Immunology: CD4+ T Lymphocytes

CD4+ T Lymphocytes

• MHC II molecules on APCs stimulate CD4+ T cells (Th0) to differentiate into various helper T cell subtypes: Th1, Th2, Th17, and Treg.
• Th1 cells secrete cytokines (IFN-γ, IL-2, TNF-α) that activate macrophages and eliminate Mtb through recruiting monocytes/neutrophils and inducing inflammatory mediators.
• Th17 cells produce IL-17A, IL-21, IL-22, and IL-26, enhancing neutrophil recruitment at infection sites and promoting an inflammatory response.
• IFN-γ is crucial for macrophage phagosome maturation; its absence in knockout models results in severe Mtb infections.
• Mutations in IFN-γ or its receptors lead to widespread infections from BCG or other mycobacterial species.
• TNF-α is critical in preventing reactivation and protecting against Mtb infection in humans and animal models.
• CD4 T cells aid in B cell activation and CD8 T cell responses, contributing to Mtb progression prevention.
• Mtb manipulates dendritic cell (DC) function, producing signals that inhibit IL-12 production, affecting adaptive immunity.
• Elevated CD13 expression on DCs during Mtb infection impairs T cell responses; blocking CD13 may enhance T cell activation.

Neutrophils

• Neutrophils are abundant in bronchoalveolar lavage and sputum of active pulmonary TB patients, being the first responders to Mtb infection.
• These cells perform antimicrobial activities and contribute to immunopathology by releasing substances like elastase and myeloperoxidase during respiratory bursts.
• Neutrophils are vital for inducing adaptive immunity and forming granulomas in Mtb infections.
• Enzymes released by neutrophils, like arginase and matrix metalloproteinase-9 (MMP-9), can damage lung tissues.
• Granulomas consist of various macrophage types (multinucleated giant cells, epithelioid cells, foam cells) and are significant in TB pathology.
• Recognition of Mtb PAMPs (like glycolipids) by macrophage-specific PRRs (TLRs, NLRs, CLRs) activates coordinated immune responses.

Macrophages

• M1 macrophages are primary effectors activated by intracellular bacteria, producing cytokines (IFN-γ, TNF-α).
• M2 macrophages help balance immune responses and bacterial growth, induced by cytokines such as IL-4 and IL-10.
• Macrophages combat Mtb through mechanisms like producing reactive oxygen and nitrogen species, cytokine secretion, phagosome acidification, and autophagy.

Dendritic Cells (DCs)

• DCs are essential for linking innate and adaptive immunity, crucial for Mtb antigen presentation.
• Human-derived DCs express receptors (DCSIGN, CD11b, CD11c) that recognize Mtb ligands and facilitate Mtb entry into DCs.

Introduction to Tuberculosis Research

• Robert Koch discovered Mycobacterium tuberculosis (Mtb) as the causative agent of tuberculosis (TB) in 1882.
• Efforts to develop vaccines and therapeutics for TB have accelerated due to rising infection rates despite existing treatments.
• The World Health Organization (WHO) reports TB as a significant cause of deaths linked to antimicrobial resistance.

Immune Response and Tuberculosis

• Infection begins when aerosolized Mtb particles interact with the mucosal tissue of the respiratory tract.
• The respiratory mucosa acts as both a physical barrier and initiator of mucosal immune responses.
• Mucosal immunity enhances pathogen recognition by immune cells (macrophages, dendritic cells, leukocytes) and promotes specific T-cell activation and antibody synthesis.

Vaccine Limitations and Challenges

• The Bacillus Calmette–Guérin (BCG) vaccine is administered intradermally but yields suboptimal CD4+ and CD8+ T cell responses.
• The ineffectiveness of BCG in establishing robust immune responses is a significant hurdle in TB control.

Role of Secretory Proteins

• Secretory proteins like MPT63 of Mtb are under investigation for their roles in modulating host immune responses.
• The TGF-β pathway, influenced by lipopeptides, has been linked to the differentiation of regulatory T cells (Tregs) which inhibit TH1 cell activation, a critical response against Mtb.

Cytokine Production and Immune Mechanisms

• Immunization approaches that favor effector and antimicrobial T cell subsets (Pool 2) lead to increased production of cytokines (TNF-α, IFN-γ, IL-17A), crucial for reducing bacterial burdens.
• TNF-α is essential for immune cell proliferation, differentiation, and macrophage activation; its neutralization post-BCG infection results in granuloma loss, diminishing effective immune response.
• IFN-γ plays a vital role in survival following Mtb infection and is produced by antigen-specific T cells and phagocytes.

Interplay of Cytokines in Infections

• IL-17A inhibits IL-10 production and enhances IL-12, leading to greater levels of IFN-γ, thereby reducing Mtb replication.
• High levels of Tregs producing IL-10 have been associated with increased bacterial burdens and severity in TB cases.

Implications for Vaccine Development

• Ongoing research aims to enhance mucosal immunity to stimulate more effective immune responses against Mtb.
• Understanding the functions and interactions of specific cytokines and immune cells can inform the development of new vaccines and therapeutic strategies for tuberculosis.

This quiz covers the role of CD4+ T lymphocytes in the immune response, specifically focusing on their differentiation into various subtypes such as Th1, Th2, and Th17. It also emphasizes the importance of cytokines in activating macrophages and enhancing antibacterial activity.