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Frontiers in Immunology 2022In 1986, Mosmann and Coffman identified 2 functionally distinct subsets of activated CD4 T cells, Th1 and Th2 cells, being key in distinct T cell mediated responses.... (Review)
Review
In 1986, Mosmann and Coffman identified 2 functionally distinct subsets of activated CD4 T cells, Th1 and Th2 cells, being key in distinct T cell mediated responses. Over the past three decades, our understanding of CD4 T cell differentiation has expanded and the initial paradigm of a dichotomic CD4 T cell family has been revisited to accommodate a constantly growing number of functionally distinct CD4 T helper and regulatory subpopulations. Of note, CD4 T cells with cytotoxic functions have also been described, initially in viral infections, autoimmune disorders and more recently also in cancer settings. Here, we provide an historical overview on the discovery and characterization of cytotoxic CD4 T cells, followed by a description of their mechanisms of cytotoxicity. We emphasize the relevance of these cells in disease conditions, particularly in cancer, and we provide insights on how to exploit these cells in immunotherapy.
Topics: CD4-Positive T-Lymphocytes; Lymphocyte Activation; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Th2 Cells
PubMed: 35572552
DOI: 10.3389/fimmu.2022.867189 -
Journal For Immunotherapy of Cancer 2016Tumor infiltrating lymphocytes (TIL) play an essential role in mediating response to chemotherapy and improving clinical outcomes in all subtypes of breast cancer.... (Review)
Review
Tumor infiltrating lymphocytes (TIL) play an essential role in mediating response to chemotherapy and improving clinical outcomes in all subtypes of breast cancer. Triple negative breast cancers (TN) are most likely to have tumors with >50 % lymphocytic infiltrate, termed lymphocyte predominant breast cancer, and derive the greatest survival benefit from each 10 % increase in TIL. The majority of HER2 breast cancers have similar level of immune infiltrate as TN breast cancer yet the presence of TILs has not shown the same survival benefit. For HER2 breast cancers, type 1 T-cells, either increased TBET tumor infiltration or increased type 1 HER2-specific CD4 T-cells in the peripheral blood, are associated with better outcomes. Hormone receptor positive HER2 negative tumors tend to have the least immune infiltrate yet are the only breast cancer subtype to show worse prognosis with increased FOXP3 regulatory T-cell infiltrate. Notably, all breast cancer subtypes have tumors with low, intermediate, or high TIL infiltrate. Tumors with high TILs may also have increased PD-L1 expression which might be the reason that TN breast cancer seems to demonstrate the most robust clinical response to immune checkpoint inhibitor therapy but further investigation is needed. Tumors with intermediate or low levels of pre-treatment immune infiltrate, on the other hand, may benefit from an intervention that may increase TIL, particularly type 1 T-cells. Examples of these interventions include specific types of cytotoxic chemotherapy, radiation, or vaccine therapy. Therefore, the systematic evaluation of TIL and specific populations of TIL may be able to both guide prognosis and the appropriate sequencing of therapies in breast cancer.
Topics: Animals; Antigens, Surface; Antineoplastic Agents, Immunological; Biomarkers; Breast Neoplasms; Cytotoxicity, Immunologic; Female; Humans; Immunomodulation; Lymphocyte Count; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Molecular Targeted Therapy; Prognosis; Survival Analysis; Treatment Outcome
PubMed: 27777769
DOI: 10.1186/s40425-016-0165-6 -
Immunology Jun 2022T-cell exhaustion has been extensively researched, compared with B-cell exhaustion and NK-cell exhaustion, which have received considerably less attention; and there is... (Review)
Review
T-cell exhaustion has been extensively researched, compared with B-cell exhaustion and NK-cell exhaustion, which have received considerably less attention; and there is less of a consensus on the precise definitions of NK-cell and B-cell exhaustion. NK-cell exhaustion, B-cell exhaustion and T-cell exhaustion are examples of lymphocyte exhaustion, and they have several differences and similarities. Lymphocyte exhaustion is also frequently confused with anergy, cellular senescence and suppression, because these conditions can have significant overlapping similarities with exhaustion. An additional source of confusion is due to the fact that lymphocyte exhaustion is not a binary state, but instead has a spectrum of severity induced by different levels and duration of continuous antigenic stimulation. Concurrent multiple types of lymphocyte exhaustion are possible, and this situation is herein called poly-lymphocyte exhaustion. Poly-lymphocyte exhaustion for the same cancer or pathogen would be especially dangerous. As there are significant advantages for a pathogen by inducing poly-lymphocyte exhaustion in an immune system, there are pathogens with an evolved capability to induce poly-lymphocyte exhaustion. These pathogens may include certain manipulative viruses, bacteria, fungi and protozoan parasites.
Topics: B-Lymphocytes; Cellular Senescence; Humans; Killer Cells, Natural; Lymphocyte Activation; Neoplasms; T-Lymphocytes
PubMed: 35266556
DOI: 10.1111/imm.13464 -
Trends in Cancer Apr 2023T follicular helper (Tfh) cells provide essential help to B cells for effective antibody-mediated immune responses. Although the crucial function of these CD4 T cells in... (Review)
Review
T follicular helper (Tfh) cells provide essential help to B cells for effective antibody-mediated immune responses. Although the crucial function of these CD4 T cells in infection and vaccination is well established, their involvement in cancer is only beginning to emerge. Increased numbers of Tfh cells in Tfh cell-derived or B cell-associated malignancies are often associated with an unfavorable outcome, whereas in various solid organ tumor types of non-lymphocytic origin, their presence frequently coincides with a better prognosis. We discuss recent advances in understanding how Tfh cell crosstalk with B cells and CD8 T cells in secondary and tertiary lymphoid structures (TLS) enhances antitumor immunity, but may also exacerbate immune-related adverse events (irAEs) such as autoimmunity during immune checkpoint blockade (ICB) and cancer immunotherapy.
Topics: Humans; T-Lymphocytes, Helper-Inducer; T Follicular Helper Cells; CD8-Positive T-Lymphocytes; B-Lymphocytes; Neoplasms
PubMed: 36642575
DOI: 10.1016/j.trecan.2022.12.007 -
Nature Immunology Mar 2019T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1...
T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8 tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8 TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8 TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8 TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8 T cells might be an important component of improving the response to checkpoint blockade.
Topics: Animals; Antibodies, Blocking; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Female; Humans; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Melanoma, Experimental; Mice, Congenic; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor
PubMed: 30778252
DOI: 10.1038/s41590-019-0312-6 -
Nature Sep 2016Chronic 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...
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 T1 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-1CD8 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.
Topics: Animals; CD28 Antigens; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Proliferation; Cell Self Renewal; Female; Hematopoietic Stem Cells; Hepatocyte Nuclear Factor 1-alpha; Immunotherapy; Inducible T-Cell Co-Stimulator Protein; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mice; Programmed Cell Death 1 Receptor; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer
PubMed: 27501248
DOI: 10.1038/nature19330 -
Clinical & Developmental Immunology 2012
Topics: Animals; Cell Differentiation; Humans; Infections; Lymphocytes
PubMed: 23251218
DOI: 10.1155/2012/510603 -
Science (New York, N.Y.) Feb 2019Although widely studied as a neurotransmitter, T cell-derived acetylcholine (ACh) has recently been reported to play an important role in regulating immunity. However,...
Although widely studied as a neurotransmitter, T cell-derived acetylcholine (ACh) has recently been reported to play an important role in regulating immunity. However, the role of lymphocyte-derived ACh in viral infection is unknown. Here, we show that the enzyme choline acetyltransferase (ChAT), which catalyzes the rate-limiting step of ACh production, is robustly induced in both CD4 and CD8 T cells during lymphocytic choriomeningitis virus (LCMV) infection in an IL-21-dependent manner. Deletion of within the T cell compartment in mice ablated vasodilation in response to infection, impaired the migration of antiviral T cells into infected tissues, and ultimately compromised the control of chronic LCMV clone 13 infection. Our results reveal a genetic proof of function for ChAT in T cells during viral infection and identify a pathway of T cell migration that sustains antiviral immunity.
Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Movement; Choline O-Acetyltransferase; Female; Interleukins; Lymphocyte Activation; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Vasodilation
PubMed: 30733420
DOI: 10.1126/science.aau9072 -
Immunity Feb 2022TbetCD11c B cells arise during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Here, we examined the developmental requirements of this B cell...
TbetCD11c B cells arise during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Here, we examined the developmental requirements of this B cell subset. In acute infection, T follicular helper (Tfh) cells, but not Th1 cells, drove TbetCD11c B cell generation through proximal delivery of help. TbetCD11c B cells developed prior to germinal center (GC) formation, exhibiting phenotypic and transcriptional profiles distinct from GC B cells. Fate tracking revealed that most TbetCD11c B cells developed independently of GC entry and cell-intrinsic Bcl6 expression. TbetCD11c and GC B cells exhibited minimal repertoire overlap, indicating distinct developmental pathways. As the infection resolved, TbetCD11c B cells localized to the marginal zone where splenic retention depended on integrins LFA-1 and VLA-4, forming a competitive memory subset that contributed to antibody production and secondary GC seeding upon rechallenge. Therefore, TbetCD11c B cells comprise a GC-independent memory subset capable of rapid and robust recall responses.
Topics: Animals; Antibodies, Viral; B-Lymphocytes; CD11 Antigens; Cell Differentiation; Germinal Center; Alphainfluenzavirus; Integrins; Lymphocyte Subsets; Lymphocytic choriomeningitis virus; Memory B Cells; Mice; Spleen; T Follicular Helper Cells; T-Box Domain Proteins; Virus Diseases
PubMed: 35090581
DOI: 10.1016/j.immuni.2022.01.002 -
Current Opinion in Immunology Apr 2015
Topics: Animals; Cell Differentiation; Humans; Lymphocyte Activation; Lymphocytes; Lymphopoiesis
PubMed: 25776004
DOI: 10.1016/j.coi.2015.03.003