Topic 11    T cell maturation, activation and differentiation

Introduction

We have learned in the preceding lessons that the first reactions to the infectious agents are nonclonal and nonspecific: the same kind of cells are activated and the same kind of molecules are produced to different stimuli.  Almost simultaneously, however, a clonal and specific response develops.  The specific and clonal responses are dominated by lymphocytes, either T or B or both, although the B cells are usually activated slightly later than T cells.  T lymphocytes recognize antigen only when it is presented to them together with MHC molecules on another, antigen presenting cell.  The maturation of progenitor T cells in the thymus and the activation of mature peripheral T cells are also influenced by the MHC molecules.  In this lessons we will learn about clonal expansion and clonal anergy occurring during T cell activation.  We will also analyze steps of T cell differentiation into various types of effector cells and memory T cells. 

This lesson is similar in nature to Lesson 7, because they both contain a large amount of very detailed information. Don’t let this discourage you. I recommend that you approach this lesson in the same manner that you approached Lesson 4 (topic 7). Although very detailed and complex, this information is organized into a logical flow.  The developmental steps in B-cell “life time” are temporally and spatially separated.  Try to divide the process of B-cell development into smaller parts.  Try to draw an idea map, or a visualizing concept representing the interactions occurring during the particular steps in T-cell activation, maturation or differentiation. Finally you may use multiple, smaller idea maps to construct a final picture, just like you would with a jig- saw puzzle.  I find this method useful because it makes me think about the correct arrangement of interactions. It reinforces the learned material and emphasizes an understanding of it rather than mechanical memorization.   More importantly, very often it makes me notice some connections I might otherwise miss.

Objectives

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

n  outline antigen processing and presentation to TCR;

n  describe the molecular pathways for T cell activation;

n  describe positive and negative selection;

n  discuss the role of accessory molecules in T cell antigen recognition.

Required Reading

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

 

P Key Words

•           accessory molecules,

•           antigen processing,

•           associative recognition model,

•           independent recognition model,

•           cell adhesion molecules,

•           subtractive hybridization

P Key Concepts

n  T cells follow a path in ontogeny (different from B-cells) and pass through the thymus gland, where they acquire specific markers and differentiate into cells with a variety of functions.

n  T cells undergo rearrangement of the genes that encode the two chains that form an antigen - specific receptor.  The T-cell receptor is    on the majority of T cells,    on a small number of T cells.  

n  In addition to the signals mediated by the TCR and its associated accessory molecules, activation of the TH cell requires an additional co-stimulatory signal provided by the antigen presenting cell.

n  The presence or absence of the co-stimulatory signal determines whether activation results in clonal expansion or clonal anergy.

DID YOU KNOW?

Superantigens

“Superantigens” is the term for a group of molecules that have in common an extremely potent stimulatory activity for T lymphocytes of several species.  They stimulate CD4+, CD8+ and gamma  + T cells by a unique mechanism: they cross-link variable parts of the T-cell receptor (TCR) with MHC class II molecules on accessory or target cells.  The interaction site on the class II molecule and on the TCR is different from the peptide binding site; on the TCR it is the variable part of the   chain.  The prototype superantigen the staphylococcal enterotoxin B, member of a family of genetically related proteins produced by Staphylococcus aureus and Streptococcus pyogenes.  These are soluble exotoxins of approximately 27 kd molecular mass.  It is intriguing that this molecular mechanism of T-cell stimulation has been independently produced at least three times in evolution.  In each case the superantigen is produced by an infectious pathogen. Other pathogens producing superantigens are retroviruses and mycoplasma.  Many additional candidate superantigens have been proposed, but in most cases unequivocal evidence for superantigen activity is still missing.  There are several reasons why these molecules have aroused such tremendous interest in recent years.  First, they have provided key information on tolerance mechanisms, both on the deletion of T cells in the thymus and on the induction of peripheral tolerance by anergy and apoptosis.  Second, of all polyclonal T-cell simulators they are the ones that most closely mimic the recognition of specific antigen.  Finally, they have been recognized as important factors in the pathogenicity of the producing pathogens, inducing shock and immunosupression.  While there is evidence that superantigens could be involved in the pathogenesis of certain human diseases, in most cases this is still very preliminary and indirect.

Recently, it has been suggested that psoriasis is a T-cell mediated autoimmune reaction triggered by a bacterial superantigen.  In vitro, T-cell clones from psoriatic skin lesions stimulate keratinocyte proliferation.  Successful treatment of psoriasis with anti-CD4 antibody, and cyclosporin, which inhibit cytokine production by CD4+ T cells, supports this hypothesis.

Immunology an Introduction, 4th Edition, I. R. Tizard, Sunders College Publishing, Harcourt Brace College Publishers, 1995.

Sayama K. et al. Dermatology 1998, 196: 194-198

Fleischer B. APMIS 102; 3-12, 1994

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 12.  The answers with explanations are available at the end of the textbook.

2.  Multiple Choice Questions

1.  Three major cytokines secreted by macrophages are

A) IL-1, IL-2, and IL-3

B)  IL-2, IFN-y, and IL-12

C)  IL-1, IL12, and TNF-o

D) IL-1, IFN-y, and TNF-a

E)  TGF-B, IL-6, and TNF-a

2.  One potent T cell mitogen is

A) phytohemagglutinin

B)  complement

C)  immunoglobulin

D) endotoxin

E)  interleukin-1

3.  The major cytokines secreted by Th1 cells are

A) IL-1 and IL-6

B)  IL-4 and IL-5

C)  IL-2 and IFN-y

D) IL-10 and LI-12

E)  TNF-a and GM-CSF

 

 

4.  CD28 is the ligand for

A) IL-1

B)  MHC class II

C)  antigen

D) B7 and related molecules

E)  endotoxin

3. Definitions/Short Answer Questions.

1.  T cell proliferation and differentiation lead to important immunological functions. What are they?

2.  Briefly discuss the collective molecular events called T-Cell activation, that lead to biologic function.

3.  What is the importance of diacylglycerol and IP3 in T-cell activation?

4.  What transcription factors are involved in T cell activation?

Where to Go from Here

Once you have completed the review, take some time and complete the objectives. If you are having trouble with any of the concepts, contact your instructor.

Remember to regularly check your Instructor and Assignment Information for assignments and due dates for completing them.

When you are confident that you can complete the objectives, proceed to the next topic.