Review of Medical Microbiology and Immunology, 13th Edition

61. Cell-Mediated Immunity

CHAPTER CONTENTS

Introduction

Tests for Evaluation of Cell-Mediated Immunity

In Vivo Tests for Lymphoid Cell Competence (Skin Tests)

In Vitro Tests for Lymphoid Cell Competence

Role of Adjuvants & Lipids in Establishing Cell-Mediated Reactivity

Self-Assessment Questions

Practice Questions: USMLE & Course Examinations

INTRODUCTION

Although humoral (antibody-mediated) immunity is an important host defense against many bacterial and viral diseases, in many other bacterial infections (especially intracellular infections such as tuberculosis) and viral infections, it is primarily the cell-mediated arm that imparts resistance and aids in recovery. Furthermore, cell-mediated immunity is important in defense against fungi, parasites, and cancers. It is also the main mechanism involved in the rejection of organ transplants. The strongest evidence for the importance of cell-mediated immunity comes from clinical situations in which its suppression (by immunosuppressive drugs or disease, e.g., acquired immunodeficiency syndrome [AIDS]) results in overwhelming infections or tumors.

The constituents of the cell-mediated immune system include several cell types: (1) macrophages, which present the antigen to T cells; (2) helper T cells, which participate in antigen recognition and in regulation (helper and suppressor) functions (see Chapter 58); (3) natural killer (NK) cells, which can inactivate pathogens; and (4) cytotoxic T cells, which can kill virus-infected cells with or without antibody. Macrophages and helper T cells produce cytokines that activate helper and cytotoxic T cells, leading to the killing of the pathogen or tumor cell.

Infection with some viruses, namely, measles virus and cytomegalovirus, can suppress cell-mediated immunity against other microorganisms. In particular, measles virus infection in people infected with Mycobacterium tuberculosis can result in a loss of purified protein derivative (PPD) skin test reactivity, reactivation of dormant organisms, and clinical disease. A proposed explanation for these findings is that when measles virus binds to its receptor on the surface of human macrophages, the production of interleukin-12 (IL-12) by the macrophages, which is necessary for cell-mediated immunity to occur, is suppressed.

The terms primary and secondary response are associated primarily with antibody formation as described in Chapter 60, but the timing of the T-cell response also follows the same pattern. After the initial exposure to the antigen, the specific T cell proliferates to form a small clone of cells (i.e., a primary response occurs). Then, on subsequent exposure to the antigen, the small clone expands, and many more specific T cells are formed. These cells constitute the secondary response.

Although the interactions between various cells and various cytokines are complex, the result is relatively simple: In the person with competent cellular immunity, opportunistic pathogens rarely or never cause disease, and the spread of other agents—for example, certain viruses (e.g., herpesviruses) or tumors (e.g., Kaposi’s sarcoma)—is limited. The assessment of the competence of cell-mediated immunity is therefore important.

TESTS FOR EVALUATION OF CELL-MEDIATED IMMUNITY

Evaluation of the immunocompetence of persons depends either on the demonstration of delayed-type hypersensitivity to commonly present antigens (equating the ability to respond with the competence of cell-mediated immunity) or on laboratory assessments of T cells.

In Vivo Tests for Lymphoid Cell Competence (Skin Tests)

Skin Tests for the Presence of Delayed-Type Hypersensitivity

Most normal persons respond with delayed-type reactions to skin test antigens of Candida and other antigens because of past exposure to these antigens. Absence of reactions to several of these skin tests suggests impairment of cell-mediated immunity.

Skin Tests for the Ability to Develop Delayed-Type Hypersensitivity

Most normal persons readily develop reactivity to simple chemicals (e.g., dinitrochlorobenzene [DNCB]) applied to their skin in lipid solvents. When the same chemical is applied to the same area 7 to 14 days later, they respond with a delayed-type skin reaction. Immunocompromised persons with incompetent cell-mediated immunity fail to develop such delayed-type hypersensitivity.

In Vitro Tests for Lymphoid Cell Competence

Lymphocyte Blast Transformation

When sensitized T lymphocytes are exposed to the specific antigen, they transform into large blast cells with greatly increased DNA synthesis, as measured by incorporation of tritiated thymidine. This specific effect involves relatively few cells. A larger number of T cells undergo nonspecific blast transformation when exposed to certain mitogens. The mitogens phytohemagglutinin and concanavalin A are plant extracts that stimulate T cells specifically. (Bacterial endotoxin, a lipopolysaccharide, stimulates B cells specifically.)

Macrophage Migration Inhibitory Factor

Macrophage migration inhibitory factor is elaborated by cultured T cells when exposed to the antigen to which they are sensitized. Its effect can be measured by observing the reduced migration of macrophages in the presence of the factor compared with the level in controls.

Enumeration of T Cells, B Cells, and Subpopulations

The number of each type of cell can be counted by use of a machine called a fluorescence-activated cell sorter (FACS) (see Chapter 64). In this approach, cells are labeled with monoclonal antibody tagged with a fluorescent dye, such as fluorescein or rhodamine. Single cells are passed through a laser light beam, and the number of cells that fluoresce is registered.

B cells (and plasma cells) making different classes of antibodies can be detected by using monoclonal antibodies against the various heavy chains. The total number of B cells can be counted by using fluorescein-labeled antibody against all immunoglobulin classes. Specific monoclonal antibodies directed against T-cell markers permit the enumeration of T-cells, CD4 helper cells, CD8 suppressor cells, and others. The normal ratio of CD4 to CD8 cells is 1.5 or greater, whereas in some immunodeficiencies (e.g., AIDS), it is less than 1.

ROLE OF ADJUVANTS & LIPIDS IN ESTABLISHING CELL-MEDIATED REACTIVITY

Weak antigens or simple chemicals tend not to elicit cell-mediated hypersensitivity when administered alone, but they do so when given as a mixture with an adjuvant. The roles of the adjuvant are to enhance the uptake of the antigen by antigen-presenting cells (e.g., macrophages), to stimulate the expression of costimulators, such as B7, and to enhance the production of cytokines, such as IL-12, that promote the development of Th-1 cells. A common experimental adjuvant is a mixture of mineral oil, lanolin, and killed mycobacteria (Freund’s adjuvant), which stimulates the formation of local granulomas. It is prohibited for human use.

SELF-ASSESSMENT QUESTIONS

1. Cell-mediated immunity is the main host defense against which one of the following organisms?

(A) Escherichia coli

(B) Mycobacterium tuberculosis

(C) Pseudomonas aeruginosa

(D) Staphylococcus aureus

(E) Streptococcus pneumoniae

2. Infection by which one of the following sets of viruses causes a reduction in cell-mediated immunity?

(A) Hepatitis A virus and hepatitis C virus

(B) Herpes simplex virus type 1 and rotavirus

(C) Influenza virus and respiratory syncytial virus

(D) Measles virus and cytomegalovirus

(E) Parvovirus B19 and rubella virus

ANSWERS

1. (B)

2. (D)

PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS

Questions on the topics discussed in this chapter can be found in the Immunology section of PART XIII: USMLE (National Board) Practice Questions starting on page 713. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.