Dendritic and NK Cells Overview

Dendritic Cells (DCs)

• Bridge the innate and adaptive immune systems by activating T cells
• Respond to microbes by producing cytokines
• Cytokines initiate inflammation and stimulate the adaptive immune response

Natural Killer (NK) cells

• Exhibit cytotoxic activity similar to CD8+ T cells
• Circulate in blood and reside in lymphoid tissues
• Kill infected cells and produce IFN-γ, which activates macrophages to destroy phagocytosed microbes
• Recognize infected and stressed cells, killing them and secreting macrophage-activating cytokine IFN-γ
• NK cells release the contents of their cytoplasmic granules into the extracellular space
• NK cell-activating cytokines include IL-15 (NK cell maturation), type I interferons, and IL-12 (enhancing killing functions)
• Deactivated by IL-10 produced by CD8 T cells
• Kill infected cells using proteins like perforin and granzymes, similar to CD8 cells
• Activate macrophages through IFN-γ
• Macrophages produce IL-12
• Perforin forms channels in the membrane of the target cell
• Granzymes enter the cell and activate caspase enzymes leading to apoptosis

Leukocyte Migration

• Leukocytes migrate through endothelial cells using a process called diapedesis
• Diapedesis requires temporary disruption of adherens junction proteins, primarily the VE-cadherin complex, holding endothelial cells together
• Kinase activation, triggered by leukocyte integrins binding ICAM-1 or VCAM-1, disrupts the VE-cadherin complex
• Kinases phosphorylate the cytoplasmic tail of VE-cadherin, leading to reversible disruption of the adherens complex
• In rare cases, leukocytes migrate through endothelial cells via a process called transcellular migration

Neutrophil and Monocyte Recruitment

• Neutrophils are the most abundant leukocytes in tissues within 24-48 hours after infection or injury, followed by monocytes
• Neutrophils respond rapidly to chemokines compared to monocytes or other leukocytes
• Neutrophils have short lifespans in tissues and die by apoptosis, while monocytes survive longer and may proliferate
• Variations in expression of adhesion molecules and chemokine receptors determine whether neutrophils or monocytes are recruited to inflammatory sites
• Neutrophils express CXCR1 and CXCR2, binding CXCL1 and CXCL8 (IL-8), chemokines with ELR motifs supporting their migration into tissues
• Early neutrophil recruitment is driven by early CXCL8 production by tissue-resident macrophages and other cells
• Classical monocytes, primarily recruited to inflammatory sites, express CCR2
• CCR2 binds CCL2 (MCP-1), crucial for monocyte recruitment
• Monocyte recruitment occurs when resident tissue cells produce CCL2 in response to infection

ILC3 Functions

• Involved in chronic inflammation and cancer in the skin, lung, and intestine
• Increased ILC3 responses contribute to skin inflammation in psoriasis and mouse models through IL-22 and IL-17 production
• Elevated ILC3s in bronchoalveolar lavage fluid of asthma patients and mouse models of obesity-induced asthma
• Activation of the NLRP3 inflammasome and macrophage production of IL-1β trigger ILC3 production of IL-17, which directly promotes airway inflammation and hyper-responsiveness
• ILC3s in the intestine can promote IL-22-dependent tumor growth
• ILC3-derived LTα1β2 or LTα3 promote IgA production by B cells indirectly by influencing stromal cell or DC responses
• ILC3-derived GM-CSF modulates myeloid cell homeostasis to promote Treg cell responses and tolerance to food antigens
• ILC3-intrinsic MHCII can directly kill commensal bacteria-specific CD4+ T cells, potentially causing intestinal inflammation
• ILC3s can limit chronic inflammation by regulating innate and adaptive immune responses in the intestine
• ILC3 responses are triggered by myeloid cell and DC-derived IL-1β and IL-23 after recognition of microbes

NK Cell Function

• Distinguish infected and stressed cells from healthy cells
• Function regulated by a balance of signals generated by activating and inhibitory receptors
• Activating receptors recognize ligands on infected and injured cells
• Inhibitory receptors recognize ligands on healthy normal cells

NK Cell Stimulating Cytokines

• IL-12, IL-15, IL-18, and type I IFNs enhance the cytotoxic activity of NK cells
• These cytokines stimulate IFN-γ secretion by NK cells
• IL-15 is a growth factor for NK cells

NK Cell Activating Receptors

• Killer cell Ig-like receptors (KIRs)
  • KIR genes exhibit polymorphism, with different allelic variants in the population
  • Individuals express various KIR receptors
  • Groups of KIR alleles are often inherited together as KIR haplotypes
  • Haplotypes differ in the number of receptors encoded
  • Some haplotypes are associated with increased susceptibility to disorders like spontaneous abortion and uveitis
• Lectin-like NK cell receptor (NKG2D) binds class 1 MHC proteins
• CD16 (FcγRIIIA) is a low-affinity receptor for IgG antibodies, binding to the Fc region of IgG1 and IgG3, producing IFN-γ

Functional Plasticity of NK Cells and ILCs

• Flexibility exists between different ILC types
• True NK cells cannot become ILC3s but can become ILC1s with sufficient TGF-beta
• ILC1 and ILC3 exhibit flexibility, crucial for proper tissue responses
• Disbalance between ILC subsets can contribute to certain immune-mediated diseases

NK/ILC in Pregnancy

• Proper placenta development requires trophoblast cells from the fetus to invade the maternal uterine layer
• Trophoblast cells grow into maternal blood vessels, allowing nutrient exchange between fetus and mother
• These blood vessels dilate to increase blood flow, primarily driven by NK cell modulation
• NK cells secrete factors that adjust blood vessel tone
• This ensures adequate blood flow to support fetal growth

ILC2 and TH2 Cells

• ILC2s are analogous to TH2 cells
• The difference lies in their activation mechanisms
• ILC2s are activated through innate mechanisms, while TH2 cells are activated through antigen-specific T cell activation