Scott Abrams, Ph.D. Professor of Oncology, x4375 scott.abrams@roswellpark.org Kuby Immunology SEVENTH EDITION CHAPTER 11 T-Cell Activation, Differentiation, and Memory Copyright 2013 by W. H. Freeman and Company
T Cell-Dendritic Cell Interactions 2
Role of the Antigen Presenting Cell in the Activation of Naïve T Cells Dendritic cells are essential for the induction of the naïve T cell response, and do so through regulation of three major events known as the 3-signal model: 1. Recognition of MHC-peptide complex (& conjugate formation) i. antigen processing ii. antigen presentation iii. co-receptors (CD4 or CD8) iv. adhesion (LFA-1/ICAM-1; CD2/LFA-3) 2. positive co-stimulation (CD28/CD80 or CD86) 3. cytokine production (e.g., IL-2) 3
Signal 1: T Cell Recognition of MHC-Peptide Complexes Antigen specificity is governed by the TCR, which recognizes an antigenic peptide in the context of self-mhc, a concept known as MHC restriction. MHC restriction is absolutely essential to ensure and instruct immune reactivity against alterations of self. MHC class I=heavy/light pair MHC class II=similar size pair 4
Summary: The Generation of MHC-Peptide Complexes for T Cell Receptor Recognition 1 MHC class I and class II molecules deliver peptides to the cell surface from two distinct intracellular compartments. 2 Peptides presented by MHC class I molecules are generated within the cytosolic compartment (aka, endogenous pathway) 3 Peptides presented by MHC class II molecules are generated in acidified endocytic vesicles (aka, exogenous pathway). 4 Cross-presentation allows exogenous proteins to be presented on both MHC class I and II molecules (i.e., via dendritic cells, which are highly effective). 5 CD8 + T cells recognize MHC class I-peptide complexes 6 CD4 + T cells recognize MHC class II-peptide complexes 5
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Spatial Localization of Cell Surface Interactions Important for T Cell Activation supramolecular activating complex, central or peripheral 7
Summary: 3-Signal Model for T Cell Activation 8
From Naïve T Cell State to T Cell Activation (role of the APC and costimulation) 9
Professional APCs and Their Ability to Activate T Cells 10
Mechanisms of Innate Immune Recognition Pattern Recognition Receptors (PRR) recognize pathogen-associated molecular patterns (PAMP) on infectious agents 11 human toll-like receptors (TLRs); 13 mouse TLRs mainly expressed by professional APCs found either on cell membrane or endosomal membrane Conserved structurally germline-encoded receptors multiple leucine-rich repeats in extracellular region conserved intercellular domain for signaling 11
TLR: Receptor Specificity and Cellular Localization 12
Signal 2: Positive Costimulation 13
Signal 3: Cytokine Production and Clonal Expansion 14
Regulation of the T Cell Response 15
Absence of Costimulation Leads to Clonal Anergy, Which Ensures Peripheral T Cell Tolerance experimental demonstration pharmacologic demonstration 16
Mechanisms of Peripheral T Cell Regulation: Negative Co-stimulation 17
From T Cell Activation to Differentiation (or Polarization) 18
Basic Model for TH Subset Differentiation 19
Prototypic Example of Cytokine Signaling- Mediated Transcriptional Regulation IFN-γ-Induced STAT1 Signaling 1 1 1. IFN-γ binds to its cognate receptor (IFN-γR) 2 2. α and β chains aggregate 1. which are constitutively associated with Janus Kinases (JAKs) 3 3. JAKs phosphorylate the α and β chains, creating a docking site for STAT1 4 4. STAT1 is phosphorylated and forms a homodimer 5 5. STAT1:STAT1 homodimer binds GAS site 4 P 2 3 P STAT1 STAT1 STAT1 P Nucleus 5 GAS 20
TH Differentiation of 5 Major Subsets 1. Unique set of polarizing cytokines 2. Unique master transcriptional regulators 3. Distinct set of effector cytokines 21
Cross-Regulation of TH Subsets: Critical to Ensure Expression of the Appropriate T Cell Response example with Th1-Th2 paradigm 22
From T Cell Activation to Differentiation to Memory 23
Model for the Development of Central and Memory T Cells 24
Hallmarks of T Cell Memory? 25
Consequences of Inappropriate Activation T Cell Responses 1. nonspecific T cell hyper-proliferation 2. immune deviation 26
Aberrant T Cell Activation During Certain Acute Viral or Bacterial Infections 27
Diseases Linked to Superantigen-Mediated T Cell Activation Inappropriate production of large quantities of inflammatory cytokines are thought to disrupt immune homeostasis and the normal process of Ag-specific immune activation 28
Immune Deviation: Pathologic Consequences of the Wrong TH Subset Response 29
Summary: T Cell Activation and Differentiation 30
Manipulation of T Cell Responses for Therapeutic Purposes in Cancer Based on basic biology to clinical practice 1. Signal 1: dendritic cell vaccines expressing relevant MHC/peptide complex (e.g. Provenge in prostate cancer) 2. Signal 2: immune checkpoint inhibitors to prevent negative costimulation (anti-ctla-4 or anti-pd-1 mabs) 3. Signal 3: IL-2 administration 4. Adoptive T cell transfer of ex vivo-expanded tumor-infiltrating lymphocytes 31
Benefits of Clinically Engaging the T Cell Response Against Cancer Melanoma Before and after pictures of a patient with advanced melanoma who underwent treatment with tumor-infiltrating lymphocytes. Within 2 weeks of treatment, the large tumor had disappeared. Source: Cancer.gov Rosenberg et al. Nature Rev Can 8:299, 2008 32