T-cell Activation

1. T Cell-Mediated Immune Responses

key concept

The primary cells that control the adaptive immune response are the lymphocytes, the T and B cells. T cells are particularly important, as they not only control a multitude of immune responses directly but also control B cell immune responses in many cases as well. Thus, many of the decisions about how to attack a pathogen are made at the T cell level, and knowledge of their functional types is crucial to understanding the functioning and regulation of adaptive immune responses as a whole.

T lymphocytes recognize antigens based on a two-chain protein receptor. The most common and important of these are the alpha-beta T cell receptors.

There are two chains in the T cell receptor, and each chain consists of two domains.

1. The variable region domain is farthest away from the T cell membrane and is so named because its amino acid sequence varies between receptors.
2. In contrast, the constant region domain has less variation.

The differences in the amino acid sequences of the variable domains are the molecular basis of the diversity of antigens the receptor can recognize. Thus, the antigen-binding site of the receptor consists of the terminal ends of both receptor chains, and the amino acid sequences of those two areas combine to determine its antigenic specificity. Each T cell produces only one type of receptor and thus is specific for a single particular antigen.

term to know

T Cell Receptor

The two-chain protein receptor that recognizes antigens and is found on the surface of a T lymphocyte.

2. Mechanisms of T Cell-Mediated Immune Responses

Mature T cells become activated by recognizing processed foreign antigen in association with a self-major histocompatibility complex (MHC) molecule and begin dividing rapidly by mitosis. This proliferation of T cells is called clonal expansion and is necessary to make the immune response strong enough to effectively control a pathogen.

think about it

How does the body select only those T cells that are needed against a specific pathogen?

Again, the specificity of a T cell is based on the amino acid sequence and the three-dimensional shape of the antigen-binding site formed by the variable regions of the two chains of the T cell receptor. Clonal selection is the process of antigen binding only to those T cells that have receptors specific to that antigen. Each T cell that is activated has a specific receptor “hard-wired” into its DNA, and all of its progeny will have identical DNA and T cell receptors, forming clones of the original T cell.

2a. Clonal Selection and Expansion

The clonal selection theory was proposed by Frank Burnet in the 1950s. However, the term clonal selection is not a complete description of the theory, as clonal expansion goes hand in glove with the selection process. The main tenet of the theory is that a typical individual has a multitude (10¹¹) of different types of T cell clones based on their receptors. In this context, a clone is a group of lymphocytes that share the same antigen receptor. Each clone is present in the body in low numbers. Otherwise, the body would not have room for lymphocytes with so many specificities.

Only those clones of lymphocytes whose receptors are activated by the antigen are stimulated to proliferate. Keep in mind that most antigens have multiple antigenic determinants, so a T cell response to a typical antigen involves a polyclonal response. A polyclonal response is the stimulation of multiple T cell clones. Once activated, the selected clones increase in number and make many copies of each cell type, each clone with its unique receptor. By the time this process is complete, the body will have large numbers of specific lymphocytes available to fight the infection (see the image above).

2b. The Cellular Basis of Immunological Memory

As already discussed, one of the major features of an adaptive immune response is the development of immunological memory.

During a primary adaptive immune response, both memory T cells and effector T cells are generated. Memory T cells are long-lived and can even persist for a lifetime. Memory cells are primed to act rapidly. Thus, any subsequent exposure to the pathogen will elicit a very rapid T cell response. This rapid, secondary adaptive response generates large numbers of effector T cells so fast that the pathogen is often overwhelmed before it can cause any symptoms of disease. This is what is meant by immunity to a disease. The same pattern of primary and secondary immune responses occurs in B cells and the antibody response, as will be discussed in a later lesson.

terms to know

Clonal Expansion

Growth of a clone of selected lymphocytes.

Clonal Selection

Stimulating growth of lymphocytes that have specific receptors.

Clone

A group of lymphocytes sharing the same antigen receptor.

Antigen Receptor

A two-chain receptor by which lymphocytes recognize antigen.

Polyclonal Response

Response by multiple clones to a complex antigen with many determinants.

Memory T Cell

A long-lived immune cell reserved for future exposure to a pathogen.

3. T Cell Types and their Functions

In the discussion of T cell development, you saw that mature T cells express either the CD4 marker or the CD8 marker, but not both. These markers are cell adhesion molecules that keep the T cell in close contact with the antigen-presenting cell by directly binding to the MHC molecule (to a different part of the molecule than does the antigen). Thus, T cells and antigen-presenting cells are held together in two ways: by CD4 or CD8 attaching to MHC and by the T cell receptor binding to antigen.

Although the correlation is not 100%, CD4-bearing T cells are associated with helper functions and CD8-bearing T cells are associated with cytotoxicity. These functional distinctions based on CD4 and CD8 markers are useful in defining the function of each type.

3a. Helper T Cells and their Cytokines

Helper T cells (Th), bearing the CD4 molecule, function by secreting cytokines that act to enhance other immune responses. There are two classes of Th cells, and they act on different components of the immune response. These cells are not distinguished by their surface molecules but by the characteristic set of cytokines they secrete.

Th1 cells are a type of helper T cell that secretes cytokines that regulate the immunological activity and development of a variety of cells, including macrophages and other types of T cells.

Th2 cells, on the other hand, are cytokine-secreting cells that act on B cells to drive their differentiation into plasma cells that make antibodies. In fact, T cell help is required for antibody responses to most protein antigens, and these are called T cell-dependent antigens.

3b. Cytotoxic T cells

Cytotoxic T cells (Tc) are T cells that kill target cells by inducing apoptosis using the same mechanism as natural killer (NK) cells. They either express Fas ligand, which binds to the Fas molecule on the target cell, or acts by using perforins and granzymes contained in their cytoplasmic granules. As was discussed previously with natural killer cells, killing a virally infected cell before the virus can complete its replication cycle results in the production of no infectious particles. As more Tc cells are developed during an immune response, they overwhelm the ability of the virus to cause disease. In addition, each Tc cell can kill more than one target cell, making them especially effective. Tc cells are so important in the antiviral immune response that some speculate that this was the main reason the adaptive immune response evolved in the first place.

3c. Regulatory T Cells

Regulatory T cells (Treg), or suppressor T cells, are the most recently discovered of the types listed here, so less is understood about them. In addition to CD4, they bear the molecules CD25 and FOXP3. Exactly how they function is still under investigation, but it is known that they suppress other T cell immune responses. This is an important feature of the immune response because if clonal expansion during immune responses were allowed to continue uncontrolled, these responses could lead to autoimmune diseases and other medical issues.

Not only do T cells directly destroy pathogens, but they regulate nearly all other types of the adaptive immune response as well, as evidenced by the functions of the T cell types, their surface markers, the cells they work on, and the types of pathogens they work against, which are shown in the table below.

terms to know

Helper T cells (Th)

T cells that secrete cytokines to enhance other immune responses, involved in activation of both B and T cell lymphocytes.

Th1 cells

Cells that secrete cytokines that enhance the activity of macrophages and other cells.

Th2 cells

Cells that secrete cytokines that induce B cells to differentiate into antibody-secreting plasma cells.

Cytotoxic T cells (Tc)

T lymphocytes with the ability to induce apoptosis in target cells.

Regulatory T cells (Treg)

(also, suppressor T cells) The class of CD4 T cells that regulates other T cell responses.