Generating the T Cell Response

Introduction to Cell-Mediated Immunity

  • Cell-mediated immunity is crucial for defending against various pathogens.
  • The lecture series covers T cell activation, control of T cell responses, contraction, homeostasis, and T cell migration.
  • Reference textbook: Basic Immunology: Functions and Disorders of the Immune System (7th Edition), Abbas, Lichtman, and Pillai.

Cell-Mediated Immunity: Definition and Importance

  • Cell-mediated immunity is essential for immune responses against diverse pathogens.
  • Microscopic and macroscopic organisms vary in size (100nm100 nm to 1mm1 mm).
  • Antibodies are approximately 10nm10 nm, while leukocytes range from 5−20μm5-20 \mu m.

Sites of Infection and T Cell Response

  • Different sites of infection determine the sources of antigens (cytosolic or extracellular), influencing the MHC antigen processing and presentation pathways, and the subsequent T cell response.
  • Cytotoxic T cells and helper T cells play roles in immunity against these pathogens.
  • Extracellular pathogens, vesicular pathogens, and cytosolic pathogens each elicit different immune responses.

Types of Adaptive Immunity

  • Humoral immunity is mediated by antibodies and is important for extracellular microbes.
  • Cell-mediated immunity is mediated by T cells, including helper T cells (CD4+) and cytotoxic T cells (CD8+).
  • Cell-mediated immunity is crucial for intracellular and extracellular microbes.
  • The immune system requires cooperation to effectively combat pathogens.

T Cell Subsets and Pathogen Elimination

  • Helper T lymphocytes recognize microbial antigens presented by antigen-presenting cells, activating macrophages and B lymphocytes.
  • Cytotoxic T lymphocytes (CTLs) kill infected cells expressing microbial antigens.

Immune Effector Modules

  • Innate and adaptive immune systems are integrated.
  • Immune effector modules are tailored for different types of pathogens:
    • Cytotoxicity: Cytosolic pathogens and tumor cells
    • Type 1 immunity: Intracellular (vesicular) pathogens
    • Type 2 immunity: Macroscopic pathogens (helminths)
    • Type 3 immunity: Extracellular pathogens

Cell-Mediated Immune Response: An Overview

  • Key phases include initiation by antigen recognition and effector functions.
  • The adaptive immune response involves antigen recognition, lymphocyte activation, clonal expansion, differentiation, antigen elimination, contraction (homeostasis), and memory.
  • Dendritic cells (DCs) play a crucial role in initiating T cell responses. Immature DCs capture antigens, while mature DCs present antigens and activate T cells.
  • DCs migrate to the lymph nodes and localize to the T cell zone.
  • Naïve T cells enter the lymph node from circulation and recognize peptide:MHC on the DCs, initiating the T cell response.
  • Activated T cells expand and differentiate into effector cells, which migrate to the site of infection.

T Cell Activation

  • T cell activation involves antigen recognition, signaling, costimulation, adhesion, clonal expansion, and differentiation into effector cells.

Antigen Recognition and Signal Transduction

  • Receptor proteins convert extracellular signals into intracellular biochemical events through signal transduction.
  • Intracellular signaling involves protein kinases, adaptor proteins, second messengers, and transcription factors, leading to changes in gene transcription.
  • TCR on the T cell recognizes peptide:MHC on DCs. Signal 1 alone is insufficient for T cell activation.

Molecular Interactions at the T Cell-APC Interface

  • Many membrane proteins, known as accessory molecules, are involved in T cell activation and inhibition.
  • CD4+ T cells recognize peptide:MHC class II, while CD8+ T cells recognize peptide:MHC class I.
  • Key molecules at the T cell:APC interface include:
    • TCR for antigen recognition
    • CD4/CD8 for signal transduction
    • CD3 and  chains for signal transduction
    • CD28 for costimulation
    • LFA-1 for adhesion

The Role of TCR and Associated Molecules

  • The TCR itself cannot transduce signals; it requires CD3 and  chains.
  • TCR complex = TCR + CD3 chains +  chains.
  • ITAMs (Immunoreceptor tyrosine-based activation motifs) on CD3 and  chains get phosphorylated during signal transduction.

Co-receptors and Signal Transduction

  • CD4 and CD8 co-receptors interact with MHC class II and MHC class I, respectively.
  • CD4 and CD8 interact with the tyrosine kinase, Lck, which is an important signaling protein.

T Cell Signal Transduction Overview

  • Membrane proximal events involve tyrosine phosphorylation, activating enzymes and creating docking sites for adaptor proteins.
  • Common biochemical cellular signaling pathways are activated, amplifying the cell surface signal and transducing signals to the nucleus.
  • Transcription factors are activated, binding to promoter regions of target genes, leading to transcription.

Detailed T Cell Signal Transduction

  • TCR recognizes peptide:MHC.
  • CD4/CD8 interacts with MHC in a peptide-independent manner.
  • Lck phosphorylates the tyrosines in the ITAMs of the CD3 and  chains.
  • ZAP-70 binds to the phosphorylated tyrosines on the CD3 and  chains and becomes activated.
  • A number of proteins are phosphorylated, including adaptor proteins and enzymes, initiating a signaling cascade.
  • Second messengers are generated, enzymes, and transcription factors are activated, turning on a number of genes.

Costimulation and Adhesion in T Cell Activation

  • Signal 1 (antigen recognition + associated signal transduction) is not enough for T cell activation.
  • Signal 2: Costimulation
  • Adhesion to stabilize the T cell:APC interaction

Costimulation: Signal 2

  • Signal 1 alone leads to T cell anergy, an important peripheral tolerance mechanism.
  • Signal 1 + Signal 2 leads to T cell activation, proliferation, and differentiation.
  • Costimulatory signal involves CD28 on T cells interacting with B7 on activated APCs.
  • B7 molecules are upregulated on DCs following signals through PRRs and cytokine receptors, indicating an "emergency."

Adhesion: Keeping Cells Together

  • TCR and peptide:MHC interactions are low affinity.
  • Upon antigen recognition and T cell signaling, T cell:APC interactions are stabilized.
  • Adhesion is mediated by the integrin, LFA-1, expressed on T cells.
  • Following antigen recognition, LFA-1 changes to a high affinity form, stabilizing T cell:APC interactions.

Review of T Cell Activation Requirements

  • Signal 1: Antigen recognition (TCR and peptide:MHC)
  • Signal transduction (through TCR complex and CD4/CD8 co-receptors)
  • Signal 2: Costimulatory signals (CD28 and B7 molecules)
  • Adhesion to stabilize the T cell:APC interaction (LFA-1 and ICAM-1)

CD8+ T Cell Activation

  • Same as CD4+ T cells: antigen recognition, signal transduction, costimulation, and adhesion.
  • CD8+ T cells may need additional help from CD4+ T cells, especially when DCs cross-present extracellular antigen on MHC class I.
  • CD4+ T cells help with CD8+ T cell activation and differentiation into cytotoxic T cells (CTLs) through cytokines and cell surface molecules.

Clonal Expansion

  • Clonal expansion builds the T cell army.
  • Following exposure to a microbe, the antigen-specific clone is "selected," leading to activation and an effective immune response.

Events Following T Cell Signaling

  • Following T cell signaling, many genes are transcribed, resulting in the expression of proteins:
    • Cell cycle proteins and transcription factors
    • Molecules important for effector functions (CD40L)
    • Molecules which control the immune response (CTLA-4)
    • Cytokines (IL-2)

IL-2 Induced T Cell Proliferation

  • IL-2 is important for clonal expansion.
  • Naïve T cells express a low/moderate affinity IL-2 receptor (IL-2R).
  • T cell activation results in expression of IL-2R chain, forming a high affinity IL-2R on activated T cells.
  • IL-2 binds to high affinity IL-2R, resulting in proliferation and survival of activated T cells.
  • IL-2 acts in a paracrine or autocrine manner.

T Cell Differentiation and Effector Functions

  • T cell differentiation and effector functions depend on cytokines and cell surface molecules.

Control of T Cell Responses, Contraction, and Homeostasis

  • Inhibitory molecules regulate T cell responses.
  • CTLA-4 and PD-1 are receptors expressed on activated T cells, acting as immune checkpoints.

Control of T Cell Responses by CTLA-4

  • CTLA-4 binds to B7 molecules with higher affinity than CD28, reducing costimulation and T cell activation.

Control of T Cell Responses by PD-1

  • PD-1 binds to PD-L1 and PD-L2, controlling and terminating effector T cell responses in the periphery, and limiting immunopathology.
  • Inhibits signal transduction through the TCR complex, reducing T cell activation and proliferation.

Contraction and Homeostasis

  • Following microbe elimination, the immune system returns to a resting state (homeostasis).
  • This decline is due to apoptosis of T cells following microbe elimination, due to lack of costimulatory molecules and IL-2 production.
  • Memory T cells remain to respond to subsequent encounters with the same antigen.

T Cell Migration

  • Cell migration is essential for effective immune responses.
  • Neutrophils and monocytes migrate to sites of infection.
  • DCs migrate from the periphery to the lymph node.
  • Naïve T cells migrate to lymph nodes (homing).
  • Activated T cells migrate to sites of infection in the periphery.
  • This is a highly coordinated process known as the leukocyte adhesion/migration cascade.

Leukocyte Migration Cascade

  • Selectins mediate rolling.
  • Chemokines activate integrins and promote chemotaxis.
  • Integrins mediate stable adhesion of leukocytes to endothelial cells.
  • Naïve and activated T cells express different sets of cell surface molecules, dictating where they can migrate.
  • The expression of these molecules changes following T cell activation signaling events.