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