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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.

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.

Memory T-helper (Th) lymphocytes are crucial for the maintenance of acquired immunity to eliminate infectious pathogens. We have previously demonstrated that most memory Th lymphocytes reside and rest on stromal niches of the bone marrow (BM). Little is known, however, regarding the molecular basis for the generation and maintenance of BM memory Th lymphocytes. Here we show that CD69-deficient effector CD4 T lymphocytes fail to relocate into and persist in the BM and therefore to differentiate into memory cells. Consequently, CD69-deficient CD4 T cells fail to facilitate the production of high-affinity antibodies and the generation of BM long-lived plasma cells in the late phase of immune responses. Thus, CD69 is critical for the generation and maintenance of professional memory Th lymphocytes, which can efficiently help humoral immunity in the late phase. The deficit of immunological memory in CD69-deficient mice also highlights the essential role of BM for the establishment of Th memory.

Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138+ MM cells, CD4+CD25+FoxP3+ regulatory T cells, and HLA-DRLow/-CD11b+CD33+ myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8+ T cells and of immune checkpoints in bone marrow cells from myeloma patients. ACY241 increased B7 (CD80, CD86) and MHC (Class I, Class II) expression on tumor and dendritic cells. We further evaluated the effect of ACY241 on antigen-specific cytotoxic T lymphocytes (CTL) generated with heteroclitic XBP1unspliced184–192 (YISPWILAV) and XBP1spliced367–375 (YLFPQLISV) peptides. ACY241 induces co-stimulatory (CD28, 41BB, CD40L, OX40) and activation (CD38) molecule expression in a dose- and time-dependent manner, and anti-tumor activities, evidenced by increased perforin/CD107a expression, IFN-γ/IL-2/TNF-α production, and antigen-specific central memory CTL. These effects of ACY241 on antigen-specific memory T cells were associated with activation of downstream AKT/mTOR/p65 pathways and upregulation of transcription regulators including Bcl-6, Eomes, HIF-1 and T-bet. These studies therefore demonstrate mechanisms whereby ACY241 augments immune response, providing the rationale for its use, alone and in combination, to restore host anti-tumor immunity and improve patient outcome.

Clonal expansion of cytotoxic T lymphocytes entails profound energetic demands. Kallies and colleagues show that the transcription factor IRF4 is critical for the metabolic reprogramming, survival and effector function of these cells during clonal expansion. During immune responses, T cells are subject to clonal competition, which leads to the predominant expansion of high-affinity clones; however, there is little understanding of how this process is controlled. We found here that the transcription factor IRF4 was induced in a manner dependent on affinity for the T cell antigen receptor (TCR) and acted as a dose-dependent regulator of the metabolic function of activated T cells. IRF4 regulated the expression of key molecules required for the aerobic glycolysis of effector T cells and was essential for the clonal expansion and maintenance of effector function of antigen-specific CD8 + T cells. Thus, IRF4 is an indispensable molecular 'rheostat' that 'translates' TCR affinity into the appropriate transcriptional programs that link metabolic function with the clonal selection and effector differentiation of T cells.

IL-9-producing CD4 + (Th9) cells are a subset of CD4 + T-helper cells that are endowed with powerful antitumor capacity. Both IL-4 and TGF-β have been reported to be indispensable for Th9 cell-priming and differentiation. Here we show, by contrast, that Th9 cell development can occur in the absence of TGF-β signaling. When TGF-β was replaced by IL-1β, the combination of IL-1β and IL-4 efficiently promoted IL-9-producing T cells (Th9 IL-4+IL-1β ). Th9 IL-4+ IL-1β cells are phenotypically distinct T cells compared to classic Th9 cells (Th9 IL-4+TGF-β ) and other Th cells, and are enriched for IL-1 and NF-κB gene signatures. Inhibition of NF-κB but not TGF-β-signaling negates IL-9 production by Th9 IL-4+IL-1β cells. Furthermore, when compared with classic Th9 IL-4+TGF-β cells, Th9 IL-4+IL-1β cells are less exhausted, exhibit cytotoxic T effector gene signature and tumor killing function, and exert a superior antitumor response in a mouse melanoma model. Our study thus describes an alternative pathway for Th9 cell differentiation and provides a potential avenue for antitumor therapies. CD4 + helper T cells producing IL-9 (Th9) have been implicated in anti-tumor immunity, with Th9 differentiation inducible in vitro via IL-4 and TGFβ treatment. Here the authors show that replacing TGFβ with IL-1β induces a distinct IL-9 + CD4 + population that have strong cytotoxic and anti-tumor activity in preclinical mouse models.

Helper T cells become polarized to effect a 'division of labor'. Sallusto and Spits and colleagues identify a new subset of skin-homing helper T cells, T H -22 cells, that secrete interleukin 22. Interleukin 22 (IL-22) is a cytokine produced by the T H -17 lineage of helper T cells and NK-22 subset of natural killer cells that acts on epithelial cells and keratinocytes and has been linked to skin homeostasis and inflammation. Here we characterize a population of human skin-homing memory CD4 + T cells that expressed the chemokine receptors CCR10, CCR6 and CCR4 and produced IL-22 but neither IL-17 nor interferon-γ (IFN-γ). Clones isolated from this population produced IL-22 only and had low or undetectable expression of the T H -17 and T helper type 1 (T H 1) transcription factors RORγt and T-bet. The differentiation of T cells producing only IL-22 was efficiently induced in naive T cells by plasmacytoid dendritic cells in an IL-6- and tumor necrosis factor–dependent way. Our findings delineate a previously unknown subset of human CD4 + effector T cells dedicated to skin pathophysiology.

CD8 + T cells rapidly commence transcriptional changes after antigenic encounter and priming. Yeo and colleagues find substantial transcriptional heterogeneity among responding lymphocytes, particularly at the first division, that influences cell fate. During microbial infection, responding CD8 + T lymphocytes differentiate into heterogeneous subsets that together provide immediate and durable protection. To elucidate the dynamic transcriptional changes that underlie this process, we applied a single-cell RNA-sequencing approach and analyzed individual CD8 + T lymphocytes sequentially throughout the course of a viral infection in vivo . Our analyses revealed a striking transcriptional divergence among cells that had undergone their first division and identified previously unknown molecular determinants that controlled the fate specification of CD8 + T lymphocytes. Our findings suggest a model for the differentiation of terminal effector cells initiated by an early burst of transcriptional activity and subsequently refined by epigenetic silencing of transcripts associated with memory lymphocytes, which highlights the power and necessity of single-cell approaches.

The costimulatory molecule ICOS is important for the development of both interleukin 17–producing and follicular T helper cells. Kuchroo and colleagues find that ICOS induces the transcription factor c-Maf, which regulates the population expansion of both helper cell types. The inducible costimulatory molecule ICOS has been suggested to be important in the development of interleukin 17 (IL-17)-producing helper T cells (T H -17 cells) and of follicular helper T cells (T FH cells). Here we show that ICOS-deficient mice had no defect in T H -17 differentiation but had fewer T H -17 cells after IL-23 stimulation and fewer T FH cells. We also show that T FH cells produced IL-17 and that T FH cells in ICOS-deficient mice were defective in IL-17 production. Both T H -17 and T FH cells had higher expression of the transcription factor c-Maf. Genetic loss of c-Maf resulted in a defect in IL-21 production and fewer T H -17 and T FH cells. Thus our data suggest that ICOS-induced c-Maf regulates IL-21 production that in turn regulates the expansion of T H -17 and T FH cells.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated downstream of many key cytokine receptors expressed by lymphocytes. As such, it plays a critical role in regulating B cells as well as CD4 and CD8 T cells. Patients with clinically significant immunodeficiency and immune dysregulation resulting from loss-of-function or gain-of-function mutations in STAT3 have been described. These individuals provide insight into the critical role of this transcription factor in the regulation of immune responses and the balance between effective immune protection and autoimmunity.