Topic  15 Cell-Mediated and Humoral Effector Responses

Introduction

In the previous lessons we have learned about various aspects of the humoral and cell-mediated effector responses.  Now we will focus on specific and nonspecific cytotoxic effector mechanisms and the primary and secondary humoral responses.  Each type of the immune response serves a different function and involves different effector mechanisms for generating immunity. 

Antigens entering the body are encountered by both T and B lymphocytes.  Basically there are two ways in which B lymphocytes can take up antigen - nonspecific and specific. In the nonspecific uptake, B lymphocytes behave as antigen-presenting cells. In the specific uptake, the B lymphocytes bind the antigen via its immunoglobulin receptor.  The effector of the humoral branch are secreted antibodies, which can neutralize soluble antigens.  Binding of antibodies to surface antigens on microorganisms can also activate the complement system.

T lymphocytes recognize antigen only when it is presented to them together with MHC molecules on another antigen presenting cell.  The primary effectors in the cell-mediated branch are various effector cells. We discuss the cytotoxic factors that T cells are able to inject into target cells and consider the regulation of this process.  In addition to the actions of cytotoxic cells, the cell-mediated immune responses encompass the activation of macrophages by T cells.  A related cell-mediated effect is the inflammatory reaction known as the delayed hypersensitivity reaction.

Objectives

On completion of this section and the required reading, you should be able to:

n  define and conceptualize immunological tolerance;

n  describe the mechanism of action of Cytotoxic T lymphocytes;

n  outline the mechanisms that induce self tolerance.

Required Reading

Please refer to the textbook key for specific readings for this section.

 

P Key Words

•    antibody dependent cell mediated cytotoxicity (ADCC)

•    antigenic competition

•    clonal anergy

•    clonal deletion

•    delayed type hypersensitivity

•    suppressor T cells

•    tolerogen

•    two receptor model

•    hemolytic plaque assay

•    effector phase

•    granuloma

•    graft-versus-host disease

•    network theory

•    granzymes

•    immunological tolerance

•    perforin

•    primary and secondary humoral response

P Key Concepts

n  The cell mediated branch of the immune system involves three types of antigen-specific effector cells: CD4+TH1 and TH2 and cytotoxic T lymphocytes (CTLs).

n  Cytotoxic effector T cells recognize antigen fragments that have been appropriately processed and presented on a class I MHC molecule.

n  Cytotoxic cells adhere to and destroy target cells by inducing apoptosis through the release of cytotoxic factors such as perforins, granzymes, and lymphotoxins.

n  Nonspecific cytotoxic cells also can kill target cells without having to interact  with antigen-MHC complex. 

n  Effector T cells participate in a characteristic skin inflammatory reaction called the delayed hypersensitivity reaction.  It plays an important role in host defenses against intracellular pathogens

n  The kinetics of antibody formation and other properties of primary and secondary humoral responses differ.       

DID YOU KNOW?

The Role of Fas in Autoimmune Diabetes

During mammalian development, many cells are programmed to die; most mediated by apoptosis.  The Fas antigen is a cell surface protein belonging to the tumor necrosis factor/nerve growth factor receptor family, and it mediated apoptosis.  Cytotoxic T lymphocytes (CTL)-mediated cytotoxicity represents the body’s major defense against virus infected and tumorigenic cells.  It contributes to transplant rejection and autoimmune disease.  During killing, CTL granules are exocytosed, releasing their contents into the intercellular space between, the target cell and the effector.  Perforin facilitates the entry of Cytotoxic cell serine proteases, the granzymes, into the target cell. There they induce apoptotic death by an unknown pathway.

Immunologically privileged sites express Fas ligand (FASL), which protects them from attack by activated T cells that express Fas and die upon contact with FasL.  Both Fas and FasL are expressed by activated T lymphocytes.  Thus when a Fas-expressing activated T cell meets another T cell (or different type of cell) that has FasL on its surface, it undergoes apoptosis.  Tumor cells expressing FasL have been shown to be resistant to T cell attack.

The insulin-dependent diabetes mellitus (IDDM) is a disease afflicting 0.2% of the population.  It is caused by an autoimmune attack on the pancreas.  The attack is directed against specialized insulin-producing cells (beta cells) that are located in spherical clusters, called the isles of Langerhans.  The autoimmune attack destroys the beta cells resulting in decreased production of insulin and consequently increases levels of blood glucose.  T cells have been shown to play a crucial role in the disease.  Although intact normal islets do not express Fas, it is believed that Fas mediated destruction of beta cells is part of the natural diabeogenic process.  In theory, expression of FasL by beta cells might lead to the destruction of activated autoreactive Fas-expressing T cells and thus protect the islets.  Such islets could be used for transplantation into diabetic recipients in order to normalize insulin production. 

Recently experiments were conducted to test the ability of ectopically expressed FasL to interfere with autoimmune destruction of target tissue cells.  The nonbese diabetic (NOD) strain of mice served as a model for human insulin-dependent diabetes mellitus. It was anticipated that expression of Fal by beta cells would lead to destruction of Fas expressing T cells and thus the protection of islets. Surprisingly the transgenic animals constructed to express FasL in pancreatic islets showed higher rates of spontaneous diabetes, and all transgenic animals were more sensitive to diabetogenic T cells than their nontransgenic littermates.    Further studies revealed that beta cells are induced to express Fas by T cells.  This suggested that FasL transgenic beta cells were committing suicide (or fratricide) upon induction of Fas.  The severity of islet’s destruction could be attributed to the induction of Fas on the beta cells.  Fas-dependent cytotoxicity may be elicited both by Cd8 T cells and Th1-type CD4 T cells

A. Chervonsky et al. The Role of Fas in Autoimmune Diabetes., Cell, Vol 89, 17-24, April 4, 1997

A. J. Darmon et al.  Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B., Nature, Vol 377, 5 October, 1995

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 16.  The answers with explanations are available at the end of the textbook.

2.  Multiple Choice Questions

1.  Which of the following is not a characteristic of cell-mediated immunity?

A) The cells originate in bone marrow.

B)  None of these.

C)  Cells are processed in the thymus gland.

D) It can inhibit the immune response.

E)  It includes macrophages

 

 

2.  The T cell response can be suppressed by all of the following except

A) HIV infection.

B)  Immune complex formation.

C)  Anti-transplant-rejection drugs.

D) Certain genes.

E)  Antibodies against CD3.

3.  Tolerance is a

A) failure to make any antibodies

B)  defect in the cell-mediated immune system

C)  method of inducing autoimmunity

D) method of preventing autoimmunity

E)  loss of resistance to infections

4.  Macrophages can be cytotoxic for other target cells as a result of the release of

A) superantigens

B)  perforins

C)  complement

D) immunoglobulins

E)  nitric oxide

3. Definitions/Short Answer Questions.

1.  Briefly discuss the three phases of an immune response. Which phase is most complex and why?

2.  In which phase does antigen have little importance and why?

3.  What distinguishes humoral immunity from cell mediated immunity?

4.  What do we mean by a primary and a secondary immune response?

5.  What characteristics usually distinguish the two responses?

6.  Briefly discuss the antigen elimination curve.

7.  What things affect the shape of the curve and how does this affect antibody production?

8.  Briefly describe the four phases of a primary antibody response.

9.  When comparing the primary and secondary antibody responses, three things change during the secondary antibody response. What are they? Which one do you consider the most important? Why?

10. Early experiments showing the importance of lymphocytes to immunity followed two approaches. What were they? How did they differ? What were some of the initial observations that arose from these two approaches?

11. Describe the carrier effect.

12. How do macrophages contribute to antibody production?

13. How can the mixed lymphocyte reaction and the cytotoxicity reaction be used to explain how T cells help other T cells and which cell provides help and which cell mediates cytotoxicity?

14. Helper T cells can be divided into two subsets based on their lymphokine secretion profile. Explain.

15. As an immune response progresses, it needs to limit itself and decrease in intensity. How does antibody feedback accomplish this?

16. Niels Jerne states that “antibodies recognize” and are “being recognized.” Explain this statement in terms of the network hypothesis.