CD4 T Cells and T Helper Subsets

CD4 T Cell Function

Overview

• This lecture focuses on CD4 T cells, a subset of T cells.
• Covers the identification of different T cell subsets and the functions of T helper 1 (Th1) and T helper 2 (Th2) cells.

Lymphocyte Development and T Cell Maturation

• Lymphocytes originate in the bone marrow.
• T cells and B cells mature in generative lymphoid organs (bone marrow and thymus).
• Pre-lymphocytes from bone marrow:
  • B cells enter circulation directly.
  • T cells mature in the thymus through positive and negative selection.
• The thymus is crucial for T cell immunity, where T cells become CD4+ or CD8+.

T Cell Circulation and Activation

• Mature T cells and B cells circulate throughout the body.
• Naive T cells search for cognate antigens in secondary lymphoid organs (lymph nodes and spleen).
• T cells enter lymph nodes from the blood; if they don't encounter their cognate antigen, they return to the blood.

Antigen Presentation and T Cell Function

• T cell activation requires peptide presentation on MHC class I or class II molecules.
  • CD8 T cells recognize endogenously processed peptides via MHC class I.
  • CD4 T cells recognize exogenously processed peptides via MHC class II.
• Peptide size differs: CD8 T cells recognize shorter peptides, while CD4 T cells recognize longer ones.

CD8 vs. CD4 T Cell Functions

• CD8 T cells are cytotoxic, lysing infected or cancerous cells by creating holes and delivering enzymes.
• CD4 T cells are helper cells, primarily functioning through cytokine production but also via cell contact-dependent mechanisms.
• Both CD4 and CD8 T cells need co-stimulatory signals via CD28.

Division of Labor in the Immune System

• Different immune cell classes exist due to the division of labor, targeting various pathogens, toxins, or soluble factors.
• B cells produce antibodies to neutralize toxins and microbial products.

CD4 T Cell Functions

• CD4 T cells activate macrophages, maintain CD8 T cell memory, and help B cells with class switching for antibody production.
• CD4 T cell help is achieved through differentiation into specialized subsets in response to microbial stimulation, creating diverse cytokine environments.
• Different microbial pathogens trigger different types of inflammation, leading to the development of distinct CD4 T cell subsets. At a population level, CD4 T cells have many different subsets.

Discovery of Th1 and Th2 Subsets

• In 1986, Tim Mossman's research identified two CD4 T cell groups based on cytokine production.
• Experiment: Immunized mice with motor antigens, isolated T cells, restimulated them in vitro with the same antigens, and analyzed cytokine production.
• T cell clones were divided into two groups:
  • Group 1: Produced interferon-gamma, IL-2, GM-CSF, and TNF.
  • Group 2: Produced IL-4, IL-5, IL-6, and IL-10.
• These groups were named T helper 1 (Th1) and T helper 2 (Th2) cells.
• Initial skepticism existed due to in vitro data and unknown functions.

Leishmania Major Mouse Model

• A mouse model involving infection with Leishmania major was used to demonstrate Th1 and Th2 functions.
• C57BL/6 mice (resistant) vs. BALB/c mice (sensitive) showed different responses to Leishmania major infection.
• C57 mice control the infection without lesion development, while BALB/c mice develop large lesions.

Th1/Th2 Cytokine Profiles in Mouse Strains

• C57 mice expressed high levels of interferon-gamma (Th1 cytokine), while BALB/c mice expressed high levels of IL-4 (Th2 cytokine).
• Injecting anti-IL-4 antibody into BALB/c mice rescued them, allowing them to control the Leishmania infection, confirming Th1/Th2 functions in vivo.

Relevance to Human Disease: Leprosy

• Leprosy, caused by Mycobacterium leprae, exhibits a Th1/Th2 dichotomy.
• Tuberculoid leprosy: Strong Th1 response, granulomas, low bacterial burden.
• Lepromatous leprosy: Weak T cell response, high bacterial burden, disseminated infection.

Cytokine Expression in Leprosy Patients

• Tuberculoid leprosy patients express high levels of IL-2, interferon-gamma, and lymphotoxin.
• Lepromatous leprosy patients express high levels of Th2 cytokines.
• This supports the idea of Th1/Th2 functional differences in human disease.

Th1 and Th2 Paradigm

• Naive T cells differentiate into Th1 or Th2 subsets based on pathogen type and genetic background.
  • Th1 cells produce interferon-gamma and TNF, activating macrophages (M1).
  • Th2 cells produce IL-10, IL-4, and IL-13, important for parasite infection and allergic response.
• Th2 response can inhibit Th1 response via IL-10 production.

Th1 Response Details

• Th1 response is crucial at multiple levels in host response to infection.
• Interferon-gamma activates macrophages, promoting phagocytosis and killing of microbes.
• Interferon-gamma enhances antigen presentation by upregulating MHC class I and II molecules.
• Interferon-gamma activates macrophages to produce antimicrobial products like nitric oxide.

Th2 Response Details

• IL-4 and IL-13 are key Th2 signature cytokines.
• IL-4 promotes class switching to IgE, which coats mast cells and leads to degranulation, causing allergic reactions.
• IL-4 and IL-13 enhance mucus production in the gut and activate M2 macrophages.
• IL-5 activates eosinophils, involved in killing helminths.
• Th2 response primarily protects against parasites, with allergic reaction as a side effect.

Regulation of Th1/Th2 Decision Making

• The key mechanism depends on the expression of transcription factors and the cytokine environment.
• Transcription factors are T cell-intrinsic, while the cytokine environment is T cell-extrinsic.
• Optimal T cell activation requires three signals:
  • Signal 1: TCR recognition of peptide.
  • Signal 2: Co-stimulatory molecules (CD28 with CD80/86).
  • Signal 3: Cytokines produced by antigen-presenting cells or tissue cells.

Cells Producing Signal 3 Cytokines

• Signal 3 cytokines can be produced by immune cells (macrophages, neutrophils, NK cells, mast cells, eosinophils) and non-immune cells (epithelial cells), depending on the context of infection.

Transcription Factors: T-bet

• T-bet is a key transcription factor for Th1 response which encodes a T-box protein expressed in T cells.
• It is usually expressed at low levels in naive T cells but is upregulated upon activation.
• Overexpression of T-bet can suppress Th2 cell generation.
• T-bet binds to the interferon-gamma locus and increases the receptor for IL-12, enhancing Th1 development.

Cytokine Enforcement for Th1 Development

• Both T-bet and IL-12 are needed for maximal Th1 response.
• Interferon-gamma’s major function is to activate macrophages.

Transcription Factors: GATA-3

• GATA-3 is crucial for Th2 development.
• It is expressed in naive T cells and controls thymocyte development.
• GATA-3 is essential for Th2 differentiation, controlling the production of IL-4, IL-5, and IL-13.
• GATA-3 and IL-4 work together for Th2 development, but the initial source of IL-4 is likely innate cells (mast cells, eosinophils).
• Major functions of Th2 cells include IgE production, mucus production, and eosinophil activation/recruitment.

Th1/Th2 Paradigm Summary

• Th1 response is important for resistance to intracellular bacteria and protozoa.
• Th2 response is important for resistance to helminth infection.

Importance of the Th1/Th2 Discovery

• Demonstrated how generating a particular effective T cell response can determine the outcome of infection.
• Showed that cytokines produced by different subsets are critical in antimicrobial action.

Limitations of the Th1/Th2 Paradigm

• Many more T cell subsets have been discovered in the last twenty years.

Key Points

• How T cells help other immune cells.
• Signature cytokines of Th1 and Th2 cells.
• Mechanisms regulating Th1/Th2 differentiation.