Discuss the role of Natural Killer (NK) cells and Antibody Dependent Cytotoxic Cells (ADCC).

Natural Killer (NK) Cells: Mechanisms and Activation

NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. Unlike T cells, they do not require prior antigen sensitization to become activated. Their activity is regulated by a balance of activating and inhibitory signals received through a variety of receptors.

• Activating Receptors: These receptors recognize stress ligands expressed on infected or cancerous cells. Examples include NKG2D, which binds to MIC-A/B and ULBPs, and natural cytotoxicity receptors (NCRs) like NKp30, NKp44, and NKp46.
• Inhibitory Receptors: These receptors recognize MHC class I molecules, which are downregulated in many infected or cancerous cells. The most well-known inhibitory receptor is KIR (Killer-cell Immunoglobulin-like Receptor), which binds to HLA-A, -B, and -C molecules.
• The “Missing Self” Hypothesis: NK cell activation occurs when inhibitory signals are absent (i.e., MHC class I expression is reduced), leading to the dominance of activating signals.
• Mechanism of Cytotoxicity: Upon activation, NK cells release perforin and granzymes. Perforin creates pores in the target cell membrane, allowing granzymes to enter and induce apoptosis. They also express FasL which binds to Fas on target cells, triggering apoptosis.

Antibody-Dependent Cellular Cytotoxicity (ADCC)

ADCC is a mechanism by which effector cells, such as NK cells, macrophages, neutrophils, and eosinophils, mediate cell lysis in response to antibody binding to target cells. It bridges the gap between humoral and cellular immunity.

• Mechanism of Action: Antibodies (typically IgG) bind to antigens on the surface of target cells. Effector cells express Fc receptors (e.g., CD16 or FcγRIIIa on NK cells) that bind to the Fc region of the antibody.
• Activation and Cytotoxicity: Binding of the antibody-coated target cell to the effector cell via Fc receptors triggers the release of cytotoxic granules (perforin and granzymes) or activation of other cytotoxic pathways, leading to target cell death.
• Role of CD16: CD16 is a key FcγR expressed on NK cells and is crucial for ADCC. Polymorphisms in the FCGR3A gene (encoding CD16) can influence ADCC activity.

Comparison of NK Cells and ADCC

While both NK cells and ADCC result in target cell lysis, they differ in their activation mechanisms and requirements.

Feature	Natural Killer (NK) Cells	Antibody-Dependent Cellular Cytotoxicity (ADCC)
Activation Requirement	Balance of activating and inhibitory signals; “missing self” recognition.	Antibody binding to target cell and Fc receptor engagement on effector cell.
Antibody Dependence	Antibody-independent.	Antibody-dependent.
Effector Cells	Primarily NK cells, but also other lymphocytes.	NK cells, macrophages, neutrophils, eosinophils.
Target Recognition	Stress ligands, downregulated MHC class I.	Antigens bound by antibodies.

Clinical Relevance

Both NK cell activity and ADCC are crucial in various clinical scenarios:

• Cancer Immunotherapy: Monoclonal antibodies (mAbs) used in cancer therapy often induce ADCC, leading to tumor cell destruction. Rituximab (anti-CD20) used in B-cell lymphomas is a prime example.
• Viral Infections: NK cells play a vital role in controlling viral infections, particularly during the early stages before adaptive immunity develops.
• Autoimmune Diseases: Dysregulation of NK cell activity and ADCC can contribute to the pathogenesis of autoimmune diseases.
• Transplantation: NK cells can contribute to graft rejection or graft-versus-leukemia effects in transplantation settings.