Immune Cell Origin and Innate Functions

Immune Cell Origin

• Immune cells originate from hematopoietic stem cells (HSCs) in the bone marrow.
• HSCs differentiate into myeloid and lymphoid lineages.
• Myeloid cells include phagocytes and dendritic cells (DCs), representing the innate immune system.
• Lymphoid cells include lymphocytes, responsible for adaptive immunity.
• Leukopoiesis, the formation of white blood cells, is stimulated by interleukins and colony-stimulating factors (CSFs).

Innate Immune System Functions

• Two major functions: inflammation and antiviral defense.
• Inflammation involves vascular permeability, recruitment of leukocytes (mainly neutrophils and monocytes), and phagocytosis of microbes.
• Neutrophils are the first responders, entering tissues within 48 hours after injury or infection.
• Monocytes arrive later and have longer lifespans.
• Different chemokine receptors on neutrophils and monocytes mediate distinct recruitment patterns.
• Neutrophils express CXCR1 and CXCR2, binding CXCL1 and CXCL8 (IL-8), attracting neutrophils to tissue.
• Monocytes express CCR2, which binds CCL2 (MCP-1), promoting monocyte recruitment.
• The process of Leukocyte migration requires transient disruption of VE-cadherin complex in endothelial cells.
• Kinases activated by leukocyte integrins binding to ICAM-1 or VCAM-1 phosphorylate VE-cadherin, leading to the disruption.
• Neutrophils die by apoptosis after entering tissues while monocytes can survive longer and proliferate.
• The innate immune system response is triggered by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) recognized by sentinel cells like macrophages, DCs, and mast cells.

Innate Lymphoid Cells (ILC3s)

• ILC3s are a type of innate lymphoid cell with roles in immunity and tissue repair.
• Activated by IL-1β and IL-23, produced by DCs.
• Produce IL-17 and IL-22, which promote innate immunity to fungi and bacteria.
• Involved in the resolution of inflammation in lymphoid tissues and the intestine.
• Promote restoration of stromal cells through production of LTα1β2 and IL-22.
• Can limit chronic inflammation by regulating innate and adaptive immune responses in the intestine.
• Contribute to the development of psoriasis, asthma, and cancer in the skin, lung, and intestine.
• ILC3s can both promote and limit chronic inflammation, depending on the context.

Sequence of Events in Acute Inflammatory Responses

• Sentinel cells (mast cells, tissue-resident macrophages, DCs) detect PAMPs and DAMPs and trigger inflammation.
• Mast cells release histamine and prostaglandins, leading to vasodilation and increased vascular permeability.
• Increased blood flow and plasma proteins (complement, antibodies, antimicrobial proteins) enter the tissues.
• Cytokines like IL-1 and TNF induce expression of endothelial adhesion molecules and chemokines, promoting leukocyte migration into tissues.
• Leukocytes phagocytose and kill microbes, clear damaged cells, and promote further inflammation and repair.

Innate Immune System & Adaptive Immune System

• Dendritic cells act as a bridge between the innate and adaptive immune systems by activating T cells.
• Dendritic cells respond to microbes by producing cytokines, which initiate inflammation and stimulate the adaptive immune response.

Natural Killer Cells (NK cells)

• NK cells have cytotoxic activity similar to CD8+ T cells.
• NK cells circulate in the blood and are present in lymphoid tissues.
• NK cells recognize and kill infected and stressed cells.
• NK cells produce IFN-y, which activates macrophages.
• NK cells are active until CD8+ cytotoxic T cells are produced, which then take over cell killing.
• NK cells are inactivated by IL-10 produced by CD8+ T cells.
• NK cells use perforin and granzymes to kill cells, similar to CD8+ T cells.
• NK cells activate macrophages through IFN-y.
• Macrophages produce IL-12.

Pattern Recognition Receptors (PRRs)

• PRRs are receptors that recognize and respond to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).
• PRRs are located on cells of the innate immune system (neutrophils, monocytes, dendritic cells) and adaptive immune system (second signal role).
• Cellular Associated PRRs:
  • Toll-like receptors (TLRs): important in defense against microbial components (bacteria and viruses).
  • Nucleotide-binding oligomerization domain-like receptors (NLRs): play an important role in inflammasome activation.
  • Retinoic acid-inducible gene I-like receptors (RLRs): important for viral RNA.
  • Cyclic GMP-AMP synthase (cGAS): detects microbial DNA.
  • C-type lectin receptors (CLRs): recognize sugars on the surface of microorganisms.
• Soluble PRRs
  • Complement: a system of proteins that helps to destroy pathogens.
  • Pentraxins: plasma proteins that recognize microbial structures and participate in innate immunity.
    • Short pentraxins: C-reactive protein (CRP) and serum amyloid P (SAP).
    • Long pentraxin: PTX3.
  • Collectins: soluble effector molecules in the innate immune system with collagen-like tails and C-type lectin heads.
    • Mannose-binding lectin (MBL): similar structure to C1q, mediates internalization of microbes.
    • Pulmonary surfactant proteins A (SP-A) and D (SP-D): lipophilic properties in the lungs, maintain alveolar function, bind to microorganisms, act as opsonins, inhibit bacterial growth, and activate macrophages.

Innate Lymphoid Cells (ILCs)

• ILCs produce cytokines similar to those secreted by CD4+ helper T cells.
• ILCs play a key role in mediating acute inflammation in response to infection.
• ILC responses are altered in several disease states.
• ILC Types:
  • ILC1
  • ILC2
  • ILC3
• ILC Origins:
  • ILCs develop in the fetal liver and bone marrow from common lymphoid progenitors (CLPs).
  • All ILCs develop from CLPs.
  • A common ILC precursor differentiates into the three subsets of ILCs.
  • Differentiation of ILCs requires transcription factors Id2, NFLI3, and Tox.
• ILC Locations:
  • ILCs are rare in the blood and are mostly present in tissues, especially mucosal tissues.

NK Cell Inhibitory Receptors

• NK cells express inhibitory receptors that recognize class I MHC molecules.
• This prevents them from attacking normal healthy cells.
• Inhibitory receptor types:
  • KIRs (killer immunoglobulin-like receptors)
  • CD94/NKG2A heterodimer

NK Cell Activation

• NK cells kill infected cells through antibody-dependent cell-mediated cytotoxicity (ADCC).
  • IgG1 and IgG3 antibodies bind to microbial antigens on infected cells.
  • CD16 on NK cells binds to the Fc region of these antibodies.
• NK cells also use activating receptors, such as NKG2D, which recognize stress-induced ligands on infected and tumor cells.
• Loss of cell surface expression of class I MHC signals infection or damage.
• NK cells are activated when the inhibitory signals are absent.
• Viruses often downregulate MHC class I expression, making them less visible to T cells.

Summary

• The innate immune system is the first line of defense against infection.
• NK cells are important cytotoxic cells of the innate immune system.
• PRRs recognize PAMPs and DAMPs to activate the immune response.
• ILCs are a type of innate immune cell with cytokine-producing capabilities.
• NK cells use inhibitory receptors to distinguish between normal and infected cells.
• NK cells are activated through ADCC and activating receptors.