Cell Types in the Immune Response: An Educational Review

Taylor R. Penn, BS ¹, William N. Rose, MD *²

*Correspondence to: William N. Rose, MD. Department of Pathology and Laboratory Medicine, University of Wisconsin Hospital, 600 Highland Ave, Madison, WI 53792, USA.

Copyright

© 2023 William N. Rose, MD. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 10 August 2023

Published: 01 September 2023

Abstract

The immune system is a collection of cells and tissue throughout the body that acts as the body’s surveillance and defense system. [1] It is divided into innate and adaptive branches. [2] The innate immune system is nonspecific and is driven by the recognition of conserved microbial micromolecules, whereas the adaptive immune system is driven by the recognition of foreign macromolecules, such as proteins. The adaptive system is composed of B lymphocytes, which produce antibodies, T lymphocytes, and antigen-presenting cells, which includes macrophages and dendritic cells. [2] Within the immune system as a whole, there are many other cell types and signaling molecules that function to coordinate the actions of the innate and adaptive systems to ultimately induce inflammation and prevent infection.

Introduction

Immunology is the study of the complex array of physiologic processes that take place throughout the human body to provide protection and maintain one’s health in the form of immunity. [2] The immune system is an interface for the human body to communicate with itself as well as the outside world to detect injury, infection, and neoplasms. [2]

At the core of this is inflammation, which can be thought of as the end-product of an immune response. [1] Upon closer inspection, one can identify the countless cells and interconnected signaling that it took to reach that point. Inflammation can be beneficial, through activation of various effector cells through these signaling molecules and pathways to prevent infection and contain areas of injured tissue. [1] However, it can also be deleterious in the form of indirect damage to nearby healthy tissue or even induce autoimmunity, when immune cells specifically target healthy tissue. [1]

The primary aim of this review is to summarize key components of the human immune system. In doing so, this should provide a simple outline of how to organize and better understand the basic functions of immunologic cells in the body. 
 

Branches of the Immune System: Adaptive vs. Innate

The immune system is a collection of cells and tissue throughout the body that work together to protect against damage, infection, and neoplasms by inducing inflammation. It can be thought of as the body’s surveillance and defense system, and it can be roughly divided into the innate and adaptive branches. [3] The innate immune system is nonspecific. It includes physical barriers to pathogen invasion (e.g. skin and mucous membranes), as well as cellular and soluble factors (e.g. granzyme) that are activated by recognition of conserved microbial macromolecules. [5]

The adaptive immune system is a branch of the immune system driven by specificity. It involves the production of an inflammatory response to specific molecules found on or within the human body. [3] These specific molecules are known as antigens, which are defined as anything that can trigger an immune response. [4] Frequently encountered antigens are proteins and carbohydrates. [3] Receptors found on adaptive immune cells have specificity for certain antigens, meaning they only respond to a single molecule based on its specific three-dimensional structure and/or its sequence of organic building blocks (i.e. amino acids or monosaccharides). [5]

Ultimately, the adaptive immune system consists of a variety of cells. The primary effectors are B lymphocytes, T lymphocytes, and antigen-presenting cells (APCs). [5] They patrol regions of the body in search of antigen that is not found in normally functioning human cells. When one of these is encountered by an effector cell of the adaptive system, an extensive cascade of cell activation, proliferation, and signaling is triggered to identify and kill the source of that antigen. [4] The adaptive system can also create immunologic memory, an ability the innate system largely lacks. [2] T and B lymphocytes contain receptors specific to a single antigen, which can be selected for to proliferate and be maintained over time. This is the principle upon which vaccination was successfully developed. [2]

Antigens & immune recognition

As noted above, antigens can be simply defined as anything that is recognized by a cell of the immune system, such as proteins, carbohydrates, and other cellular products from both one’s own cells, often described as self, or from bacteria, viruses, and other pathogens, termed non-self. [5] The goal of the immune system is to recognize these antigens to determine if an immune response should take place. If that is the case, a variety of processes can be activated, ranging from induction of cell cytotoxicity, antibody production, or phagocytosis to name a few. [4]

The immune system is designed so that cells that successfully recognize non-self are maintained through positive selection, i.e. they are given positive feedback to replicate and persist. Cells that do not successfully recognize non-self or react to self undergo negative selection, i.e. they apoptose or become inactive. [6]

Human Leukocyte Antigens & the importance of specificity

Human Leukocyte Antigen (HLA) are encoded on a set of genes found on Chromosome 6 that encodes for the Major Histocompatibility Proteins (MHC). [6] Each human inherits HLA alleles that produce two types of MHC: Class I and II. [4] Together, these MHC molecules function to present antigen and activate T cells with a compatible TCR. [4]

While both Class I and II MHC serve the same essential function, there are key differences to note between them. Firstly, Class I MHC is determined by the loci A, B, and C, and are present at the surface of nearly all somatic cells to present intracellular proteins such as autologous proteins, tumor antigens, viral proteins, and proteins from other intracellular microbes. [4] Class II MHC is determined by the subregions DR, DQ, and DP, and are present at the surface of Antigen Presenting Cells only. [6] Class II MHC functions to present extracellular proteins such as those from bacteria, non-replicating vaccines, and toxins/allergens. [4]

Lymphocytes: The key effectors of adaptive immunity

B and T lymphocytes are the primary effectors of the adaptive immune system alongside Antigen Presenting Cells (APCs). [4] They are distinct from other immune cells due to their specificity for a particular antigen. While B cells mature in the bone marrow and T cells mature in the thymus (a lymphatic organ located in the anterior mediastinum), they are both subject to a complex and highly regulated process that eventually produces a unique surface receptor. [4] Every cell’s receptor is slightly different, as it can bind to a different type of antigen.

T Lymphocytes

T cells mature within the thymus, hence their name. [2] During development, they function to rearrange their genome to produce a T cell receptor (TCR). This is a protein composed of two equal length chains that is expressed at the T lymphocyte surface and functions to bind antigens of 9-20 amino acids in length. [7]

In addition to producing a functional TCR in the thymus, developing T cells express different surface markers that help determine their function. The two main T cell surface markers include CD4 and CD8. [2] CD4+ T cells are also called Helper T Cells. [2] This is derived from the fact that their main role is to support the activation of other cells involved in an immune response, particularly B cells. [2] A key feature of CD4+ T cells is that they interact with major histocompatibility complex II (MHC II) antigens that are presented by the APC. [2]

CD8+ T cells are also called Cytotoxic or Killer T cells. [2] This is derived from the fact that their main role is to kill foreign invaders. A key feature of CD8+ T cells is that they require antigens to be presented in MHC I by the APC. [2]

A third important subtype of T lymphocytes includes T regulatory cells. [2] These are CD4+ and express a unique transcription factor FOXP3. [2] Their niche involves targeting self-reactive T cells, which could otherwise lead to autoimmune reactions and disease if left unregulated. [8, 9]

B Lymphocytes

Similar to T cells, the B cell is a type of lymphocyte that develops from hematopoietic stem cells in the bone marrow that eventually proceed through a complex maturation process. [2] Following initial development, they are primarily found in lymph nodes throughout the body and are able to proliferate and differentiate further. Similar to T cells, they function to rearrange their genome to produce a B cell receptor (BCR), which is a membrane-bound form of immunoglobulin (Ig). Ig is composed of 4 different peptide chains and functions to recognize and bind the 3-dimensional structure of the protein and carbohydrate antigens specific for that molecule. [5]

They act in the adaptive immune system in two main ways. First, they act as professional antigen presenting cells to activate T lymphocytes. [2] Second, they can differentiate further to become plasma cells. [2] The main role of a plasma cell is to produce immunoglobulin and secrete it into the bloodstream. [2]

Another subtype of B lymphocyte is the memory B cell. These are nondividing, long-lived plasma cells that are maintained in the bone marrow for long periods of time beyond the initial immune response for which they were originally activated. [5] In turn, these cells provide the foundation for immunologic memory if the particular pathogen the memory cells are specific for is encountered again in the future. [2]

Immunoglobulins: A library of antigen-specific proteins

The 5 main classes (or isotypes) of immunoglobulins (also known as antibodies) are: IgM, IgG, IgA, IgE, and IgD. [4] In general, immunoglobulins mark antigens for opsonization, which helps promote phagocytosis and clearance of that molecule. [5]

The primary response to a new non-self antigen that is encountered for the first time involves the production of predominantly IgM. IgM a pentamer that can sometimes activate complement strongly. [10] The secondary response involves the production of predominantly IgG. IgG is a monomer and the most abundant isotype of Ig in the body. [10] Another common Ig is IgA, which is a dimer that is mostly found in secretions. [10] IgE is a monomer that present in very small quantities and is usually involved in hypersensitivity reactions such as allergic or anaphylactic reactions. [10] IgD is also a monomer and is poorly understood. [2]

Antigen Presenting Cells: Triggering adaptive immunity

Antigen Presenting Cells (APCs) are a specific subset of immune cells that function to activate other elements of cell-mediated immunity through binding and processing of antigens with subsequent placement at their cell surface in MHC Class I or II for presentation. [2] In the case of Class II MHC, these antigens are usually brought into the cell through phagocytosis or by binding to membrane-bound receptors. In doing so, other cells such as T lymphocytes can recognize if their TCR is specific to that antigen. [2]

Professional APCs include macrophages, monocytes, B cells, and dendritic cells. [2] A defining characteristic that distinguishes professional APCs from other immune cells is that they express both Class I and Class II MHC, enabling them to activate both CD4 and CD8 T cells. [10,11] Aside from antigen presentation, APCs are a crucial source of cytokine signaling that drives the composition of an immune reaction. [2]

Monocytes and macrophages constitute a group of myeloid cells that are APCs that mainly function as phagocytic cells, particularly for antibody and/or complement-coated antigens that bind to their surface receptors. [9] Monocytes are found in the bloodstream while macrophages are found in tissue. An example of a resident macrophage is the Kupffer cell, found along the sinusoids of the liver. [6]

Dendritic cells (DC) are a complex lineage of cells that can be myeloid or lymphoid and act as APCs. An example is a Langerhans cell, a resident DC within places such as the skin, intestines, and lung. [9] DCs are phagocytic and uniquely present antigen in both MHC Class I and II externally. [9] This process is termed cross-presentation and allows an APC to process extracellular antigen and present it directly in MHC Class I to CD8+ Cytotoxic T cells. [7]

As mentioned earlier, B cells are a type of lymphocyte. While they can differentiate into plasma cells to secrete antibody, B cells are also a type of APC. They are able to recognize extracellular antigen via the membrane-bound Ig receptor, endocytose this complex, and then process and present the antigen on MHC Class II. [2] Upon interacting with a CD4+ Helper T Cell specific for that antigen, they are able to activate that cell in the context of the correct costimulatory signals. [2] This directly links humoral immunity with cell-mediated immunity. 

Natural Killer Cells: A hybrid effector cell

Natural Killer (NK) cells stem from lymphoid precursors, meaning they stem from similar progenitor cells as lymphocytes. [9] They function to react to cells that are not expressing MHC Class I. In doing so, this provides nonspecific cytotoxicity to identify tumor and virally infected cells that have induced downregulation of MHC Class I expression at the cell surface as a defense mechanism. [9] This is accomplished via the expression of Killer Cell Immunoglobulin-like Receptors (KIR), which must bind to MHC I to inhibit activation of the killing pathways in the NK cell. [11] If MHC I is not recognized, the NK cell kills that particular cell. [2]

Cytokines & their role in coordinating immune function

While the adaptive immune system is composed of each of these different effector cells, spread throughout the body in the bone marrow, thymus, circulation, skin, and other lymphoid and non-lymphoid tissue, they all need to be able to interact with each other to produce a coordinated immune response. [12] This is primarily made possible through protein signaling via cytokines. [12]

Cytokines are a broad group of regulatory proteins. These are produced by all cells of the body, but mainly function to communicate with immune cells. Cytokines can signal in an autocrine or paracrine fashion, and doing so can initiate, terminate, or modulate an immune response. [12] Additionally, they can alter the function of non-immune cells, such as the endothelium, as well. Throughout the development of a hematopoietic stem cell to mature myeloid or lymphoid cell, cytokines provide inhibitory and stimulatory signals that influence that cell's phenotype. [13]

Many of these proteins are known as interleukins (IL), named for the fact that they are predominantly synthesized by leukocytes to act on leukocytes. [5] Each cytokine has a distinct profile in terms of what cells produce it, where it acts, and what downstream effects this leads to. Below is a brief and simplified overview of important examples: [13]

• IL-2 – produced by activated T lymphocytes to induce lymphocyte proliferation
• IL-6 – produced by macrophages to promote fever and acute phase reactant synthesis
• Tumor necrosis factor (TNF)-alpha – produced by macrophages to cause fever and promote inflammation
• Transforming growth factor (TGF)-beta – produced by Treg cells to inhibit pro-inflammatory enzymes and induce repair pathways

As noted above, this list is not comprehensive in terms of cell types that produce each cytokine, where the cytokines acts, or the physiologic effects they induce. [1,2,13]

Teaching Points

• The immune system is a collection of cells and tissue throughout the body that protect against damage, infection, and neoplasms by inducing inflammation.
• The innate immune system is nonspecific, and it includes physical barriers as well as conserved microbial macromolecules.
• The adaptive immune system is composed of cell types that have specificity. They recognize specific molecules based on their biologic sequence and structure to induce an immune response, and can create memory as a result.
• Lymphocytes are cells of the adaptive immune system of lymphoid origin.
• T lymphocytes can be either Helper T cells (CD4+) to support B cells and immune response activation or Cytotoxic T cells (CD8+) to bind antigen and kill directly cells.
• Human Leukocyte Antigens (HLA) are genes that encode for the Major Histocompatibility Proteins (MHC) that are inherited by all humans and function to present antigen to T cells.
• B lymphocytes are a type of professional APC that express a BCR, or membrane-bound immunoglobulin (Ig), at their surface to bind antigen and activate T cells.
• Immunoglobulins are antibodies produced by B cells to help bind antigen and activate immune cells. The 5 main isotypes are IgM, IgG, IgA, IgE, and IgD.
• Professional APCs include B cells, dendritic cells, and macrophages. These are the only cells capable of presenting exogenous antigen via MHC Class II to activate CD4+ T cells.
• Macrophages are activated monocytes and a type of professional APC that utilizes phagocytosis.
• Dendritic cells are a type of professional APC. They are unique in their ability to present exogenous antigen on MHC Class I.
• Natural Killer (NK) cells are of lymphoid origin and survey the body for cells lacking MHC Class I at the surface.
• Cytokines are regulatory proteins of the immune system that modulate function of cells in the body, primarily immune cells.

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