Neutrophils, monocytes, eosinophils and basophils form the backbone of the body’s innate immune system. Although these white blood cells differ in appearance, abundance and longevity, they share some key features in common. First, all of these cells arise in the bone marrow from non-lymphocyte precursors termed myeloid cells. Second, upon encountering foreign antigens, each cell type responds in a highly predictable, invariant manner; this response is the hallmark of innate immunity. This article will explore some of the cell surface receptors involved in the innate immune response, with particular emphasis on foreign antigen recognition, chemotaxis and cell migration from the bloodstream into the surrounding tissues.
Innate immune cells become activated in three main ways: 1) they encounter foreign antigens directly 2) they respond to signals called cytokines produced by other white blood cells or 3) they bind to adhesion molecules expressed by vascular endothelial cells in regions of infection or inflammation.
In the first scenario, white blood cells express one or more classes of surface proteins called toll-like receptors (TLRs) that bind to bacterial and viral antigens. For example, monocytes express TLR-4, which binds to a bacterial membrane component called lipopolysaccharide (LPS). The cell instantly recognizes LPS as a foreign antigen and sounds the alarm, so to speak, by attracting other white blood cells to the site of infection.
In the second scenario, white blood cells follow a trail of soluble signals called cytokines that lead them to the site of infection. The ability to migrate in response to chemical signals is called chemotaxis. Some cytokines attract specific white blood cells; in contrast, others induce chemotaxis in multiple cell types. Leukotriene B4 and Interleukin-8 selectively target neutrophils, while a protein called RANTES attracts basophils and eosinophils.
Although the details of cytokine signaling are incompletely understood, it appears that many cytokine receptors are members of the JAK-STAT protein family. The term JAK-STAT is an acronym for Janus Kinase Signal Transduction and Activator of Transcription. Basically, when a cytokine signal binds to the JAK membrane receptor, its cytosolic domains phosphorylate the nearby STAT proteins, which proceed to pair up, travel to the cell nucleus, and turn on gene transcription. Changes in gene expression lead to assembly and rearrangement of cytoskeletal proteins and ultimately to cell migration.
In the final scenario, white blood cells exit the circulation and enter the extravascular tissues in a three step process: First, the white blood cells roll along the endothelial lining of veins and capillaries until they come to a halt. Next, they squeeze themselves between the endothelial cells (diapedesis). Last, the white blood cells migrate through the extracellular matrix to combat microbial invaders in the tissues.
This process, known as endothelial transmigration or extravasation, is governed by multiple sets of cell surface receptors. The best characterized interaction involves proteins called integrins, located on the white blood cell surface, that bind to endothelial cell proteins called CAMs (cell adhesion molecules). Meanwhile, a white blood cell receptor called the sialyl Lewis X antigen binds to a group of endothelial cell glycoproteins called selectins. E-selectin is found mostly on vascular endothelial cells. P-selectin was isolated from placental tissue, and L-selectin is most abundant in the spleen, lymph nodes and other lymphocyte rich tissues.
All in all, the innate immune system relies on a multitude of surface receptors to effectively serve as the body’s first line of cellular defense.