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. 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
) cells, CD8
T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4
T
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.
During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral ...replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5(+) CD8(+) T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory receptors and exhibited more potent cytotoxicity than the CXCR5(-) corrected subset. Furthermore, we identified the Id2-E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5(+) CD8(+) T-cell subset, and its number was inversely correlated with viral load. The CXCR5(+) subset showed greater therapeutic potential than the CXCR5(-) corrected subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8(+) T cells that has a pivotal role in the control of viral replication during chronic viral infection.
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.
Skin-resident dendritic cells (DCs) are well positioned to encounter cutaneous pathogens and are required for the initiation of adaptive immune responses. There are at least three subsets of skin DC— ...Langerhans cells (LC), Langerin+ dermal DCs (dDCs), and classic dDCs. Whether these subsets have distinct or redundant function in vivo is poorly understood. Using a Candida albicans skin infection model, we have shown that direct presentation of antigen by LC is necessary and sufficient for the generation of antigen-specific T helper-17 (Th17) cells but not for the generation of cytotoxic lymphocytes (CTLs). In contrast, Langerin+ dDCs are required for the generation of antigen specific CTL and Th1 cells. Langerin+ dDCs also inhibited the ability of LCs and classic DCs to promote Th17 cell responses. This work demonstrates that skin-resident DC subsets promote distinct and opposing antigen-specific responses.
► LCs are necessary and sufficient for antigen-specific Th17 cell responses ► Langerin+ dDC are required for the generation of antigen-specific Th1 cell responses ► Langerin+ dDC inhibit the development of antigen-specific Th17 cell responses ► Langerin+ dDC but not LC can cross present antigen to CTL
Radiotherapy is a highly effective anticancer treatment forming part of the standard of care for the majority of patients, but local and distal disease recurrence remains a major cause of mortality. ...Radiotherapy is known to enhance tumor immunogenicity; however, the contribution and mechanisms of radiotherapy-induced immune responses are unknown.
The impact of low-dose fractionated radiotherapy (5 × 2 Gy) alone and in combination with αPD-1 mAb on the tumor microenvironment was evaluated by flow cytometry and next-generation sequencing of the T-cell receptor (TCR) repertoire. A dual-tumor model was used, with fractionated radiotherapy delivered to a single tumor site to enable evaluation of the local and systemic response to treatment and ability to induce abscopal responses outside the radiation field.
We show that fractionated radiotherapy leads to T-cell infiltration at the irradiated site; however, the TCR landscape remains dominated by polyclonal expansion of preexisting T-cell clones. Adaptive resistance via the PD-1/PD-L1 pathway restricts the generation of systemic anticancer immunity following radiotherapy, which can be overcome through combination with αPD-1 mAb leading to improved local and distal tumor control. Moreover, we show that effective clearance of tumor following combination therapy is dependent on both T cells resident in the tumor at the time of radiotherapy and infiltrating T cells.
These data provide evidence that radiotherapy can enhance T-cell trafficking to locally treated tumor sites and augment preexisting anticancer T-cell responses with the capacity to mediate regression of out-of-field tumor lesions when delivered in combination with αPD-1 mAb therapy.
.
Considerable advances have been made in recent years in understanding the generation and function of memory T cells. Memory T cells are typically parsed into discreet subsets based on phenotypic ...definitions that connote distinct roles in immunity. Here we consider new developments in the field and focus on how emerging differences between memory cells with respect to their trafficking, metabolism, epigenetic regulation, and longevity may fail to fit into small groups of “memory subsets.” Rather, the properties of individual memory T cells fall on a continuum within each of these and other parameters. We discuss how this continuum influences the way that the efficacy of vaccination is assessed, as well as the suitability of a memory population for protective immunity.
Memory T cells are typically parsed into discreet subsets based on phenotypic definitions that connote distinct roles in immunity. Jameson and Masopust argue that the conventional subset nomenclature fails to accurately encompass the distribution of functional traits within this diverse population.
Tissues such as the skin and mucosae are frequently exposed to microbial pathogens. Infectious agents must be quickly and efficiently controlled by our immune system, but the low frequency of naive T ...cells specific for any one pathogen means dependence on primary responses initiated in draining lymph nodes, often allowing time for serious infection to develop. These responses imprint effectors with the capacity to home to infected tissues; this process, combined with inflammatory signals, ensures the effective targeting of primary immunity. Upon vaccination or previous pathogen exposure, increased pathogen-specific T cell numbers together with altered migratory patterns of memory T cells can greatly improve immune efficacy, ensuring infections are prevented or at least remain subclinical. Until recently, memory T cell populations were considered to comprise central memory T cells (TCM), which are restricted to the secondary lymphoid tissues and blood, and effector memory T cells (TEM), which broadly migrate between peripheral tissues, the blood, and the spleen. Here we review evidence for these two memory populations, highlight a relatively new player, the tissue-resident memory T cell (TRM), and emphasize the potential differences between the migratory patterns of CD4(+) and CD8(+) T cells. This new understanding raises important considerations for vaccine design and for the measurement of immune parameters critical to the control of infectious disease, autoimmunity, and cancer.
Inappropriately sustained inflammation is a hallmark of chronic ischemic heart failure (HF); however, the pathophysiological role of T lymphocytes is unclear.
Permanent coronary ligation was ...performed in adult C57BL/6 mice. When compared with sham-operated mice, mice with HF (8 weeks after ligation) exhibited the following features: (1) significant (
<0.05) expansion of circulating CD3
CD8
cytotoxic and CD3
CD4
helper (Th) T lymphocytes, together with increased Th1, Th2, Th17, and regulatory T-cell (Treg) CD4
subsets; (2) significant expansion of CD8
and CD4
T cells in failing myocardium, with increased Th1, Th2, Th17, and Treg CD4
subsets, marked reduction of the Th1/Th2 ratio, augmentation of the Th17/Treg ratio, and upregulation of Th2 cytokines; and (3) significantly increased Th1, Th2, Th17 cells, and Tregs, in the spleen and mediastinal lymph nodes, with expansion of splenic antigen-experienced effector and memory CD4
T cells. Antibody-mediated CD4
T-cell depletion in HF mice (starting 4 weeks after ligation) reduced cardiac infiltration of CD4
T cells and prevented progressive left ventricular dilatation and hypertrophy, whereas adoptive transfer of splenic CD4
T cells (and, to a lesser extent, cardiac CD3
T cells) from donor mice with HF induced long-term left ventricular dysfunction, fibrosis, and hypertrophy in naive recipient mice.
CD4
T lymphocytes are globally expanded and activated in chronic ischemic HF, with Th2 (versus Th1) and Th17 (versus Treg) predominance in failing hearts, and with expansion of memory T cells in the spleen. Cardiac and splenic T cells in HF are primed to induce cardiac injury and remodeling, and retain this memory on adoptive transfer.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in ...children (MIS-C) associated with COVID-19, presenting 4–6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.
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•Hyperinflammation in MIS-C differs from that of acute COVID-19•T cell subsets discriminate Kawasaki disease patients from MIS-C•IL-17A drives Kawasaki but not MIS-C hyperinflammation•Global profiling reveals candidate autoantibodies with pathogenic potential
A systems immunology approach describes how multisystem inflammatory syndrome in children (MIS-C) is distinct from Kawasaki disease as well as the cytokine storm associated with severe COVID-19 in terms of its molecular and immune profiles.
There is abundant evidence that tumor-infiltrating CD8
T cells contribute positively to antitumor immunity; however, the role of tumor-infiltrating B cells (TIL-B) and plasma cells (PC) remains ...controversial, leading to differing opinions about whether immunotherapies should be designed to enhance or inhibit these cells. Through a comprehensive PubMed search, we reviewed publications with cohorts of 50 or more cases in which the prognostic value of TIL-B/PC was assessed by immunohistochemistry and/or gene-expression analysis. Sixty-nine studies representing 19 cancers met our review criteria. The large majority of studies assessed TIL-B by immunohistochemical detection of CD20. Of these, 50.0% reported a positive prognostic effect for CD20
TIL-B, whereas the remainder found a neutral (40.7%) or negative (9.3%) effect. These differences in prognostic effect were not attributable to cancer type, other clinicopathologic factors, or differing technical approaches. The prognostic significance of TIL-B/PC was generally concordant with that of CD3
and/or CD8
T cells, and the prognostic effect of T cells was generally stronger when TIL-B and/or PC were also present. Additionally, 21 studies inferred the presence of TIL-B/PC from gene-expression data, and a large majority reported a positive prognostic effect. Although more studies are required involving additional cancer types and independent patient cohorts, the weight of evidence supports a positive role for TIL-B and PC in antitumor immunity, suggesting that enhancement of these responses should be considered in the design of cancer immunotherapies.
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