T Cell Immunology - Study Notes

T Cell Immunology

Aims

  • To explain how different subsets of T cells generate different types of immune responses.

Learning Outcomes

By the end of the session, you should appreciate:

  • How different T-helper cell (TH cell) cytokines produce different types of immunity.

  • How immune responses need to be appropriate for the type of pathogen.

T-helper Cells - General Overview

  • T-helper (TH) cells are recognized as the main immunoregulators in the adaptive immune response.

  • They are prolific producers of cytokines, which play a crucial role in determining the type of immune response.

  • TH subsets are defined by their unique cytokine profiles, thus influencing immune system activation and control.

TH Cell Subset Activation

  • The activation of TH cell subsets is determined by the cytokine environment.

  • During an antigenic challenge, naive TH cells (which have not yet encountered antigens) differentiate into:

    • TH1 cells

    • TH2 cells

  • This differentiation is influenced by the cytokines present in the environment.

Polarization of TH Cells

  • Naive TH cells need an antigenic challenge to commit to a specific subset.

  • TH1 cells:

    • Promoted by the presence of IFN-g (Interferon gamma) and IL-12 (Interleukin 12).

    • Sources:

    • IFN-g is secreted by Natural Killer (NK) cells.

    • IL-12 is secreted by macrophages and dendritic cells.

  • TH2 cells:

    • Development is promoted by IL-4 and IL-13 (both secreted by mast cells) and IL-5 (secreted by eosinophils).

TH1 Cytokines and Immunity

  • TH1 cytokines include:

    • IFN-g:

    • Responsible for macrophage activation which increases killing efficacy, crucial for eliminating intracellular bacteria.

    • Enhances the production of other cytokines by macrophages and B cells.

    • IL-2:

    • Promotes enhanced activity of NK (Natural Killer) cells and cytotoxic T lymphocytes (CTLs).

    • Critical in anti-viral and anti-tumor immunity.

    • Furthermore, contributes to the production of memory T cells.

TH2 Cytokines and Immunity

  • TH2 cytokines include:

    • IL-4 and IL-13:

    • Facilitate the production of IgM, IgA, and IgE antibodies.

    • IgM is the first isotype of antibody produced, while IgA and IgE interact with eosinophils and mast cells, enhancing mucosal immunity against parasites.

    • IgE is associated with Type I hypersensitivity (allergic) reactions.

    • IL-5:

    • Promotes the development of eosinophils and the production of IgA.

    • Vital for mucosal immunity.

    • IL-10:

    • Inhibits IL-12 synthesis, thus downregulating TH1 development.

TH17 Cells

  • TH17 cells are characterized by specific characteristics:

    • FoxP3-positive cells (a transcription factor).

    • Produces IL-17 and does not secrete other signature cytokines.

    • IL-17 plays a role in promoting neutrophil accumulation in tissues, leading to inflammatory responses.

    • These cells are associated with tissue damage in chronic inflammatory diseases.

T Regulatory (Treg) Cells

  • Treg cells are defined as:

    • FoxP3+ cells that secrete several important cytokines, including:

    • IL-4

    • IL-10

    • TGF-b (Transforming Growth Factor beta), which is their signature cytokine.

  • Key Functions:

    • TGF-b downregulates inflammatory responses driven by TH1 cells, leading to reduced cellular responses.

    • Critical in maintaining peripheral tolerance to self-antigens, thereby controlling autoimmunity.

    • Play a role in tumor resistance to immune killing.

    • Treg cells can downregulate CTL and NK cell responses, sometimes enhancing tumor survival via tumor-infiltrating lymphocytes (TILs) with a Treg profile.

TH Cells in Disease - Tuberculosis

  • In the context of tuberculosis (TB):

    • Upon infection, M. tuberculosis survives within alveolar macrophages resistant to phagocytosis.

    • IFN-g and TNF-a (Tumor Necrosis Factor alpha) are necessary for killing this bacterium.

    • Granuloma formation occurs with TH1 cells surrounding macrophages, facilitating the killing of bacteria while limiting their spread.

    • TH2 cell cytokines promote antibody production, which is ineffective against intracellular bacteria.

    • As a result, M. tuberculosis continues to replicate, leading to disseminated TB.

TH Profiles in Disease - Tuberculosis Overview

  • Pulmonary TB:

    • Characterized by a TH1 response that leads to granuloma formation and destruction of bacilli within macrophages.

  • Disseminated TB:

    • Characterized by a TH2 response where antibodies are produced, but bacteria are not eliminated.

Individual Variability in Disease Response

  • Different individuals respond differently to diseases, which necessitates diverse treatment approaches.

Cytotoxic T Lymphocytes (CTLs)

  • Cytotoxic T Cells:

    • CD8+ T cells that recognize antigens presented by MHC class I molecules.

  • Upon contact with target cells:

    • CTLs release perforin, which polymerizes to form transmembrane channels in the target cell membrane.

    • Delivered into the target cells are apoptosis-inducing factors, leading to the cell's demise.

Mechanisms of CTL Action

  • FasL (Fas Ligand or CD95L):

    • CTLs express FasL, which binds to the Fas receptor (CD95) on target cells.

    • This interaction induces apoptosis in those target cells, highlighting its essential role in anti-viral and anti-tumor immunity.

Memory T Cells

  • Memory cells (for T and B cells) enable faster and stronger adaptive immune responses upon subsequent encounters with the same pathogen.

  • Characteristics of memory cells include:

    • Less stringent activation criteria.

    • Wide distribution throughout tissues.

    • Faster immune responses compared to naive cells.

    • Different recirculation patterns, with migration preferred to the tissues where the initial infection occurred.

Summary

  • T-helper cell subsets, specifically TH1 and TH2, dictate the specific type of immune response.

  • The immune response must be appropriately matched to effectively combat the pathogen.

  • CTLs play a pivotal role in eliminating intracellular infections, such as viral pathogens and tumor cells.

  • Treg cells are crucial for regulating the extent of immune responses and may contribute to tumor survival.