Th Cell Polarization

T-Lymphocyte Biology: Objectives

• Recall the process of Th activation and the mechanism of T-lymphocyte class restriction
• Compare the function and location of costimulator, co-receptor, and adhesion molecules during APC-Th interaction
• Describe the role of IL-2 in lymphocyte activation and its mechanism of release

T-Cell Activation

• 2-step process: signal 1 and signal 2
• Signal 1a: T-cell receptor interacting with HLA-2 (specificity of adaptive immunity)
• Signal 1b: CD4 co-receptor interacting with HLA-2 (increases T-cell activation)
• Signal 2: co-stimulatory interaction (CD28 on Th cell binding to CD80/86 on APC)
• Costimulators (CD80/86) are key to Th activation, increasing HLA-2 and costimulator expression only when APC recognizes a DAMP or PAMP

Interleukin 2 (IL-2) and Lymphocyte Activation

• IL-2 is a major T-cell and B-cell growth factor
• Proliferation and differentiation of activated naïve T cells and B cells
• IL-2 binding to Th IL-2R acts in an autocrine fashion, activating the Th cell and causing it to enter the cell cycle
• Synthesis of both IL-2 and the high-affinity IL-2R is induced after CD28-CD80/86 binding and recognition of antigen by the TCR

Helper T-Cells and Immunity

• CD4+ helper T-lymphocytes (Th) aid immunity by activating or inhibiting other cells through direct contact and secretion of cytokines
• Th cells differentiate after activation to "help" in a specific way (T-cell polarization)

T-Cell Polarization

• T-helper cells become polarized after activation, determined by the environment they are found in
• Polarization: specialized Th phenotype secreting a "profile" of cytokines that mediate distinct effector cell functions
• Key information: inducing cytokines, transcription factors, cytokines secreted, and microenvironment

Th1, Th2, Th17, Tfh, and Treg Helper T-Cells

• Th1: viral or intracellular bacteria infections, polarizing cytokines (IL-12, IFN-γ), transcription factor (T-bet), cytokines secreted (IFN-γ, TNF-α), microenvironment (intracellular)
• Th2: parasitic infections, polarizing cytokines (IL-4, IL-13), transcription factor (GATA-3), cytokines secreted (IL-4, IL-5, IL-13), microenvironment (parasitic)
• Th17: bacterial and fungal infections, polarizing cytokines (IL-6, TGF-β, IL-23), transcription factor (ROR-γt), cytokines secreted (IL-22, IL-17), microenvironment (chronically inflamed tissue)
• Tfh: activation of B-cells, polarizing cytokines (IL-6, IL-21), transcription factor (Bcl-6), cytokines secreted (IL-21, IL-4), microenvironment (B-cell follicles)
• Treg: down-regulation of effector activities, polarizing cytokine (TGF-β), transcription factor (FoxP3), cytokines secreted (TGF-β, IL-10), microenvironment (anti-inflammatory)

Cross-Regulation between Th Cells

• Signals generated by a polarized Th cell tend to prevent other local Th cells from being polarized into a different type
• Exception: Tfh cells often "re-polarize" to another Th type after the antibody response they help is completed

T Cell Activation

• T cell activation is a 2-step process involving co-stimulators, which are key to Th activation
• Major co-stimulator: CD80/86 on the APC, which binds to CD28 on the Th
• CD80/86 expression on APCs increases only when the APC recognizes a DAMP or a PAMP

Interleukin 2 (IL-2) and Lymphocyte Activation

• IL-2 is a major T cell and B cell growth factor
• IL-2 promotes proliferation and differentiation of activated naïve T cells and B cells
• IL-2 binding to the Th IL-2R acts in an autocrine fashion, activating the Th cell and causing it to enter the cell cycle, and avoid apoptosis
• Synthesis of IL-2 and the high-affinity IL-2R is induced after CD28-CD80/86 binding and recognition of antigen by the TCR (via HLA-2)

Helper T-cells and Immunity

• CD4+ helper T-lymphocytes (Th) never kill pathogens or other “foreign-looking” entities directly
• Instead, they activate or inhibit other cells through direct contact or secretion of cytokines
• Th cells differentiate after activation to “help” in a specific way, known as T-cell polarization

Th Polarization

• Th cells become polarized after activation, specializing in a specific Th phenotype
• Polarization is determined by the environment, particularly the types of cytokines present in high concentrations
• Key information about Th polarization includes:
  • Inducing cytokines and transcription factors
  • Cytokines secreted by the Th
  • The microenvironment and effects of the cytokines

Th1 Polarization

• Th1 polarization occurs in response to infection, likely viral or intracellular bacterial
• Dendritic cells phagocytose the pathogen, activating PRRs and migrating to lymph nodes or secondary lymphatic organs
• Th1 cells secrete IL-2, IFN-γ, and TNF-β, which activate macrophages and enhance antibody secretion

Th17 Polarization

• Th17 cells were discovered recently and are implicated in protection from infection and many autoimmune disorders
• Th17 cells are polarized by IL-6, IL-23, and TGF-β, which are produced by activated dendritic cells
• Th17 cells produce IL-22 and IL-17, which:
  • Induce release of IL-6, IL-1, TNF-α, and GM-CSF
  • Cause release of chemokines that recruit neutrophils and macrophages
  • Cause secretion of anti-microbial proteins from cells in inflamed tissue

Follicular Th Cells and Antibody Production

• Follicular Th cells (Tfh) are the main Th cell that aids full B-cell development in SLOs
• Tfh cells remain in SLOs, inducing formation of germinal centers and aiding B-cell antibody production
• Tfh cells are polarized by IL-21 and IL-12, which are different from Th1 and Th17 polarizing cytokines

Cytotoxic T-cells

• Cytotoxic T-cells kill cells that express abnormal intracellular antigens on HLA-1
• Activation of cytotoxic T-cells requires two signals:
  • An activating signal from a dendritic cell that has been licensed to present antigen
  • An activating signal from a Th1 cell in the near vicinity of the cytotoxic T-cell and its activating dendritic cell

Learn about the polarization of Th cells, including Th1 and Th2 cells, Tfh cells, and Th17 cells. Understand the signals that prevent other Th cells from being polarized into a different type and the role of cytokines.