solid tumors. Here, we found that overexpression of the transsulfuration pathway enzyme cystathionine‐gamma‐lyase (CTH, alias CSE or cystathionase) in antitumor T cells enhanced tumor growth control in vivo upon adoptive cell transfer. Unexpectedly, this effect was not associated with increased cysteine production by T cells but with decreased concentration of three other amino acids within the tumor interstitial fluid.

The restoration of CD4⁺ T cells, especially T-helper type 17 (Th17) cells, remains incomplete in the gut mucosa of most human immunodeficiency virus type 1 (HIV-1)–infected individuals despite sustained antiretroviral therapy (ART). Herein, we report an increase in the absolute number of CXCR3⁺ T cells in the duodenal mucosa during ART. The frequencies of Th1 and CXCR3⁺ CD8⁺ T cells were increased and negatively correlated with CCL20 and CCL25 expression in the mucosa. In ex vivo analyses, we showed that interferon γ, the main cytokine produced by Th1 and effector CD8⁺ T cells, downregulates the expression of CCL20 and CCL25 by small intestine enterocytes, while it increases the expression of CXCL9/10/11, the ligands of CXCR3. Interleukin 18, a pro-Th1 cytokine produced by enterocytes, also contributes to the downregulation of CCL20 expression and increases interferon γ production by Th1 cells. This could perpetuate an amplification loop for CXCR3-driven Th1 and effector CD8⁺ T cells recruitment to the gut, while impairing Th17 cells homing through the CCR6-CCL20 axis in treated HIV-1–infected individuals.

Chronic infection with lymphocytic choriomeningitis virus promotes the establishment of a population of stem-like PD-1 + CD8 + T cells that reside in lymphoid tissues and preferentially expand when the PD-1 inhibitory pathway is blocked. CD8 + T cells controlling chronic viral infections The long-term persistence of viral antigens drives the functional exhaustion of effector CD8 + T cells, yet the exhausted cells can still achieve a level of pathogen control during a chronic viral infection. Two groups reporting in this issue of Nature examine the mechanisms underlying the antiviral role of these immune cells. In a study of a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection and human HIV patients, Lilin Ye and colleagues report a population of partially exhausted CXCR5 + CD8 + T cells that is induced by chronic virus infection, resides in B-cell follicles, and controls viral replication. Differentiation and effector function of virus-specific CXCR5 + CD8 + T cells is regulated by the Id2–E2A signalling axis. Anti-PD-L1 antibody treatment is shown to inhibit viral replication in mice synergistically with adoptively transferred CXCR5 + CD8 + T cells. Rafi Ahmed and colleagues show that chronic LCMV infection in mice promotes a population of virus-specific CD8 + T cells with a T follicular helper (T FH )-like signature. These T cells expressed the PD-1 inhibitory receptor but also expressed co-stimulatory molecules and had a gene signature that was related to CD8 + T-cell memory precursor cells and hematopoietic stem cells. These findings provide a better understanding of T-cell exhaustion and have implications towards optimizing PD-1-directed immunotherapy. Chronic viral infections are characterized by a state of CD8 + T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor 1 , 2 , 3 , 4 . A better understanding of the mechanisms that regulate CD8 + T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 + T cells. Here we identify a population of virus-specific CD8 + T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8 + T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8 + T-cell subset was characterized by a unique gene signature that was related to that of CD4 + T follicular helper (T FH ) cells, CD8 + T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4 + T H 1 cells and CD8 + terminal effectors. This CD8 + T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8 + T cells. These PD-1 + CD8 + T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8 + T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8 + T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8 + T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.

The T cell infiltrates that are formed in human cancers are a modifier of natural disease progression and also determine the probability of clinical response to cancer immunotherapies. Recent technological advances that allow the single-cell analysis of phenotypic and transcriptional states have revealed a vast heterogeneity of intratumoural T cell states, both within and between patients, and the observation of this heterogeneity makes it critical to understand the relationship between individual T cell states and therapy response. This Review covers our current knowledge of the T cell states that are present in human tumours and the role that different T cell populations have been hypothesized to play within the tumour microenvironment, with a particular focus on CD8+ T cells. The three key models that are discussed herein are as follows: (1) the dysfunction of T cells in human cancer is associated with a change in T cell functionality rather than inactivity; (2) antigen recognition in the tumour microenvironment is an important driver of T cell dysfunctionality and the presence of dysfunctional T cells can hence be used as a proxy for the presence of a tumour-reactive T cell compartment; (3) a less dysfunctional population of tumour-reactive T cells may be required to drive a durable response to T cell immune checkpoint blockade.Recent single-cell RNA-sequencing studies have revealed a range of intratumoural T cell states, both within and between patients. This Review outlines the CD8+ T cell states that have been identified in human tumours and the potential roles they play in tumour control as well as how they are influenced by immune checkpoint blockade.

The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients’ T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1 + CD57 + exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4 + T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19. COVID-19 is a serious pandemic threat to public health, but insights on the pathophysiological and immunological conditions are only emerging. Here the authors use multi-color flow cytometry to characterize CD4 + and CD8 + T cells in peripheral blood from 39 COVID-19 patients in Italy to report altered T cell activation, function and polarization.