T-Cell Mechanisms against Infectious Disease

Abstract

The functions of the immune system in the human body are related to immune response to the entry of foreign components into the body. In protecting the body from disease, the immune system has four main functions: recognition, effect, adjustment, and memory function. Lymphocytes are specific immune systems against pathogen antigens, to ensure that when the next attack of the same pathogen comes, it can be dealt with quickly and vigorously as well as become more immune. These lymphocytes, when formed for the first time, have specific properties, which, in the absence of use, remain in the body as naive. Basically, lymphocytes are divided into two based on their roles, namely, B and T lymphocytes. Activation of T cells will form several types of effector cells, such as cytotoxic, T-helper (Th), and regulator (Treg) cells. Cytotoxics kill pathogens and body cells infected by the virus. Th cells provide additional signals aimed at activating B cells to produce antibodies, also capable of activating other cells such as macrophages to eliminate pathogen in the body. Treg cells function to suppress the activity of the immune system of other lymphocytes so that the immunological reaction does not occur excessively.

1. Introduction

Pathogens enter and thrive in the body by several mechanisms. Most bacteria live and thrive in the intercellular space or travel with the bloodstream, although some can live inside human cells. Unlike bacteria, viruses must live inside their host cells, so these pathogens can mostly be found inside cells. The humoral immune system does have a great ability to reach parts of the body such as plasma and intercellular spaces. However, antibodies produced by plasma cells (the mature form of B cells) cannot reach pathogens living inside cells. So, the body needs a defense system that is able to attack pathogens that live inside cells such as viruses, bacteria, parasites, and other foreign bodies that will damage the body’s cells [1, 2].

The cellular immune system is an immune system that works by eliminating pathogenic and non-pathogenic cells that live inside the body’s cells. This immune system is so named because the effectors are cells and not immunoglobulins. Cells that become the effectors of this cellular immune system are played by T cells that come from the lymphoid organs to produce lymphocytes [3].

T cells kill cells infected by the virus directly. This is done by activating the caspase enzyme. This enzyme can cause the activation of nuclease enzymes that will eventually cut the DNA of the virus and its host cell. In order to kill the cell first, the T-cell needs to recognize the cell. This recognition process occurs because the cell infected with the virus will secrete antigens derived from the virus on the surface of the cell. This recognition process occurs because the cell infected with the virus will produce antigens derived from the virus [3].

T cells are designated based on the type of receptor found on the surface of T cells called CD (cluster of differentiation), which is divided into two types, namely, CD8 cells and CD4 cells. The basis of this naming is the protein found on their surface. CD8 cells have CD8 protein on their surface, and CD4 cells have CD4 protein on their surface. These two proteins provide guidance on the relationship between T cells and other cells. This is important because these markers will determine the direction of the cell’s function. CD8 cells have the ability to kill cells directly or often referred to as cytotoxic (Tc) T cells, while CD4 cells have the ability to activate cells they recognize and are commonly referred to as T-helper cells (Th) [4].

When leaving the thymus as naïve lymphocytes, CD8 and CD4 cells are actually already set to become such cells when activated; however, CD4 cells can still differentiate further into several types of T-helper cells, namely, T-helper1 (Th1) and T-helper2 (Th2). Although they both function to eliminate pathogens, these two types of cells work in different ways. Th1 works by controlling the bacteria living inside the cell by inducing the action of macrophages. Th1 also induces the production of antibodies by B cells. Th2 cells, on the other hand, work to activate naïve B cells to become antibody-producing B cells (Figure 1) [2, 5, 6].

Figure 1.

Mechanisms of cellular immune response [2].

To function properly, especially in their interactions with other cells, T cells require the role of major histocompatibility complex (MHC) molecules. MHC is a protein on the cell surface that serves to present antigens to the receptors of T cells. This protein obtains antigens from processing that occurs first in cellular organelles. Based on how T cells recognize antigens, MHC is divided into two classes, namely, MHC class I and MHC class II. These two MHCs differ based on the source of the antigen obtained and the target of the type of cell that receives the protein. MHC-I receives antigen peptides or proteins found in the cytosol. As the source of these fragments comes from the cytosol, these proteins are able to present antigens from viruses. Meanwhile, MHC-II presents peptides obtained from cell vesicles, which are usually fragments of pathogens trapped in vesicles and degraded during phagocytosis [1, 7, 8].

Beyond the source of antigen acquisition, MHC also differs from its target cells. MHC-I targets CD8 cells, while MHC-II targets CD4 cells. Therefore, the presence of MHC-I makes it easier for CD8 cells to recognize virus-infected body cells because MHC-I is able to take peptides from the cytosol. Given the role of MHC in the antigen recognition process, this protein is often referred to as a coreceptor (Figures 2 and 3).

Figure 2.

T-cell receptor antibody that binds to antigen [1].

Figure 3.

T-cell receptors bind to antigens that are already complexed with MHC molecules [1].

1.1 MHC class I

MHC class I molecules will bind to endogenous peptides (short-chain proteins), which are peptides degraded by intracellular pathogens such as viruses by proteosomes in cells. These peptides are about 8–10 amino acids long (Figure 4). This peptide – MHC-T-cell receptors (TCR) complex – will then be recognized by the T-cell receptor and then bound. In addition, the peptide – MHC-TCR complex – will also be recognized by CD8 of cytotoxic T-lymphocyte (CTL) cells. This CD8 cell acts as a coreceptor (Figure 5). This MHC class I molecule is found on all nucleated cells. To make it easier, you can see the following caricature, which shows how foreign antigens can be degraded in the cell until they can be introduced to cytotoxic T cells through MHC class I (Figure 6).

Figure 4.

Mechanism of CD4 molecule loss in HIV disease infection [9, 10].

Figure 5.

A Simple Illustration of MHC I Antigen Presentation Antigens are degraded by the proteasome to yield peptide fragments. These peptides are then translocated from the cytosol into the endoplasmic reticulum (ER) lumen where MHC I in waiting for peptides is retained by a series of chaperones including a dedicated chaperone tapasin in the peptide-loading complex. A second dedicated chaperone (TAPBPR) can further optimize the peptides in MHC I. Only MHC I with optimal peptides is allowed to leave the ER to present the peptide fragments at the cell surface to CD8+ T cells (1) [11].

Figure 6.

MHC class I process [7].

1.2 MHC class II

MHC class II molecules have characteristics that are slightly different from MHC class I. MHC class II molecules will bind to exogenous peptides, meaning that these peptides are peptides that come from pathogens from outside the cell such as bacteria. These pathogens will then be degraded by proteases in the cell to produce peptides that can then bind to MHC class II. The length of the peptide that can bind to MHC class II is 13 amino acids or more. The peptide – MHC-TCR complex – is then recognized by T-cell receptors and CD4 on T-helper lymphocyte cells as coreceptors (Figure 7). This is what distinguishes between MHC class I and class II. If MHC class I can bind to CD8, then MHC class II can bind to CD4. So, the cells that bind to MHC classes I and II are also different. MHC class I can bind to cytotoxic T cells, while MHC class II can bind to T-helper lymphocyte cells. In addition, there are other differences, namely, MHC class II molecules are found in APC cells such as dendritic cells and macrophages.

To facilitate your understanding of the process of antigen recognition through MHC class II, consider the following illustration (Figures 7–9).

Figure 7.

A Simple Illustration of MHC II Antigen Presentation MHC II proteins are made in the ER where they pair with a third chain, the invariant chain or Ii. Ii fills (through a peptide sequence called CLIP) the MHC II peptide-binding groove and allows efficient exit of MHC II from the ER. Ii also guides MHC II through the cells to a late endosomal compartment, MIIC. Ii is degraded by endosomal proteases, as are antigens taken up by endocytosis or phagocytosis. The CLIP segment is protected from destruction and exchanged for an antigenic peptide with the help of a dedicated chaperone called DM (HLA-DM in human). Another chaperone expressed in a few immune cell types (immature B cells, some DC forms). called DO (HLA-DO) can compete for DM binding to MHC II and thereby affect the peptide repertoire on MHC II that is ultimately presented at the cell surface to CD4+ T cells [11].

Figure 8.

MHC class I molecules [7].

Figure 9.

MHC class II molecules [7].

Figure 9 describes how the source of the peptides that affect the binding to the MHC molecule. Endogenous peptides are the result of degradation from endogenous antigens or endogenous pathogens such as viruses that can bind to class I MHC. Meanwhile, exogenous antigens or exogenous pathogens will be degraded by proteases in cells into peptides and can bind to MHC class II.

2. T-cell mechanisms in human immunodeficiencyb virus (HIV)

HIV infection causes disruption of natural and acquired immune system function. The most obvious disruption is to cellular immunity, and it is carried out through various mechanisms, namely, direct and indirect cytopathic effects. The most important cause of CD4+ T-cell deficiency in HIV patients is the direct cytopathic effect. Some of the direct cytopathic effects of HIV on CD4+ T cells include (Figure 10):

1. In HIV virus production, gp41 expression occurs in the plasma membrane and the budding of virus particles, which causes an increase in plasma membrane permeability and the entry of large amounts of calcium that will induce apoptosis or osmotic lysis due to water entry. Virus production can interfere with protein synthesis and expression in cells, causing cell death.

2. Free viral DNA in the cytoplasm and large amounts of viral RNA are toxic to the cell.

3. The plasma membrane of HIV-infected T cells will merge with uninfected CD4+ T cells through the gp120-CD4 interaction and will form multinucleated giant cells or syncytia. This process leads to the death of the merged T cells. This phenomenon has been studied in vitro, and syncytia is rarely found in AIDS patients.

Figure 10.

HIV infection [9].

HIV initially infects T cells and macrophages directly or is carried to them by Langerhans cells. Viral replication in regional lymphatic nodes will lead to viremia and widespread spread to lymph tissues. Viremia is controlled by the host immune response, and the patient enters the latent clinical phase. In this phase, there is control of viral replication, but viral replication in T cells and macrophages will continue to occur. There is then a gradual decline in CD4 T cells due to productive infection. Finally, the patient develops clinical symptoms (AIDS stage).

Besides direct cytopathic effects, there are several indirect mechanisms that result in impaired T-cell number and function, including:

1. Non-HIV-infected cells are chronically activated by other infections that affect HIV patients and by cytokines formed in these other infections. This activation is followed by apoptosis, which is called activation-induced cell death. This mechanism explains the death of T cells that far exceeds HIV-infected cells.

2. HIV-specific cytotoxic T cells are present in many AIDS patients. These cells can kill HIV-infected CD4+ T cells.

3. Antibodies to HIV envelope proteins can bind to infected CD4+ T cells and cause antibody-dependent cell-mediated cytotoxicity (ADCC).

4. Attachment of gp120 to newly synthesized intracellular CD4 will interfere with protein processing in the endoplasmic reticulum and inhibit CD4 expression on the cell surface, making it unable to respond to antigen stimulation.

5. Impaired maturation of CD4+ T cells in the thymus. The importance of these indirect mechanisms to the lack of CD4+ T cells in HIV patients remains unclear and controversial.

Immune system disorders in HIV patients can be detected even before a significant CD4+ T-cell deficiency occurs. These disorders include decreased memory T-cell responses to antigens, decreased cytotoxic T-cell responses to viral infections, and weak humoral immune responses to antigens, even though total IgE levels may be elevated. Dysregulation of cytokine production in HIV infection will also result in CD4 T-cell activation tending toward H2 cell activation, that is, activation of humoral immunity (B cells) [12, 13].

3. T-cell mechanism in hepatitis disease

The T-cell mechanism in response to hepatitis disease involves a complex series of stages involving the identification, activation, and effective role of T cells in overcoming hepatitis virus infection in liver cells. Here is a more detailed explanation of the T-cell mechanism in hepatitis disease:

3.1 Antigen recognition

During hepatitis infection, the virus enters the liver cells and begins to multiply. The hepatitis virus enters the liver cells in different ways depending on the type of virus. For example, hepatitis B and hepatitis D enter liver cells through incorporation with specific receptors on the cell surface, while hepatitis C enters liver cells through a mechanism involving various proteins and complex interactions.

Infected liver cells process and present viral antigen fragments on their surface through major histocompatibility complex (MHC) class I molecules. MHC class I is a molecule located on the cell surface of all cells of the human body, including liver cells. The main function of MHC class I is to present intracellular antigen fragments to CD8+ T cells (cytotoxic cells). MHC class I molecules consist of alpha chains and beta chains of microglobulin and have a binding pocket on their surface that can carry antigen fragments (Figure 11).

Figure 11.

MHC [14].

3.2 Activation CD8+ T cells

CD8+ T cells, also known as cytotoxic T cells, have receptors that can bind to viral antigens presented by MHC class I on infected liver cells and are important in the immune response mechanism against hepatitis virus infection. CD8+ T cells are a group of T cells that have the ability to recognize and respond to cells infected by viruses, including hepatitis virus-infected liver cells. This recognition process triggers the activation of CD8+ T cells. After CD8+ T cells successfully bind to viral antigens on target cells, CD8+ T cells become activated [12].

3.3 Proliferation of T cells

Activated CD8+ T cells undergo proliferation, which is cell division to increase the number of hepatitis virus-specific T cells. Proliferation is the process of cell division, where activated CD8+ T cells undergo division to form more identical CD8+ T cells. This division increases the total number of CD8+ T cells in the immune system, increasing the capacity of the immune system to respond to and control hepatitis infection. The main goal of CD8+ T-cell proliferation is to increase the army of T cells that can target and respond to hepatitis virus-infected liver cells. CD8+ T-cell proliferation not only occurs during the acute phase of infection but can also lead to the formation of immune memory cells. These memory cells can persist for a long period of time and provide faster and stronger protection if the individual is re-exposed to the hepatitis virus in the future.

3.4 Differentiation into effector cells

The majority of CD8+ T cells that develop become effector cells, which have an active role in fighting infection. They are able to identify and target liver cells infected with the hepatitis virus. Effector cells serve as the immune system’s “fighting force”, ready to respond to and destroy infected cells. CD8+ T-effector cells produce cytotoxic substances, such as perforin and granzyme, which can damage infected liver cells. CD8+ T-effector cells in the immune response to hepatitis infection produce cytotoxic substances, such as perforin and granzyme, which play an important role in fighting virus-infected liver cells. Perforin functions to form a pore on the membrane of target cells, particularly infected liver cells, allowing cytotoxic substances such as granzymes to easily enter the cell. Granzymes, as serine protease enzymes, play a key role in damaging the internal structure of target cells and triggering the apoptotic pathway, a highly regulated cell death program mechanism. This apoptotic process helps eliminate hepatitis virus-infected liver cells without causing excessive inflammation. CD8+ T-effector cells not only directly damage infected liver cells but also help control virus replication, limit virus production in the body, and prevent the spread of infection to healthy liver cells.

3.5 Migration to area of infection

Effector T cells travel to the area of infection in the liver through the bloodstream to seek out and recognize infected liver cells. Once activated by antigens, effector T cells migrate from the initial activation site, such as the lymph nodes, to the liver via the bloodstream. This migration process allows effector T cells to seek out and recognize liver cells infected with the hepatitis virus. During the journey and upon arrival at the area of infection, effector T cells interact with the infected liver cells using their specific receptors, reactivating them and preparing themselves to mount a cytotoxic response. This activation involves the release of cytotoxic substances, such as perforin and granzyme, which play a role in damaging and destroying the infected liver cells. Thus, effector T cells, with their migratory capabilities and cytotoxic responses, ensure that hepatitis virus infection is efficiently controlled at the local level, helping to protect the integrity and health of the liver organ, as well as minimizing the damage that may result from the infection.

3.6 Infected cell recognition and destruction

CD8+ T cells recognize viral antigens on the surface of infected liver cells and release cytotoxic substances to damage the cells. T-cell cytotoxicity contributes to the elimination of infected liver cells, helps control viral replication, and reduces viral load in the body.

3.7 Regulation by CD4+ T cells

T-helper-mediated CD4+ T cells play an important role in the T-cell response in hepatitis. Helper T cells help regulate the activation and function of CD8+ T cells to kill hepatitis viruses and contribute to activating B cells to produce antibodies.

4. T-cell mechanisms in COVID-19 disease

COVID-19 is a disease caused by infection with the SARS-CoV-2 virus. The virus infects human cells through the angiotensin-converting enzyme 2 (ACE2) receptor. After entering the cell, the virus will use its genetic material to replicate itself. This replication process can cause cell and tissue damage, which can lead to various symptoms of COVID-19 disease.

The human immune system has two main lines of defense against viral infections: the natural immune system and the adaptive immune system. The natural immune system consists of cells and molecules that work nonspecifically against a wide range of pathogens. The adaptive immune system, on the other hand, consists of cells and molecules that work specifically against certain pathogens. One important component of the adaptive immune system is T cells. T cells are lymphocytes that play a role in recognizing and fighting specific pathogens. T cells can be divided into two main types: helper T cells and cytotoxic T cells.

T-helper cells play a role in activating and inducing various other components of the adaptive immune system. Helper T cells express T-cell receptors (TCRs) that are specific to MHC class II molecules. MHC class II molecules are molecules expressed by virus-infected cells. When T-helper cells bind to MHC class II molecules, they secrete cytokines, which are proteins that activate other components of the immune system. Cytokines secreted by T-helper cells can activate B cells to produce antibodies, activate dendritic cells to present antigens to cytotoxic T cells and induce cytotoxic T cells to kill virus-infected cells.

Cytotoxic T cells play a role in killing virus-infected cells. Cytotoxic T cells express TCRs that are specific to MHC class I molecules. MHC class I molecules are molecules that are expressed by all human cells, including virus-infected cells. When cytotoxic T cells bind to MHC class I molecules, they secrete perforin and granzyme B proteins. Perforin will form pores in the membrane of virus-infected cells, while granzyme B will cause the death of virus-infected cells.

COVID-19, caused by the SARS-CoV-2 virus, has become a serious challenge to global health. An effective immune response is essential in fighting this viral infection. T-cell mechanisms, especially CD4+ T cells and CD8+ T cells, play a crucial role in coordinating and executing the immune response to COVID-19 infection (Figure 12).

Figure 12.

Innate and adaptive immune system [15].

4.1 T-cell activation in response to Covid

The coronavirus enters human cells through ACE2 receptors on the cell surface. Upon entry, the virus begins to replicate and stimulate an immune response. CD4+ T cells detect viral antigens that are processed by antigen-presenting cells and activated to stimulate CD8+ T cells and B cells. CD8+ T cells then target infected cells, causing their death and stopping viral replication.

4.2 T-cell CD4+ dynamic

CD4+ T cells have a key role in the immune response to SARS-CoV-2. They provide assistance to CD8+ T cells and B cells. Type T-helper 1 (Th1) stimulates CD8+ T cells and macrophages, while type T-helper 2 (Th2) facilitates antibody responses. The role of Th17 has also been found to be important in the coordination of immune responses and regulation of inflammation.

4.3 CD8+ T cells and cytotoxic effectors

CD8+ T cells have the ability to recognize and destroy virus-infected cells. They do this through the release of cytokines and cytotoxic enzymes, which damage the target cell membrane and trigger apoptosis. CD8+ T cells also form immune memory, allowing the immune system to respond more quickly in case of recurrent infections.

5. Conclusions

T cells are part of the specific immune system that can kill cells infected by viruses. T cells are divided into two based on the type of receptor, which are CD4 and CD8. The process of recognizing antigens that will be eliminated by T cells through two classes, namely, MHC-I and MHC-II.

Acknowledgments

The authors would like to thank the Director and Head of the Center for Research and Community Service at Poltekkes Kemenkes Medan.

Conflict of interest

None of the authors have a conflict of interest in the book chapters.

Appendices

Antibody: immunoglobulin protein secreted by antigen-fixated B cells.

Antigen-presenting cells: cells that have the ability to process antigens and present a piece of peptide on their cell surface. They also convey co-stimulatory molecules and trigger the activation of previously naïve T cells.

Antigens: antigens are molecules that can induce an immune response from the host organism. Antigens are substances that can cause the immune system to produce antibodies. These antibodies produced have a specific match with the antigen molecule and form the basis of the adaptive immune system.

B cells: B cells or B lymphocytes are one of the two important cell types in the adaptive immune system. Activated B cells then form plasma cells that have the ability to produce specific antibodies. Therefore, B cells play an important role in the humoral immune response.

Complement: complement is a plasma protein that works to attack pathogens that enter the body. The complement system can work alone or work together with other immune system components.

Coronavirus disease 2019 or COVID-19: the disease is caused by coronavirus, a virus that can cause infections in the respiratory tract ranging from mild to moderate to severe symptoms. This disease is zoonotic or transmitted between animals and humans.

Cytokines: small proteins involved in cellular signaling. The release of these signals can affect the behavior of surrounding cells as well as target cells that are located far away. Cytokines can act as autocrine, paracrine, or endocrine. For the immune system – the human body, cytokines play an important role as they are associated with cell-to-cell interactions in the immune system.

Hepatitis: a disease in which the liver tissue undergoes an inflammatory or necrotizing process caused by viral infections, drugs, toxins, metabolic disorders, or antibody system abnormalities.

HIV (Human immunodeficiency virus): RNA virus that belongs to the family Retroviridae, sub-family Lentivirinae. This virus is the cause of AIDS (Acquired immunodeficiency syndrome), which can cause a complete decrease in the body’s immune system.

Interferon-gamma (IFN-γ): interferon-gamma is a cytokine that is a member of class II interferons. This cytokine is important for adaptive and acquired immunity. IFN-γ can activate macrophages and induce MHC class II expression. This cytokine is produced by natural killer cells, T cells, and cytotoxic T cells.

Lymphocytes: lymphocytes are components of white blood cells that have antigen receptors on their cell surface. These cells are divided into two types, namely, B lymphocytes (B cells) and T lymphocytes (T cells).

Macrophages: macrophages are large phagocytic cells that have an important role in the process of eliminating pathogenic microorganisms as well as a series in the immune system. Macrophages have the ability to recognize a variety of pathogens because they have surface receptors that can recognize a variety of microorganisms. Macrophages also act as antigen-presenting cells or cells in charge of conveying antigens to stimulate the adaptive immune system.

Major histocompatibility complex (MHC): MHC is a glycoprotein produced by a series of genes on the human chromosome. MHC functions to convey antigens to the cells of the adaptive immune system. MHC consists of two types, namely, MHC-I and MHC-II. MHC-I conveys antigens from the cytosol to CD8 T cells, while MHC-II conveys antigens from intracellular vesicles to CD4 T cells.

Mast cells: these are important for healing wounds and defense against infections.

Memory: once our body encounters a pathogen, it activates the immune system to destroy it. It also remembers what antibodies were released in response to the pathogen, so that the next time it enters, a similar procedure is followed by the body to eliminate it.

Phagocytes: These circulate through the body and look for any foreign substance. They engulf and destroy it, defending the body against that pathogen.

T cells: T cells are lymphocyte cells that develop in the thymus tissue and have the CD3 protein on their cell surface. T cells have several roles such as interacting with other cells involved in the immune system (CD4) or directly eliminating pathogenic microbes (CD8).

T-cytotoxic (Tc) cells: they play a role in destroying infected or mutated cells, helping fight infections and cancer.

T-helper (Th) cells: they are responsible for coordinating the body’s immune response by assisting in the activation of other immune cells.

T-helper 1 or Th1 cells: they are part of CD4 cells that function to activate macrophages. These cells are often referred to as inflammatory CD4 T cells.

T-helper 2 or Th2 cells: they are cells that are known to stimulate B cells to produce antibodies.