Inmunidad mediada por células T: principios y mecanismos
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Biología de los linfocitos T. Curso: Principios de Immunología aplicada, UCV (postgrado)
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Inmunidad mediada por células T: principios y mecanismos
- 1. Inmunidad mediada por células T Principios de Inmunología aplicada. Tema 7 Daniel Perez-Witzke, M.Sc. Laboratorio de Patología celular y molecular C. Medicina Experimental, IVIC
- 2. Células T • Origen - clasificación • Selección Tímica – Repertorio células T • Presentación Ag – Moléculas Coestimuladoras, de adhesión y sinapsis. • Señalización intracelular – intervención terapéutica • Activación respuesta inmunitaria • Apoptosis regulación Activación inmunitaria
- 6. Células T • Origen - clasificación • Selección Tímica – Repertorio células T • Presentación Ag – Moléculas Coestimuladoras, de adhesión y sinapsis. • Señalización intracelular – intervención terapéutica • Activación respuesta inmunitaria • Apoptosis regulación Activación inmunitaria
- 12. Células T • Origen - clasificación • Selección Tímica – Repertorio células T • Presentación Ag – Moléculas Coestimuladoras, de adhesión y sinapsis. • Señalización intracelular – intervención terapéutica • Activación respuesta inmunitaria • Apoptosis regulación Activación inmunitaria
- 15. Células T • Origen - clasificación • Selección Tímica – Repertorio células T • Presentación Ag – Moléculas Coestimuladoras, de adhesión y sinapsis. • Señalización intracelular – intervención terapéutica • Activación respuesta inmunitaria • Apoptosis regulación Activación inmunitaria
- 27. Células T • Origen - clasificación • Selección Tímica – Repertorio células T • Presentación Ag – Moléculas Coestimuladoras, de adhesión y sinapsis. • Señalización intracelular – intervención terapéutica • Activación respuesta inmunitaria • Apoptosis regulación Activación inmunitaria
- 32. Células T • Origen - clasificación • Selección Tímica – Repertorio células T • Presentación Ag – Moléculas Coestimuladoras, de adhesión y sinapsis. • Señalización intracelular – intervención terapéutica • Activación respuesta inmunitaria • Apoptosis regulación Activación inmunitaria
- 35. Fin
- 36. Literatura Bevan MJ. 2004. Helping the CD8+ T Cell response. Nature reviews Immunology 4:595-602 Russ BE, Prier JE, Rao S, Turner SJ. 2013. T cell immunity as a tool for studying epigenetic regulation of cellular differentiation. Frontiers in Genetics 4 (218) Zhu J, Paul WE. 2008. CD4 T cells: fates, functions, and faults. Blood 112(5):1557-68 Laethem Fv, Tikhonova AN, Singer A. 2012. MHC restriction is imposed on a diverse T cell receptor repertoire by CD4 and CD8 co-receptors during thymic selection. Trends in Immunology 33(9):437-41 Hsieg CS, Lee HM, Lio CW. 2012. Selection of regulatory T cells in the thymus. Nature reviews Immunology 12: 157-67 Stritesky GL, Jameson SC, Hogguist KA. 2012. Selection of Self-Reactive T Cells in the Thymus. Annual Reviews Immunology 30:95-114 Klein L, Kyewski B, Allen PM, Hogguist KA. 2014. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nature Reviews Immunology AOP Anderson G, Takahama Y. 2012. Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends in Immunology 33(6):256-63 Boes M, Ploegh HL. 2004. Translating cell biology in vitro to immunity in vivo. Nature IRA 430:264-71 Rudensky AY, Campbell DJ. 2006. In vivo sites and cellular mechanisms of T reg cell–mediated suppression. Journal of Experimental Medicine 203(3):489-92 Josefowicz SZ, Lu LF, Rudensky AY. 2012. Regulatory T Cells: Mechanisms of Differentiation and Function. Annual Reviews Immunology 30:531-64 Maus MV, Grupp SA, Porter DL, June CH. 2014. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123(17):2625-35 Makalowski J, Abken H. 2013. Adoptive Cell Therapy of Melanoma: The Challenges of Targeting the Beating Heart. licensee InTech Chapter 13:365-90 Kershaw MH, Westwood JA, Darcy PK. 2013. Gene-engineered T cells for cancer therapy. Nature Reviews Cancer Restifo NP, Dudley ME, Rosenber SA. 2012. Adoptive immunotherapy for cancer: harnessing the T cell response. Nature Reviews Immunology 13:525-41 Wherry EJ. 2011. T cell exhaustion. Nature Immunology 12(6):492-99
Notas del editor
- Figure 1 | The classical understanding of how CD4+ T cells are required for certain cytotoxic T lymphocyte (CTL) responses but not for others. An antigen-presenting cell (APC), often a dendritic cell (DC), might acquire cellular antigen by phagocytosis of an apoptotic or necrotic cell that carries helper (that is, MHC class-II-restricted) and killer (that is, MHC class-I-restricted) antigens. Phagocytosed antigen is presented to CD4+ T cells, which activate the APC through CD40–CD40-ligand (CD40L) interactions. The activated DC can then promote the CD8+ T-cell response, generating cytotoxic effector T cells and memory cells. By contrast, certain infectious agents, viruses or bacteria, might circumvent the need for CD4+ T-cell recognition of antigen on the DC by stimulating Toll-like receptors (TLRs) directly, or by causing the release of inflammatory cytokines such as interleukin-1 or type 1 interferons. HELPING THE CD8+ T-CELL RESPONSE Michael J. Bevan Department of Immunology, Howard Hughes Medical Institute,University of Washington, USA.
- Figure 1. Summary of the 4 CD4 T helper cell fates: their functions, their unique products, their characteristic transcription factors, and cytokines critical for their fate determination. CD4 T cells: fates, functions, and faults Jinfang Zhu and William E. Paul Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda USA
- Figure 1. Diversity of antigen recognition by antibodies and T cell receptors (TCRs). Light and heavy immunoglobulin chains, as well as TCRa and TCRb chains, are composed of discrete variable (V), diversity (D), joining (J) and constant (C) gene segments. During T cell development, these diverse segments are joined by somatic recombination. Additional insertions, mutations (for Ig genes) and deletions add further diversity to yield a potential 1015 different Ig and TCR combinations. After protein synthesis, two pairs of light and heavy chains form a functional membrane-bound immunoglobulin peptide on B lymphocytes. The hugely diverse immunoglobulins can recognize and bind to conformational shapes on the surface of native antigens. Similarly, both TCRa and TCRb chains form a functional membrane-bound heterodimer expressed on the surface of ab T cells. Before thymic selection, we think that TCRa and TCRb pairs recognize peptides bound to the MHC chains as well as native antigens. However, after thymic selection, ab T cells only express TCRs with MHC specificity. MHC restriction is imposed on a diverse T cell receptor repertoire by CD4 and CD8 co-receptors during thymic selection Franc¸ois Van Laethem, Anastasia N. Tikhonova and Alfred Singer Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Figure 2. Co-receptor basis of MHC-specific thymic selection. T cell receptor (TCR) signaling requires the juxtaposition of Lck with TCR. In immature preselection CD4+CD8+ double positive (DP) thymocytes, all available tyrosine kinase Lck is co-receptor-associated and bound to the tails of both CD4 and CD8 co-receptors. Consequently, TCRs on preselection DP thymocytes can only access Lck when they bind to the identical pMHC complexes as CD4 and CD8 co-receptors. TCRs that bind MHC-independent native ligands cannot access co-receptor-associated Lck because the CD4 and CD8 co-receptors only bind to extracellular MHC complexes. Thus, only MHC-specific TCRs transduce thymic selection signals with the result that thymic selection is strictly MHC-specific. However, genetic deletion of both CD4 and CD8 co-receptors makes Lck freely available to all TCRs, so that TCRs that bind to any ligand in the thymus can transduce selection signals and be expressed on mature T cells in the periphery. Consequently, deletion of both CD4 and CD8 co-receptors allows the generation of mature T cells expressing MHC-independent TCRs with antibody-like recognition specificities. According to this perspective, the TCR repertoire is intrinsically diverse with specificity for both native and MHC-dependent ligands. However, MHC restriction is imposed on this diverse TCR repertoire by CD4 and CD8 co-receptors during thymic selection because of their dual specificity for intracellular Lck and extracellular MHC. MHC restriction is imposed on a diverse T cell receptor repertoire by CD4 and CD8 co-receptors during thymic selection Franc¸ois Van Laethem, Anastasia N. Tikhonova and Alfred Singer Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Figure 1 | Stromal cell interactions during T cell development. a | Successive stages of double-negative (DN) T cell development are accompanied by an outward movement of thymocytes towards the subcapsular zone. Subsequent to β‑selection at the DN3 stage, double-positive (DP) cells ‘randomly walk’ through the outer cortex, which possibly facilitates the ‘scanning’ of cortical thymic epithelial cells (cTECs) for positively selecting ligands. At this stage, DP thymocytes may be engulfed by cTECs and form so‑called thymic nurse cells; however, the molecular control and physiological relevance of this process remains to be established. Interactions between DP cells and cortical conventional dendritic cells (cDCs) may lead to negative selection. It remains unknown whether these cortical cDCs exclusively belong to the migratory signal-regulatory protein‑α (SIRPα)-expressing subset. Positively selected CD4 or CD8 lineage-committed thymocytes relocate into the medulla by directed migration. Upon reaching the medulla, single-positive (SP) cells again assume a ‘random walk’ motion pattern. Through this random migration, SP cells may now ‘scan’ resident and migratory cDCs, plasmacytoid dendritic cells (pDCs), medullary thymic epithelial cells (mTECs) and B cells. It is estimated that SP cells engage in around five contacts with antigen-presenting cells (APCs) per hour, so that during their 4- to 5‑day residency in the medulla, T cells may serially interact with several hundred APCs. Solid arrows indicate main migratory pathways that are involved in thymocyte selection. Dashed arrows indicate other relevant migratory pathways. b | Key functional properties of thymic APCs that are discussed in this Review. AIRE, autoimmune regulator; BCR, B cell receptor; TRA, tissue-restricted antigen. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see) Ludger Klein1, Bruno Kyewski2, Paul M. Allen3 and Kristin A. Hogquist4 1Institute for Immunology, Ludwig Maximilians University, 80336 Munich, Germany. 2Division of Developmental Immunology, German Cancer Research Center, 69120 Heidelberg, Germany. 3Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. 4Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55414, USA.
- Figure 1. Role for Aire-mediated XCL1 expression in DC positioning in the thymus. The positioning of DCs in the thymic medulla is thought to be an important aspect in the screening of positively selected thymocytes as they migrate from the cortex to the medulla. In normal mice, XCL1 expression by medullary thymic epithelial cells acts to correctly position DCs in this region (a). In Aire-deficient mice, XCL1 expression by mTECs is absent, resulting in mislocalisation of thymic DCs (b). Mice deficient in XCL1 also manifest some symptoms of autoimmunity, demonstrating that Aire is involved in antigen-dependent and antigen-independent mechanisms of central tolerance. Thymic epithelial cells: working class heroes for T cell development and repertoire selection Graham Anderson1 and Yousuke Takahama2 1MRC Centre for Immune Regulation, College of Medical and Dental Sciences, Medical School, University of Birmingham, Birmingham B15 2TT, UK 2 Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan
- Figure 7 | The antigenic repertoire presented by thymic medullary APCs. Multiple thymic antigen-presenting cell (APC) types are capable of facilitating thymic regulatory T (TReg) cell differentiation in the medulla. Stromal APCs, including medullary thymic epithelial cells (mTECs), can express and present tissue-specific antigens that are induced by autoimmune regulator (AIRE). Tissue-specific antigens are processed by autophagosomes and presented on the cell surface as peptide–MHC class II complexes. Haematopoietic APCs include dendritic cells (DCs), macrophages and B cells. However, the role of macrophages and B cells is unclear (not shown). The DC subsets include plasmacytoid DCs (pDCs) and SIRPα+ conventional DCs, which both migrate from the periphery and thus could potentially present extracellular antigens captured from the peripheral microenvironment. By contrast, resident SIRPα– conventional DCs originate in the thymus and thus probably present antigens from the thymus. In addition to presenting extracellular antigens, DCs can present mTEC-expressed antigens following antigenic transfer. Selection of regulatory T cells in the thymus Chyi-Song Hsieh1, Hyang-Mi Lee1 and Chan-Wang J. Lio1,2 1Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. 2Present address: Department of Signalling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
- Figure 2 Presentation pathways of exogenously acquired antigens. Proteins acquired from the surroundings of the antigen-presenting cell can provide a source of peptide for presentation on class II major histocompatibility (MHC) molecules, and in the case of cross-presentation, on class I MHC molecules. Top, bacteria-derived antigens (green) are internalized by dendritic cells and displayed as class II MHC–peptide complexes to antigen-specific CD4-positive T cells in draining lymph nodes. Bottom, dendritic cells can acquire viral antigens (red) by internalization of virally infected tissue (fibroblasts, muscle). Virus-infected tissue cells are proteolysed by the dendritic cells and proteins are processed into class I MHC–peptide complexes to allow activation of naive CD8-positive T cells. Translating cell biology in vitro to immunity in vivo Marianne Boes* & Hidde L. Ploegh Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
- Figure 4 The T-cell synapse. Molecules on a T cell and counterstructures on an antigen-presenting cell (APC) that are known to be involved in T-cell activation are shown. Far left, the face of the synapse with its characteristic distribution of cell-surface molecules, which form a supramolecular activation complex (SMAC). Some of the molecules that are enriched in different regions of the SMAC are shown. The T-cell receptor (TCR) occupies a central region known as the cSMAC; a peripheral ring, the pSMAC, contains adhesion molecules. CTLA4, cytotoxic-T-lymphocyte antigen 4; ICAM1, intercellular adhesion molecule 1; LFA1, lymphocyte-function-associated antigen 1; MHC, major histocompatibility complex; PI(3)K, phosphatidylinositol-3-OH kinase; SHP2, SH2-domain-containing protein tyrosine phosphatase; ZAP70, -chain (TCR)-associated protein kinase, 70 kDa. Translating cell biology in vitro to immunity in vivo Marianne Boes* & Hidde L. Ploegh Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
- Figure 3. Th2 differentiation driven by low concentration of peptide stimulation in vitro consists of an IL-4–independent initiation phase and an IL-4–dependent amplification phase. (A) TCR stimulation by low concentration of peptide induces IL-4–independent GATA-3 expression and IL-2–mediated Stat5 activation. (B) GATA-3 binds to CNS-1 and VA whereas activated Stat5 binds to HSII and HSIII of Il4 locus. Both are critical for TCR-mediated IL-4 production at the initial phase of Th2 cell differentiation. (C) IL-4 produced by T cells can further induce GATA-3 expression through Stat6 activation. GATA-3 also regulates itself once it reaches a certain threshold. Thus, IL-4–mediated GATA-3 expression together with IL-2–mediated Stat5 activation drives full Th2 differentiation. (D) High levels of GATA-3 and activated Stat5 play critical roles in inducing large amount of IL-4 production. CD4 T cells: fates, functions, and faults Jinfang Zhu and William E. Paul Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda USA
- Figure 4. Cross regulation among the factors that are involved in Th1 and Th2 differentiation. CD4 T cells: fates, functions, and faults Jinfang Zhu and William E. Paul Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda USA
- Figure 1. Suppressive mechanisms used by T reg cells. (A) In lymphoid tissues, T reg cell interactions with DCs help restrict their ability to form stable contacts with self-reactive T cells, resulting in only transient interactions between DCs and naive CD4+ T cells. Proinfl ammatory stimuli activate DCs, resulting in sustained T cell interactions that lead to effi cient T cell priming. (B) T reg cells can inhibit target cell killing by effector CD8+ T cells in a TGF-β–dependent fashion. (C) Upon priming and migration to nonlymphoid tissues, production of antiinfl ammatory cytokines, such as IL-10 or TGF-β, by T reg cells may limit effector T cell function and inhibit recruitment of infl ammatory myeloid cells such as neutrophils, eosinophils, and monocytes. In vivo sites and cellular mechanisms of T reg cell–mediated suppression Alexander Y. Rudensky and Daniel J. Campbell A.Y.R. is at Howard Hughes Medical Institute, Department of Immunology, University of Washington, Box 357370, Seattle, WA 98195. D.J.C. is at Department of Immunology, University of Washington, Box 357370, Seattle, WA 98195 and Benaroya Research Institute, Seattle, WA 98101.
- Figure 1. The ‘‘two-signal’’ model of T-cell activation. first requiring the interaction of T-cell receptor (TCR) with a major histocompatibility complex (MHC) molecule expressed by antigen presenting cells (APCs). To complete T-cell activation, the interaction of the CD28 receptor on T-cells with B7 co-stimulatory molecules (B7-1 and B7-2) on APCs is necessary. This phase occurs primarily within the lymph nodes. To prevent inappropriate T-cell activation, negative regulators of T-cell immunity, including CTLA-4 and PD-1, are required. CTLA-4 competes with CD28 for the interaction with B7, and it is upregulated shortly after T-cell activation. Anti-CTLA-4 antibodies, such as ipilimumab and tremelimumab, block CTLA4 and, thereby, enhance antitumor activity. The PD-1 inhibitory receptor plays an important role in modulating T-cell activity in the peripheral tissues during the effector phase. The ligation of PD-1 with PD-L1 causes the negative regulation of T-cells in the tumor microenvironment. Blockade with antibodies of PD-1 or PD-L1 (e.g., nivolumab and MK-3475) results in the activation of T-cells. TAA, tumor-associated antigen; NK, natural killer. Immune Checkpoint Blockade in Cancer Treatment: A Double-Edged Sword Cross-Targeting the Host as an “Innocent Bystander” Lucia Gelao, Carmen Criscitiello, Angela Esposito, Aron Goldhirsch andGiuseppe CuriglianoDivision of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy
- Figure 1. Therapeutic approaches to overcome immune tolerance to tumors. Cytokines and vaccines can be used to augment natural T-cell responses to tumor. Antibodies targeting negative regulatory molecules such as programmed death 1 (PD-1) and cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) can be infused to release the brakes on natural T cells responsive to tumor. Chemotherapy can reduce immune suppressive cells such as Tregs and myeloid-derived suppressor cells (MDSC) in addition to its direct effect on the tumor cells. Adoptive T-cell transfer strategies using clonally expanded cytotoxic T cells or T cells engineered to express TCRs or CARs are being tested. Antibody-modified T cells: CARs take the front seat for hematologic malignancies Marcela V. Maus,1,2 Stephan A. Grupp,1,3,4 David L. Porter,1,2 and Carl H. June1,5 1Abramson Cancer Center, 2Department of Medicine, and 3Division of Oncology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 4Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA; and 5Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
- Figure 1. Adoptive cell therapy for metastatic melanoma. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL´s) makes use of melanoma-specific TIL´s which are isolated from a melanoma biopsy, amplified ex vivo by stimulation with melanoma biopsy cells and propagated to high numbers in the presence of IL-2. In more recent trials, TIL´s are propagated short-term ex vivo without stimulation by melanoma cells and administered as "young" TIL´s. Adoptive Cell Therapy of Melanoma: The Challenges of Targeting the Beating Heart Jennifer Makalowski and Hinrich Abken
- Figure 1 | Derivation of TCRs and CARs for the genetic modification of T cells. a | T cell receptor (TCR) genes, made up of α- and β-chains, can be derived from tumour-specific T cells, which can naturally occur in humans, or from the immunization of human leukocyte antigen (HLA)-transgenic mice. Alternatively, they can be derived from screening bacteriophage libraries of antibodies. The α- and β-chains associate with the γ-, δ-, ε- and ζ-chains of the CD3 complex. When the TCR encounters a processed tumour antigen peptide fragment displayed on the major histocompatibility complex (MHC) of the tumour cell, phosphorylation of immunoreceptor tyrosine-base activation motifs (ITAMs) occurs, leading to a cascade of intracellular signalling that results in the release of cytokines and cytotoxic compounds from T cells. b | Chimeric antigen receptors (CARs) are composed of a single-chain antibody variable fragment (scFv) extracellular domain linked through hinge and transmembrane domains to a cytoplasmic signalling region. Genes encoding the scFv are derived from a B cell that produces a tumour-specific antibody. An scFv is shown linked by a CD8 hinge to transmembrane cytoplasmic signalling regions derived from CD3ζ. CARs usually exist as a dimer, and they recognize tumour antigen directly (with no requirement for MHC) on the surface of a tumour cell. MHCI, MHC class I. Gene-engineered T cells for cancer therapy Michael H. Kershaw1,2, Jennifer A. Westwood1 and Phillip K. Darcy1,2 1Cancer Immunology Research Program, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia. 2Department of Immunology, Monash University, Prahran, Victoria 3181, Australia. Correspondence to M.H.K.
- Figure 2 | The design of successive generations of CARs. Developments in chimeric antigen receptor (CAR) structure have led to several design formats that are termed generations, which primarily differ in their cytoplasmic signalling domains. First-generation CARs contained a single cytoplasmic signalling domain that was derived from either CD3ζ or FcεRIγ. Co-stimulatory signals were lacking in these first-generation CARs, and consequently T cell responses against tumour cells were suboptimal. Therefore, second-generation CARs were developed that contained a co-stimulatory domain, represented in the figure by CD28, but could be derived from CD27, CD134, CD137, CD244, inducible T‑cell co-stimulator (ICOS) or leukocyte C‑terminal SRC kinase (LCK). Third-generation receptors have an additional signalling domain, represented in the figure by CD137. Although not fully characterized, the inclusion of additional cytoplasmic domains could trigger several molecular signalling pathways as shown, leading to the amplification of the response against tumour antigen. These pathways could be initiated by the association of ZAP70, TNF receptor-associated factor 1 (TRAF1), PI3K and growth factor receptor-bound protein 2 (GRB2) with elements in the cytoplasmic domain of CARs, leading to the triggering of signalling intermediates and gene transcription. With successive generations of CARs, the complex signalling events that normally occur within an immune synapse between T cells and antigen are more closely replicated, enabling a stronger response to cancer cells. ASK1, apoptosis signal-regulating kinase 1; ATF2, activating transcription factor 2; CAN, calcineurin; DAG, diacylglycerol; LAT, linker for activation of T cells; MKK, MAP kinase kinase; NFAT, nuclear factor of activated T cells; NF‑κB, nuclear factor‑κB; PIP3, phosphatidylinositol- (3,4,5)-trisphosphate; PKCα, protein kinase Cα; PLCγ, phospholipase Cγ; SLP76, SH2 domain-containing leukocyte protein of 76 kDa. Gene-engineered T cells for cancer therapy Michael H. Kershaw1,2, Jennifer A. Westwood1 and Phillip K. Darcy1,2 Figure 2. Chimeric antigen receptors. CARs target surface antigens in an MHC-independent fashion and consist of an ectodomain, hinge domain, transmembrane domain, and endodomain. The initial trials tested first-generation CARs that have a single cytoplasmic domain. Current trials are testing second- and thirdgeneration CARs that have combinations of signaling domains. Antibody-modified T cells: CARs take the front seat for hematologic malignancies Marcela V. Maus,1,2 Stephan A. Grupp,1,3,4 David L. Porter,1,2 and Carl H. June1,5
- Figure 3. Recombinant receptors to redirect T cells for use in antigen-specific cell therapy. The physiologic T cell receptor (TCR)/CD3 complex consists of the α and β TCR chains, which recognize major histocompatibility complex (MHC)-presented antigen by binding through both variable regions Vα Vβ, and of the CD3 chains. Antigen engagement induces clustering of the TCR complex and the primary signal for T cell activation is generated by the intracellular CD3ζ chain. Recombinant TCR α and β chains can be engineered to T cells in order to provide a new specificity. Alternatively, the V regions of the TCR chains can be combined and fused to the intracellular CD3ζ chain to produce a T cell activation signal upon binding to antigen. The chimeric antigen receptor (CAR) makes use of an antibody binding domain for antigen recognition which is enigneered by fusing the variable (V) regions of the immunoglobulin heavy (H) and light (L) chain. The VH-VL single chain antibody is linked via a spacer to the intracellular CD3ζ chain to produce the primary T cell activation signal upon antigen binding. Intracellular signaling domains of costimulatory molecules like CD28 can be added to provide appropriate costimulation in addition to the primary CD3ζ signal. Adoptive Cell Therapy of Melanoma: The Challenges of Targeting the Beating Heart Jennifer Makalowski and Hinrich Abken
- Figure 2 | Three ways to genetically engineer T cells to confer specificity for tumour-associated antigens. T cells can be genetically engineered to recognize tumour-associated antigens in various ways in current clinical trials. If a patient expresses a tumour-associated antigen that is recognized by an available receptor structure, autologous T cells can be genetically engineered to express the desired receptor. New receptors can be generated in a variety of ways. a | T cells can be identified and cloned from patients with particularly good antitumour responses. Their T cell receptors (TCRs) can be cloned and inserted into retroviruses or lentiviruses, which are then used to infect autologous T cells from the patient to be treated. b | Chimeric antigen receptors (CARs) can be generated in a variety of ways. Most commonly, sequences encoding the variable regions of antibodies are engineered to encode a single chain, which is then genetically engrafted onto the TCR intracellular domains that are capable of activating T cells. These CARs have antibody-like specificities, which enable them to recognize MHC-nonrestricted structures on the surfaces of target cells. c | TCRs can also be isolated from humanized mice that have been primed to recognize tumour antigens. These mice express human MHC class I or MHC class II molecules and can be immunized with the tumour antigen of interest. Mouse T cells specific for the MHC-restricted epitope of interest can then be isolated, and their TCR genes are cloned into recombinant vectors that can be used to genetically engineer autologous T cells from the patient. Adoptive immunotherapy for cancer: harnessing the T cell response Nicholas P. Restifo, Mark E. Dudley and Steven A. Rosenberg Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
- Figure 3 | There are two phases of the response to acute antigen exposure, the first when antigen is present and the second when antigen has been cleared. During the first phase, antigen-presenting cells, CD8+ and CD4+ T cells interact to determine the outcome of the cytotoxic T lymphocyte response. CD8+ T cells might be programmed to carry out multiple divisions, gain effector function and contract in numbers by apoptosis to leave about 10% as long-lived memory cells. When antigen is cleared and the contraction stage ends, memory CD8+ T cells require signals from cytokines, such as interleukin-7 (IL-7) and IL-15, to maintain their number and functionality. Figure 2 | Recent reports have indicated that although the primary cytotoxic T lymphocyte (CTL) response is independent of CD4+ T-cell help, all secondary responses require CD4+ T-cell help. b | Similarly, in the response to viral or bacterial infection, the primary response is equal in wild-type and CD4+ T-cell-help-deficient animals, but memory fades in the latter environment. Note that the primary response to cellular antigen is weak, and many previous studies have assayed a secondary response to make conclusions about the dependence of CTL responses on CD4+ T-cell help.
- Figure 1 Hierarchical T cell exhaustion during chronic infection. During initial infection, naive T cells are primed by antigen, costimulation and inflammation and differentiate into effector T cells. Clearance of infection and antigen allows a subset of these functional effector T cells to further differentiate into highly polyfunctional memory T cells able to coproduce many cytokines (such as IFN-γ, tumor necrosis factor (TNF) and IL-2), becoming cytolytic and proliferating vigorously (top). These cells also have considerable survival capacity and are maintained long term without antigen. During chronic infection (bottom), infection persists after the effector phase. As antigen and/or viral load increases, T cells progress through stages of dysfunction, losing effector functions and other properties in a hierarchical manner. T cell exhaustion is also accompanied by a progressive increase in the amount and diversity of inhibitory receptors expressed. In addition, altered inflammation and changes in immunoregulatory cytokines such as IL-10 and/or TGF-β can have an increasingly important role. Ultimately, if the severity and/or duration of the infection is high and/or prolonged, virus-specific T cells can be completely eliminated, leading to loss of virus-specific T cell responses. The severity of T cell exhaustion is correlated with increasing inhibitory receptor expression, high viral (or antigen) load, loss of CD4+ T cell help and prolonged infection. The activity of each property is presented on a scale from high (+++) to low (—); ‘CTL’ indicates cytotoxic potential. T cell exhaustion E John Wherry Department of Microbiology, Institute for Immunology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA