1203CHAPTER 101 Adaptive Immunity CD40 on APCs binding to CD40 ligand on activated CD4+ T cells CD40 CD40L binding further activates APCs, enhancing their expression of B7 molecules and their secretio[.]
CHAPTER 101 Adaptive Immunity 1203 TABLE 101.2 T-Cell Costimulatory Receptors of the CD28 Family and Their Ligands Receptor Ligand(s) Cells That Express Ligand(s) Effects CD28 B7-1 (CD80), B7-2 (CD86) DC, macrophages, B cells Costimulate naïve T-cell activation ICOS ICOS-L DC, macrophages, B cells Promote differentiation of follicular helper T cells CTLA-4 B7-1(CD80), B7-2 (CD86) DC, macrophages, B cells Negatively regulate T-cell response PD-1 PD-L1(CD274) PD-L2 (CD273) DC, macrophages, B cells, epithelial cells Negatively regulate T-cell response Positive Costimulation Negative Costimulation CTLA-4, Cytotoxic T-lymphocyte antigen 4; DC, dendritic cell; ICOS, inducible costimulatory molecule; PD, programmed death CD40 on APCs binding to CD40 ligand on activated CD4+ T cells CD40:CD40L binding further activates APCs, enhancing their expression of B7 molecules and their secretion of cytokines (such as IL-12) to promote T-cell differentiation Although the CD28:B7 costimulatory pathway provides positive second signals that promote T-cell activation, cytotoxic T-lymphocyte antigen (CTLA-4) and programmed death (PD-1) are examples of negative costimulatory pathways These negative costimulatory pathways (also referred to as immune checkpoints) are important mechanisms to control the inflammatory cascade and to guard against hyperinflammatory responses or responses to self-antigens However, in certain circumstances, these negative signals may be overly robust and may inappropriately decrease T-cell function As such, these pathways have emerged as important therapeutic targets for cancer immunotherapies; investigations into their roles in sepsis and multiple-organ dysfunction are underway.3–6 CTLA-4, expressed on the surface of T cells, is a high-affinity receptor for B7 molecules As such, CTLA-4 is capable of binding low levels of B7 on resting APCs displaying self-antigen CTLA-4:B7 binding then inhibits access of CD28 to B7, which blocks the positive costimulatory pathway PD-1 expression on peripheral lymphocytes is induced upon activation Binding of PD-1 to its ligands (e.g., PD-L1 or PD-L2) on APCs negatively regulates T-cell responses by inhibiting T-cell receptor signaling and by promoting the differentiation and function of immunosuppressive regulatory T cells CYTOTOXIC T CELL TARGET CELL Cytotoxic granule Perforin pore Granzyme CD8 + α β CD3 MHC I + peptide A Fas-ligand CD95L Fas CD95 CD81 T Cells Differentiate Into Cytotoxic T Cells CD8+ T cells are integral to the immune response against viruses and other intracellular pathogens As discussed earlier, CD8+ T-cell activation begins with recognition of antigenic peptide presented by MHC I molecules on the surface of an infected cell or an APC In some cases, CD4+ helper T cells may help promote CD8+ T-cell development via APC activation or by cytokine secretion Cytokines that stimulate CD8+ T-cell growth and differentiation include IL-2, IL-12, IFN-g, IL-15, and IL-21 Once activated, CD8+ T cells undergo clonal expansion and differentiation into fully functional cytotoxic T lymphocytes (CTLs) Activated CTLs use one of two mechanisms to kill infected target cells (Fig 101.4) In the first mechanism, the CTL delivers the cytotoxic protein content of its cytoplasmic granules (perforins and granzymes) to the target cell Perforins facilitate the transport of granzymes to the cytosol of the target cell where the granzymes Apoptosis Death signal + CD8 α CD3 B β MHC I + peptide Apoptosis • Fig 101.4 Cytotoxic T cells induce target cell apoptosis by two mecha- nisms (A) Contents of cytotoxic granules (granzymes) are delivered to the target cell via perforin proteins Granzymes directly activate caspases, initiating apoptotic cell death (B) Fas-ligand binding to Fas on target cells initiates a signal transduction cascade leading to apoptosis MHC, Major histocompatibility complex 1204 S E C T I O N X I Pediatric Critical Care: Immunity and Infection cleave caspase proteins, initiating apoptotic cell death A second method of CTL-mediated target cell death involves the binding of FasL (CD178) on the CTL surface with Fas (CD95) on the target cell surface Fas:FasL binding initiates a signal transduction cascade leading to caspase activation and apoptosis In addition to directing target cell death, cytotoxic T lymphocytes secrete the cytokine IFN-g, which serves to activate local macrophages and promote particular helper T-cell responses (e.g., TH1), providing additional crosstalk between innate and adaptive immunity CD41 T Cells Differentiate Into Multiple T Helper Cell Subtypes + When naïve CD4 T cells are activated, they proliferate and differentiate into a variety of effector helper T-cell subtypes, each with distinct function and cytokine signatures Cytokines present in the local environment at the time of T-cell activation largely determine the direction of subtype differentiation Properties of individual T helper cell subtypes are outlined in Table 101.3 Though it is helpful to think about effector T helper cell subtypes as distinct, fully differentiated cells, evidence suggests that effector T cells retain the ability to change subtype.7,8 This degree of plasticity coupled with ever increasing recognition of novel T helper cell subtypes speaks to a high degree of complexity, our understanding of which continues to evolve TH1 Cells TH1 cells are primarily responsible for activating innate immune cells and controlling infections caused by phagocytosed pathogens TH1 cells develop in response to activation of the transcription factors STAT4 and Tbet by the cytokines IL-12 and IFN-g Activated TH1 cells function via a combination of cytokine secretion and CD40:CD40L binding to activate phagocytic cells (mainly macrophages) as follows: (1) they induce production of nitric oxide and other reactive oxygen species, initiating oxidative burstmediated microbial killing; and (2) they upregulate cell surface expression of MHC molecules and B7 costimulatory molecules to enhance antigen presentation This form of macrophage activation, which promotes inflammation and effective microbial killing, has been termed classic macrophage activation TH2 Cells TH2 cells, by contrast, promote “alternative” macrophage activation characterized by the production of antiinflammatory cytokines, IL10, and transforming growth factor-b (TGFb) For this reason, TH2 cells are generally thought of as an antiinflammatory helper T-cell subset TH2 cells develop in response to IL-4–mediated activation of the transcription factors STAT6 and GATA-3 The primary antiinfective role of TH2 cells is to direct mast cells, eosinophils, and the humoral immune response toward control of parasitic infection These cells also play important roles in promoting IgE-mediated allergic reactions TH17 Cells TH17 cells develop in response to activation of the transcription factors STAT3 and RORgt in the setting of multiple cytokines, including IL-1, IL-6, IL-23, and TGFb TH17 cells are often found associated with mucosal surfaces (e.g., the gastrointestinal TABLE 101.3 CD4 Effector T-Cell Subsets Subset Cytokines Directing Development Cytokines Secreted by Subset Role in Promoting Inflammation TH17 IL-1, IL-6, IL-23, TGFb IL-17, IL-21, IL-22 TH1 IL-12, IFN-g IFN-g, IL-2, GM-CSF, TNFb, CCL2 TFH IL-6, IL-21 IL-4, IL-21 • Activate B cells and promote differentiation to antibodysecreting plasma cells TH9 IL-4, TGFb IL-9, IL-10, IL-21 • • • • TH2 IL-4 IL-4, IL-5, IL-10, IL-13 12 • Direct macrophages toward alternative (immunosuppressive) activation • Direct B cells to produce IgE • Activate eosinophils • Increase TH2 differentiation and decrease TH1 Treg IL-2, TGFb IL-10, TGFb 22 • Suppress macrophage activation • Suppress TH1 development 111 11 Functions • Recruit neutrophils and macrophages to site of inflammation • Promote G-CSF production to increase neutrophil numbers • Promote epithelial cell barrier function • Induce epithelial cell cytokine production • • • • Classic macrophage activation Increase macrophage NO, ROS production Direct B cells to increase IgG and decrease IgE Increase TH1 differentiation and decrease TH2 Increase mast cell proliferation and activity Increase eosinophil recruitment Increase TH2 responses and IgE production Promote lymphocyte recruitment and IFN-g production G-CSF, Granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; Ig, immunoglobulin; IL, interleukin; NO, nitric oxide; ROS, reactive oxygen species; TGFb, transforming growth factor beta; Treg, regulatory T cells CHAPTER 101 Adaptive Immunity 1205 tract) and are likely involved in immunity to mucosal pathogens They are potently proinflammatory cells and have been implicated in a number of autoimmune and inflammatory conditions.9,10 Specific functions of TH17 cells include recruiting leukocytes (primarily neutrophils) to sites of infection, promoting the production of antimicrobial peptides such as defensins, enhancing epithelial barrier function and cytokine production, and enhancing CD8+ T-cell activity Natural killer (NK) T cells are a second small subset of T cells with distinct function NKT cells are so named because they carry both natural killer cell markers (e.g., CD56) and a T-cell receptor NKT cells function like innate immune cells in that they quickly produce cytokines in response to pathogens They also respond in an antigen-dependent manner via T-cell receptor recognition of lipid antigens bound to MHC-like molecules called CD1d.20 T Follicular Helper (TFH) Cells Adaptive Immunity in the Intensive Care Unit TFH cells primarily reside in and around germinal centers of secondary lymphoid organs.11 Their development relies on interaction with activated B cells via the inducible costimulatory (ICOS) molecule and activation of the transcription factor BCL-6 TFH cells function within germinal centers to promote B-cell proliferation and immunoglobulin production TH9 Cells TH9 cells are a relatively recently identified T helper cell subset As the name implies, they are characterized by secretion of the cytokine IL-9 TH9 cells may be primarily located in the skin and along mucosal surfaces Like TH2 cells, activated TH9 cells enhance mast cell function, eosinophil recruitment, and IgE production and provide immunity against parasitic infection They also promote lymphocyte recruitment and IFN-g production and have been implicated in autoimmune and allergic diseases, including eczema, asthma, food allergies, and inflammatory bowel disease.12,13 Regulatory T Cells (Treg) Naturally occurring regulatory T cells (Treg) are an immunosuppressive subset of CD4+ T cells characterized by high expression of the cell surface marker CD25 and diminished expression of the IL-7 receptor, CD127 The transcription factor FOXP3 is required for Treg development and function, and it serves as an additional Treg marker Treg cells arise in the thymus during T-cell development in response to recognition of self-peptide Though they constitute a relatively small percentage of the total circulating T-cell population (5%–10% under normal circumstances), they play an important role in maintaining T-cell tolerance to selfantigens In the ICU, whereas downregulation of Treg cells may contribute to autoimmune and allergic disease, pathologic upregulation of Treg cells has been associated with immunosuppression and adverse outcomes in critically ill septic adults These studies, however, have not been consistent; whether Treg cells play a role in pediatric sepsis is currently unclear.14–18 Additional T-Cell Subtypes Although the majority of circulating T cells carry T-cell receptors composed of an a and b chain, a minority of T cells (,5%) contain T-cell receptors composed of a g chain and d chain These cells are referred to as gd T cells Unlike ab T cells, gd T cells are not MHC restricted, meaning that they can recognize antigens not bound by MHC molecules The gd T cells also may be activated by nonprotein microbial antigens such as phosphates and lipids as well as heat shock proteins When activated, gd T cells produce inflammatory cytokines, IFN-g, tumor necrosis factor–alpha (TNF-a), and IL-17 Because gd T cells often reside at epithelial surfaces, it is thought that they serve an important function in the early defense against epithelial microbes.19 A well-functioning immune response is vital to the resolution of infection, prevention of new infection, and recovery from critical illness However, as will be reviewed in greater detail in Chapter 104, critical illness is often associated with suppressed immune cell function, which is associated with increased risks of nosocomial infection and mortality.15,21–24 Although much of the work in critical illness–associated immunosuppression has focused on innate immunity, data from septic adults and children suggest that suppressed or downregulated adaptive immune responses are also associated with adverse outcomes.5,15,25,26 Specifically, multicenter genomic studies of children with septic shock consistently demonstrate downregulation of genes within adaptive immunity pathways, a pattern that may be exacerbated by corticosteroid use.26–28 Mechanisms of adaptive immunosuppression in septic shock have yet to be fully elucidated Lymphocyte apoptosis has been long recognized in both adult and pediatric sepsis and likely plays a role in sepsis-induced immunosuppression.29,30 However, other mechanisms may be important as well As mentioned previously, immunosuppressive regulatory T cells may contribute to sepsis-induced immunosuppression, though data to support this mechanism are currently mixed.14–18 Additionally, increased expression of negative costimulatory molecules CTLA-4 and PD-1 has been demonstrated in animal models of sepsis and in septic adults, which may represent an additional mechanism for critical illness–associated immunosuppression.4–6,31,32 For instance, elevated PD-1 expression is associated with higher mortality in septic adults, and blocking the PD-1 pathway results in reversal of immunosuppression and improved survival in animal models of sepsis.6,31 These pathways may provide future therapeutic targets for sepsis-induced immunosuppression and are the subject of much ongoing study Aside from critical illness–associated immunosuppression, the pediatric intensivist often cares for patients whose adaptive immune responses are intentionally suppressed to treat autoimmune disease or to prevent posttransplant organ rejection Glucocorticoids represent one of the most common immunosuppressants administered in the ICU Antiinflammatory glucocorticoids, such as methylprednisolone and dexamethasone, potently suppress T-cell function by blocking cytokine production and inducing T-cell apoptosis Other immunosuppressive medications commonly encountered in the ICU are outlined in Table 101.4 Given the importance of adaptive immune function in the ICU, particularly in the setting of infection, it is likely that immunosuppressive medications may need to be tailored to the unique individual needs of the critically ill patient Unfortunately, available evidence to guide immunosuppressive medication management in the pediatric ICU is lacking and adult data are limited, with a single report suggesting that rapidly tapering immunosuppression in transplant patients with sepsis and documented severe immunosuppression may be beneficial without sacrificing graft survival.33 1206 S E C T I O N X I Pediatric Critical Care: Immunity and Infection TABLE 101.4 Selected Immunosuppressive Medications Targeting Adaptive Immune Function Drugs Mechanism of Action Select Uses Lymphocyte depletion Posttransplant induction therapy Basiliximab, daclizumab Prevent T-cell activation and proliferation by blocking the IL-2 receptor (CD25) Posttransplant induction therapy Rituximab Binds CD20 on B-cell surface leading to B-cell lysis Pretransplant therapy for HLA-sensitized recipients, certain refractory autoimmune diseases, autoimmune cytopenias, antibody-mediated autoimmune encephalitis Inhibit T-cell cytokine production by blocking phosphatase activity of calcineurin Posttransplant maintenance therapy Block T-cell proliferation and differentiation by blocking the serine/threonine protein kinase, mTOR Posttransplant maintenance therapy Azathioprine Converts to purine analog, which competitively inhibits DNA synthesis and blocks proliferation of bone marrow–derived cells Posttransplant maintenance therapy, autoimmune hepatitis Mycophenolate mofetil Inhibits lymphocyte proliferation by inhibiting purine synthesis Posttransplant maintenance therapy, lupus nephritis Methotrexate Inhibits folic acid pathway, which inhibits purine and pyrimidine synthesis Juvenile idiopathic arthritis, psoriasis, inflammatory bowel disease Cyclophosphamide DNA alkylating agent inhibits lymphocyte proliferation Lupus nephritis, refractory autoimmune disease Polyclonal Antibody Sera Antithymocyte globulin Monoclonal Antibodies Calcineurin Inhibitors Cyclosporine, tacrolimus mTOR Inhibitors Sirolimus, everolimus Antiproliferative Drugs HLA, human leukocyte antigen; IL, interleukin In sharp contrast to pharmacologic immunosuppression, cancer immunotherapy is an evolving field that involves augmenting adaptive immune responses in order to treat malignancy The underlying premise of antitumor immunotherapy involves stimulating immune cell responses and often targeting those responses toward tumor-specific antigens Although these therapies show promise in the treatment of relapsed or metastatic disease, some patients experience potentially life-threatening side effects related to significant immune activation and the associated cytokine release syndrome.34 These patients often require transition to the ICU for support of hemodynamics and organ function (see also Chapter 92) One example of cancer immunotherapy in pediatrics is the use of the monoclonal antibody (mAB) ch14.18, which recognizes the disialoganglioside GD2, found on neuroectodermal cells and highly expressed on neuroblastoma In a phase III trial of high-risk neuroblastoma patients, ch14.18 combined with IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) was significantly associated with improved event-free survival compared with standard therapy.35,36 A second example of cancer immunotherapy involves the infusion of autologous T cells that are genetically modified to express chimeric antigen receptors (CARs) that recognize tumor cell surface markers and are fused to T-cell receptor signaling domains Tisagenlecleucel is a CAR T-cell product with a CAR that recognizes the cell surface marker CD19 (a B-cell marker) Tisagenlecleucel is approved by the US Food and Drug Administration to treat relapsed or refractory B-cell acute lymphoblastic leukemia in young adults and children.37,38 In a multicenter phase trial in 75 young adults and children, treatment with tisagenlecleucel was associated with an overall 81% remission rate at months, though cytokine release syndrome occurred in 77% of patients.38 As the use of cancer immunotherapies continues to expand, the need for critical care intervention to manage acute toxicities will likely increase and necessitate an understanding of both innate and adaptive immune responses involved A more detailed review of CAR T-cell therapies and the cytokine release syndrome can be found in Chapter 92 Summary As is highlighted further in subsequent chapters, attention to maintaining a well-regulated and functional immune response is essential for many of the children cared for in the ICU The cellular components of adaptive immunity, B cells and T cells, help drive a complex, well-regulated interchange of cellular responses and chemical signaling leading to optimum performance of both innate and adaptive immunity As attention focuses on maintaining and restoring coordinated, functional immune responses in the ICU, it will be increasingly important for the pediatric intensivist to understand the components of both the innate and adaptive immune systems CHAPTER 101 Adaptive Immunity Key References Boomer JS, To K, Chang KC, et al Immunosuppression in patients who die of sepsis and multiple organ failure JAMA 2011;306:2594-2605 Fallon EA, Biron-Girard BM, Chung CS, et al A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis J Leukoc Biol 2018 Epub ahead of print Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure J Immunol 2005;174: 3765-3772 Maude SL, Laetsch TW, Buechner J, et al Tisagenlecleucel in children and young adults with B-cell lymphphoblasitic leukemia N Engl J Med 2018;378:439-448 1207 Muszynski JA, Nofziger R, Moore-Clingenpeel M, et al Early immune function and duration of organ dysfunction in critically ill children with sepsis Am J Respir Crit Care Med 2018;198:361-369 Parks T, Wilson C, Curtis N, Norrby-Teglund A, Sriskandan S Polyspecific intravenous immunoglobulin in clindamycin-treated patients with streptococcal toxic shock syndrome: a systematic review and meta-analysis Clin Infect Dis 2018;67:1434-1436 Wong HR, Cvijanovich N, Lin R, et al Identification of pediatric septic shock subclasses based on genome-wide expression profiling BMC Med 2009;7:34 The full reference list for this chapter is available at ExpertConsult.com ... is helpful to think about effector T helper cell subtypes as distinct, fully differentiated cells, evidence suggests that effector T cells retain the ability to change subtype.7,8 This degree of... surface expression of MHC molecules and B7 costimulatory molecules to enhance antigen presentation This form of macrophage activation, which promotes inflammation and effective microbial killing,... the production of antiinflammatory cytokines, IL10, and transforming growth factor-b (TGFb) For this reason, TH2 cells are generally thought of as an antiinflammatory helper T-cell subset TH2