Section 21.7: T Lymphocytes - Overview

Learning Objectives

• Describe the process of T-cell maturation and thymic selection
• Explain the genetic events that lead to diversity of T-cell receptors
• Compare and contrast the various classes and subtypes of T cells in terms of activation and function
• Explain the mechanism by which superantigens effect unregulated T-cell activation

As explained in Overview of Specific Adaptive Immunity, the antibodies involved in humoral immunity often bind pathogens and toxins before they can attach to and invade host cells. Thus, humoral immunity is primarily concerned with fighting pathogens in extracellular spaces. However, pathogens that have already gained entry to host cells are largely protected from the humoral antibody-mediated defenses. Cellular immunity, on the other hand, targets and eliminates intracellular pathogens through the actions of T lymphocytes, or T cells (Figure \(\PageIndex{1}\)). T cells also play a more central role in orchestrating the overall adaptive immune response (humoral as well as cellular) along with the cellular defenses of innate immunity.

Figure \(\PageIndex{1}\): This scanning electron micrograph shows a T lymphocyte, which is responsible for the cell-mediated immune response. The spike-like membrane structures increase surface area, allowing for greater interaction with other cell types and their signals. (credit: modification of work by NCI)

T Cell Production and Maturation

T cells, like all other white blood cells involved in innate and adaptive immunity, are formed from multipotent hematopoietic stem cells (HSCs) in the bone marrow (see Figure 17.3.1). However, unlike the white blood cells of innate immunity, eventual T cells differentiate first into lymphoid stem cells that then become small, immature lymphocytes, sometimes called lymphoblasts. The first steps of differentiation occur in the red marrow of bones (Figure \(\PageIndex{2}\)), after which immature T lymphocytes enter the bloodstream and travel to the thymus for the final steps of maturation (Figure \(\PageIndex{3}\)). Once in the thymus, the immature T lymphocytes are referred to as thymocytes.

The maturation of thymocytes within the thymus can be divided into tree critical steps of positive and negative selection, collectively referred to as thymic selection. The first step of thymic selection occurs in the cortex of the thymus and involves the development of a functional T-cell receptor (TCR) that is required for activation by APCs. Thymocytes with defective TCRs are removed by negative selection through the induction of apoptosis (programmed controlled cell death). The second step of thymic selection also occurs in the cortex and involves the positive selection of thymocytes that will interact appropriately with MHC molecules. Thymocytes that can interact appropriately with MHC molecules receive a positive stimulation that moves them further through the process of maturation, whereas thymocytes that do not interact appropriately are not stimulated and are eliminated by apoptosis. The third and final step of thymic selection occurs in both the cortex and medulla and involves negative selection to remove self-reacting thymocytes, those that react to self-antigens, by apoptosis. This final step is sometimes referred to as central tolerance because it prevents self-reacting T cells from reaching the bloodstream and potentially causing autoimmune disease, which occurs when the immune system attacks healthy “self” cells.

Despite central tolerance, some self-reactive T cells generally escape the thymus and enter the peripheral bloodstream. Therefore, a second line of defense called peripheral tolerance is needed to protect against autoimmune disease. Peripheral tolerance involves mechanisms of anergy and inhibition of self-reactive T cells by regulatory T cells. Anergy refers to a state of nonresponsiveness to antigen stimulation. In the case of self-reactive T cells that escape the thymus, lack of an essential co-stimulatory signal required for activation causes anergy and prevents autoimmune activation. Regulatory T cells participate in peripheral tolerance by inhibiting the activation and function of self-reactive T cells and by secreting anti-inflammatory cytokines.

It is not completely understood what events specifically direct maturation of thymocytes into regulatory T cells. Current theories suggest the critical events may occur during the third step of thymic selection, when most self-reactive T cells are eliminated. Regulatory T cells may receive a unique signal that is below the threshold required to target them for negative selection and apoptosis. Consequently, these cells continue to mature and then exit the thymus, armed to inhibit the activation of self-reactive T cells.

It has been estimated that the three steps of thymic selection eliminate 98% of thymocytes. The remaining 2% that exit the thymus migrate through the bloodstream and lymphatic system to sites of secondary lymphoid organs/tissues, such as the lymph nodes, spleen, and tonsils (Figure \(\PageIndex{3}\)), where they await activation through the presentation of specific antigens by APCs. Until they are activated, they are known as mature naïve T cells.

Figure \(\PageIndex{2}\): (a) Red bone marrow can be found in the head of the femur (thighbone) and is also present in the flat bones of the body, such as the ilium and the scapula. (b) Red bone marrow is the site of production and differentiation of many formed elements of blood, including erythrocytes, leukocytes, and platelets. The yellow bone marrow is populated primarily with adipose cells.

Figure \(\PageIndex{3}\): The thymus is a bi-lobed, H-shaped glandular organ that is located just above the heart. It is surrounded by a fibrous capsule of connective tissue. The darkly staining cortex and the lighter staining medulla of individual lobules are clearly visible in the light micrograph of the thymus of a newborn (top right, LM × 100). (credit micrograph: modification of micrograph provided by the Regents of University of Michigan Medical School © 2012)

Exercise \(\PageIndex{1}\)

1. What anatomical sites are involved in T cell production and maturation?
2. What are the three steps involved in thymic selection?
3. Why are central tolerance and peripheral tolerance important? What do they prevent?

Classes of T Cells

T cells can be categorized into three distinct classes: helper T cells, regulatory T cells, and cytotoxic T cells. These classes are differentiated based on their expression of certain surface molecules, their mode of activation, and their functional roles in adaptive immunity (Table \(\PageIndex{1}\)).

All T cells produce cluster of differentiation (CD) molecules, cell surface glycoproteins that can be used to identify and distinguish between the various types of white blood cells. Although T cells can produce a variety of CD molecules, CD4and CD8 are the two most important used for differentiation of the classes. Helper T cells and regulatory T cells are characterized by the expression of CD4 on their surface, whereas cytotoxic T cells are characterized by the expression of CD8.

Classes of T cells can also be distinguished by the specific MHC molecules and APCs with which they interact for activation. Helper T cells and regulatory T cells can only be activated by APCs presenting antigens associated with MHC II. In contrast, cytotoxic T cells recognize antigens presented in association with MHC I, either by APCs or by nucleated cells infected with an intracellular pathogen.

The different classes of T cells also play different functional roles in the immune system. Helper T cells serve as the central orchestrators that help activate and direct functions of humoral and cellular immunity. In addition, helper T cells enhance the pathogen-killing functions of macrophages and NK cells of innate immunity. In contrast, the primary role of regulatory T cells is to prevent undesirable and potentially damaging immune responses. Their role in peripheral tolerance, for example, protects against autoimmune disorders, as discussed earlier. Finally, cytotoxic T cells are the primary effector cells for cellular immunity. They recognize and target cells that have been infected by intracellular pathogens, destroying infected cells along with the pathogens inside.

Table \(\PageIndex{1}\): Classes of T Cells

Class	Surface CD Molecules	Activation	Functions
Helper T cells	CD4	APCs presenting antigens associated with MHC II	Orchestrate humoral and cellular immunity
			Involved in the activation of macrophages and NK cells
Regulatory T cells	CD4	APCs presenting antigens associated with MHC II	Involved in peripheral tolerance and prevention of autoimmune responses
Cytotoxic T cells	CD8	APCs or infected nucleated cells presenting antigens associated with MHC I	Destroy cells infected with intracellular pathogens

Exercise \(\PageIndex{2}\)

1. What are the unique functions of the three classes of T cells?
2. Which T cells can be activated by antigens presented by cells other than APCs?

Key Concepts and Summary

• Immature T lymphocytes are produced in the red bone marrow and travel to the thymus for maturation.
• Thymic selection is a three-step process of negative and positive selection that determines which T cells will mature and exit the thymus into the peripheral bloodstream.
• Central tolerance involves negative selection of self-reactive T cells in the thymus, and peripheral toleranceinvolves anergy and regulatory T cells that prevent self-reactive immune responses and autoimmunity.
• The TCR is similar in structure to immunoglobulins, but less complex. Millions of unique epitope-binding TCRs are encoded through a process of genetic rearrangement of V, D, and J gene segments.
• T cells can be divided into three classes—helper T cells, cytotoxic T cells, and regulatory T cells—based on their expression of CD4 or CD8, the MHC molecules with which they interact for activation, and their respective functions.
• Activated helper T cells differentiate into T_H1, T_H2, T_H17, or memory T cell subtypes. Differentiation is directed by the specific cytokines to which they are exposed. T_H1, T_H2, and T_H17 perform different functions related to stimulation of adaptive and innate immune defenses. Memory T cells are long-lived cells that can respond quickly to secondary exposures.
• Once activated, cytotoxic T cells target and kill cells infected with intracellular pathogens. Killing requires recognition of specific pathogen epitopes presented on the cell surface using MHC I molecules. Killing is mediated by perforin and granzymes that induce apoptosis.
• Superantigens are bacterial or viral proteins that cause a nonspecific activation of helper T cells, leading to an excessive release of cytokines (cytokine storm) and a systemic, potentially fatal inflammatory response.

Footnotes

1. 1 Blaschitz C., Raffatellu M. “Th17 cytokines and the gut mucosal barrier.” J Clin Immunol. 2010 Mar; 30(2):196-203. doi: 10.1007/s10875-010-9368-7.