Immunology. Richard Coico
of TH cells into effector cells is regulated, in part, by exposure of naïve CD4+ T cells to certain cytokines as shown in Figure 2.12. However, TH cell differentiation can be somewhat plastic. What determines subset differentiation is multifactorial and does not only depend on TCR engagement. Dose of antigen can play a role but most importantly, it is the cytokine milieu at the site of priming that is most relevant. There is also controversy regarding the possible plasticity of T‐cell subsets. Evidence suggests that T‐cell differentiation towards a specific functional subset may be subject to change at a later time under different conditions of antigen activation.
Table 2.2 summarizes the surface phenotypes, cytokine profiles, transcription factors, and functional properties of the major TH cell subsets.
Natural Killer T Cells
Like other T cells defined as TH cells, this small population of T cells express CD4 and TCRs, although with restricted variability. Unlike conventional T cells in general, natural killer (NK) T cells also express markers found on innate lymphoid cells called NK cells (see below), including CD56. In addition, unlike conventional T lymphocytes, the rearranged TCR only recognizes lipid antigens presented on CD1d, a “major histocompatibility complex (MHC)‐like molecule,” instead of MHC itself, as will be discussed in subsequent chapters.
Figure 2.10. The TCR/CD3 complex. The α and β chains of the TCR are associated with multiple CD3 dimers including εγ and εδ dimers and ζ homodimers.
Source: © John Wiley & Sons, Inc.
Table 2.1. Properties of Naïve CD4+ and CD8+ Cells
| T cell | Surface phenotype | Cytokines | Transcription factors | Function |
|---|---|---|---|---|
| CD4+ | αβ TCR, CD3, CD4, CCR7, CD62Lhi | IL‐2 | THPOK | Patrol through lymph nodes scanning peptide–MHC class II molecule complexes on APCs for the presence of their cognate antigen. Following activation by APCs, naïve CD4+ T cells differentiate into effector or regulatory T cells; activated naïve T cells also give rise to memory T cells |
| CD8+ | αβ TCR, CD3, CD8, CCR7, CD62Lhi | IL‐2 | RUNX3 | Patrol through lymph nodes scanning peptide–MHC class I molecule complexes for the presence of their cognate antigen. Following activation by APCs, they differentiate into CTLs and memory T cells |
Innate Lymphoid Cells
Innate lymphoid cells (ILCs) constitute a heterogeneous family of innate immune cells also derived from common lymphoid progenitors. Currently, ILCs are divided into three functionally distinct groups (ILC1, ILC2, and ILC3) based upon the cytokines they produce (Table 2.3). The first ILCs to be characterized were those defined as NK cells which are now defined as members of the ILC1 group. Not to be confused with the small population of CD4+ NKT cells that express CD4 as described above. NK cells are large granular lymphocytes. They contain intracellular granules with preformed biologically potent molecules that are released when NK cells make contact with target cells. Some of these molecules cause the formation of pores in the membrane of the target cell, leading to its lysis (see Chapter 3). Other molecules enter the target cell and cause apoptosis (programmed cell death) of the target cell by enhanced fragmentation of its nuclear DNA. Hence, they are able to lyse certain virus‐infected cells and tumor cells without prior stimulation. A more detailed discussion regarding the role of ILCs in innate immune responses is given in Chapter 3 but it is noteworthy that our understanding of this population of immune cells is still in its infancy.
Myeloid Lineage Immune Cell Populations
Polymorphonuclear Leukocytes
Polymorphonuclear (PMN) leukocytes are a population of cells also referred to as granulocytes. These include the basophils, eosinophils, and neutrophils. Granulocytes are short‐lived phagocytic cells that contain the enzyme‐rich lysosomes, which can facilitate destruction of infectious microorganisms. They also produce peroxide, superoxide radicals, and nitric oxide, which are toxic to many microorganisms. Some lysosomes also contain bactericidal proteins, such as lactoferrin. PMN leukocytes play a major role in protection against infection. Defects in PMN cell function are accompanied by chronic or recurrent infection.
Figure 2.11. CTL killing of target cells. CTLs interact in a cognate fashion via antigen‐specific TCRs in conjunction with CD8. Antigenic peptides expressed by class I MHC molecules on target cells bind to antigen‐specific TCRs in a process called antigen presentation (see Chapter 8). Following direct cell contact, pore‐forming perforin and granzymes are released by the CTL to promote destruction of the target cell.
Macrophages.
Macrophages are phagocytes derived from blood monocytes (Figure 2.13). The monocyte itself is a small, spherical cell with few projections, abundant cytoplasm, little endoplasmic reticulum, and many granules. Following migration of monocytes from the blood to various tissues, they undergo further differentiation into a variety of histological forms which, historically, have been classified in accordance with their anatomical location as follows.
Kupffer cells, in the liver; large cells with many cytoplasmic projections.
Alveolar macrophages, in the lung.
Splenic macrophages, in the red pulp.
Peritoneal macrophages, free‐floating in peritoneal fluid.
Microglial cells, in the brain and spinal cord.
Osteoclasts, in the bone.
More recently, recognition of the functional heterogeneity of macrophage subsets has given rise to a new paradigm for classification of these innate immune cells. Macrophages are functionally polarized into M1 or M2 macrophages. Such polarization is regulated by the cytokines and other molecules and conditions present in the local environment. M1 macrophages are typically activated by IFN‐γ or lipopolysaccharide, and