Immune Cell Activity or Development

Cell migration and adhesion

The movement of immune cells from the bloodstream to sites of infection or inflammation involves the interaction of cell adhesion molecules and chemokines that guide immune cells to their target locations.

Agranulocyte and granulocyte adhesion and diapedesis depend on leukocyte extravasation signaling

The two-step process of adhesion and diapedesis accomplished through leukocyte extravasation signaling is crucial in immune response, allowing rolling white blood cells to exit the blood stream and migrate to sites of infection and inflammation. This process is used by both agranulocytes, such as monocytes and lymphocytes, and granulocytes, such as neutrophils, eosinophils and basophils.

The leukocytes first adhere to the endothelial cells of blood vessels, with first contact (capture) initiated by P/E-selectin on endothelial cells binding to ligands like P-selectin glycoprotein ligand-1 (PSGL-1) and E-selectin glycoprotein ligand-1 (ESL-1) on leukocytes. Rolling slows as chemokines induce leukocyte cell surface integrins to change from low to high affinity states strengthening adhesion. The leukocytes then use transmigration, also known as diapedesis, to squeeze through the vessel walls and migrate to the site of infection for effective, localized targeting and elimination of pathogens and inflammation (1).

Cell development and differentiation

These topics focus on the development and specialization of two types of immune cells critical to adaptive immune response: B cells and T helper cells. B cell development is crucial for antibody production, while T helper cell differentiation determines the type of response mounted.

B cell development

B cells are important components of the adaptive immune response, producing antibodies that target specific pathogens. Their ability to create a diverse repertoire of antibodies, in turn allowing the immune system to recognize a wide array of antigens, arises from the process of gene rearrangement that B cells undergo as they differentiate through a series of stages from hematopoietic stem cells located in bone marrow (2). B cells are important for mounting an effective response to infection as well as for providing long-term immunity through memory B cells.

T helper cell differentiation

T helper cell differentiation is a critical component of the adaptive immune response, determining the type of immune response that will be mounted. Depending upon the pathogen or allergen that is present plus the activating cytokine, naïve T helper cells differentiate into distinct subsets including Th1, Th2, Th17 and Treg cells (2). In addition to stimulating B cells to generate antibodies, each T helper cell subset produces and secretes a characteristic set of cytokines that orchestrate different aspects of the immune response, including macrophage activation, antibody production and inflammation.

Immune cell activation and function

These processes describe the activation and functional roles of various immune cells including mature dendritic cells, macrophages and monocytes, which are important for detecting and clearing pathogens, as well as natural killer cells, which play a role in tumor surveillance.

Dendritic cell maturation

Dendritic cells are antigen-presenting cells that capture, process and present antigens to T cells. As dendritic cells mature, they express higher levels of surface molecules that are necessary for T cell activation during the process of antigen presentation, which leads to production of cytokines that influence the type of immune response (3, 4). This maturation process is triggered by Toll-like receptors (TLRs), a family of pattern recognition receptors (PRRs) that detect molecular patterns associated with pathogens. Critically, some TLRs recognize host molecules helping to establish and maintain tolerance for non-pathogens.

Fcγ receptor-mediated phagocytosis in macrophages and monocytes, production of nitric oxide and reactive oxygen species in macrophages

Macrophages and monocytes eliminate pathogens through a variety of mechanisms, including phagocytosis mediated by Fcγ receptors. These receptors recognize and bind to the Fc region of antibodies that coat pathogens, facilitating engulfment and destruction of the pathogen. This process not only clears infections but also contributes to the regulation of immune responses by producing pro-inflammatory cytokines, reactive oxygen species (ROS) and nitric oxide (NO) (5). All three play roles in modulating inflammation, influencing the recruitment and activation of other immune cells. ROS and NO also have powerful antimicrobial properties, attacking and damaging multiple cellular components of microorganisms. Tight regulation is required to avoid tissue damage.

Tumoricidal function of hepatic natural killer cells

Hepatic natural killer cells (NK cells) are cytotoxic lymphocytes with the ability to recognize and kill tumor cells within the liver. They do so not through antigen recognition, but through complex communication via activating and inhibitory receptors. When the balance shifts in favor of activation, NK cells induce tumor cell apoptosis by releasing cytotoxic granules, producing pro-inflammatory cytokines such as interferon-gamma (IFNγ) and activating pro-apoptosis receptors such as TRAIL and FasL (6). Their activity is essential for preventing tumor growth and metastasis, making them an attractive target for cancer immunotherapy.

Immune signaling pathways

These signaling pathways are crucial for regulating immune cell functions and responses. GM-CSF and IL-3 signaling influence immune cell differentiation and proliferation, while PKR and RIG1-like receptors are involved in blocking viral replication.

GM-CSF signaling

GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) signaling plays a significant role in the development and function of the immune system. While it can promote differentiation and proliferation of myeloid cells into granulocytes and macrophages, it’s not essential for either. Instead, GM-CSF acts as a communicator between T cells and myeloid cells, modulating the activity of these cells in inflammation and autoimmunity (7).

IL-3 signaling

IL-3 is a cytokine that induces growth and differentiation of multi-potential hematopoietic stem cells into a range of cell types including basophils, neutrophils, eosinophils, macrophages, erythroid cells, megakaryocytes and dendritic cells (8). In addition to its role in hematopoiesis, IL-3 plays an important role in regulating immune response – a role that can be protective or detrimental depending on the cells/tissues and disease involved.

Role of PKR in interferon induction and antiviral response

Self-activated by sensing viral double-stranded RNA within the cell, protein kinase R (PKR) signaling results in phosphorylation of eukaryotic initiation factor 2 (eIF2α). Phosphorylated eIF2α binds more tightly to eIF2B, blocking translation initiation, inhibiting protein synthesis and limiting viral replication (9). PKR activation separately results in activation of NF-κB, inducing expression of type I interferons which also block viral replication through regulation of downstream genes.

Role of RIG1-like receptors in antiviral innate immunity

RIG-1-like receptors (RLRs) are a family of cytoplasmic receptors that recognize and bind 5’-phosphate containing viral RNA. Binding frees the C-terminus of the RLR to interact with mitochondrial-antiviral signaling protein (MAVS), initiating a signaling cascade that induces expression of type I interferons which, as discussed above, block viral replication through regulation of downstream genes (10).

Immune system communication and recognition

The innate immune system relies heavily on recognition of conserved molecular patterns found in bacterial and viral pathogens. PRRs detect nucleic acids, and to a lesser degree proteins, while CD1 molecules detect lipids. The ability to communicate the presence of these pathogens to adaptive immune cells is critical to a coordinated immune response.

Communication between innate and adaptive immune cells

Communication between innate and adaptive immune cells is essential for an effective short- and long-term immune response. Innate immune cells, such as dendritic cells and macrophages, recognize and capture pathogens, presenting their antigens to adaptive immune cells like T and B cells (11). As antigens are presented, the cell-cell interaction activates the adaptive immune cells, enabling them to mount a targeted immune response to clear the pathogen as well as establish immunological memory to prevent future infections.

Role of pattern recognition receptors in recognition of bacteria and viruses

Pattern recognition receptors (PRRs), including the TLR and RLR families discussed above, recognize conserved molecular patterns present in bacterial and viral nucleic acids, and to a lesser degree bacterial and viral proteins. When triggered, they activate signaling pathways that lead to production of interferons and cytokines, activating an immune response that leads to elimination of the pathogens (12).

Lipid antigen presentation by CD1

CD1 molecules on the surface of antigen presenting cells present lipid antigens to T cells, activating them and initiating an immune response (13). This process is crucial for the recognition and elimination of lipid-containing pathogens, such as mycobacteria, which are not effectively targeted by classical peptide antigen presentation pathways, such as those mediated by classical PRRs. CD1-mediated presentation expands the range of antigens that the immune system can detect, enhancing the body's ability to respond to diverse microbial threats.

References

1. Grönloh MLB, Arts JJG, Buul JD. Neutrophil transendothelial migration hotspots - mechanisms and implications. J Cell Sci. 2021;134(7):jcs255653.
2. R Luz, Cano E, Damaris H, Lopera E. Introduction to T and B lymphocytes. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al, eds. Autoimmunity: From Bench to Bedside. El Rosario University Press; 2013.
3. Zanna MY, Abd Rahaman Yasmin AR, Omar AR, Arshad SS, Mariatulqabtiah AR, et al. Review of dendritic cells, their role in clinical immunology, and distribution in various animal species. Int J Mol Sci. 2021;22(15):8044.
4. Dalod M, Chelbi R, Malissen B, Lawrence T. Dendritic cell maturation: Functional specialization through signaling specificity and transcriptional programming. EMBO J. 2014;33(10):1104–16.
5. Tridandapani S, Anderson CL. In: Madame Curie Bioscience Databases. Landes Bioscience; 2000-2013.
6. Fernandez JP, Luddy KA, Harmon C, O’Farrelly C. Hepatic tumor microenvironments and effects on NK cell phenotype and function. Int J Mol Sci. 2019;20(17):4131.
7. Lotfi N, Thome R, Rezaei N, Zhang G, Rezaei A, et al. Roles of GM-CSF in the pathogenesis of autoimmune diseases: An update. Front Immunol. 2019;4:101265.
8. Podoiska MJ, Grutzmann R, Pilarsky C, Benard A. IL-3: Key orchestrator of inflammation. Front Immunol. 2024;13:15:1411047.
9. Cesaro T, Michiels T. Inhibition of PKR by viruses. Front Microbiol. 2021;12:757238.
10. Rehwinkel J, Gack MU. RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol. 2020;20(9):537–551.
11. Principles of innate and adaptive immunity. In: Janeway CA, Traver P, Walport M, et al, eds. Immunobiology: The immune system in health and disease. 5^th edition. Garland Science; 2001.
12. Thompson MR, Kaminski JJ, Kurt-Jones EA, Fitzgerald KA. Pattern recognition receptors and the innate immune response to viral infection. Viruses. 2011;3(6):920–40.
13. Kim S, Cho S, Kim JH. CD1-mediated immune responses in mucosal tissues: Molecular mechanisms underlying lipid antigen presentation system. Exp Mol Med. 2023;55(9):1858–1871.