Topic 10 T-cell receptor

Introduction

The receptors for antigen that are found on B cells and T cells must be able to bind an enormous variety of molecules.  In previous sections, we have learned about the molecular basis of generation of antibody diversity. Now we will discuss the to T-cell receptor (TCR), and we will examine the mechanisms of generation of its diversity.  TCR is a glycoprotein capable of binding antigens and MHC molecules specifically, and it is expressed on all T lymphocytes.  Like immunoglobulins, the four peptide chains that make up the two types of TCR can bind specific epitopes.  They do this because each consists of a variable region attached to a constant region. The diversity of the TCR variable region is generated in much the same way as the immunoglobulins but with some interesting and significant differences.  T-cell receptor and immunoglobulin gene rearrangements are specific in that immunoglobulin genes are not rearranged in T cells and TCR genes are not rearranged in B cells.

Objectives

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

n  draw the structure of the T cell receptor (TCR);

n  compare and contrast the structure of TCR with B cell receptor;

n  draw a diagram of the T cell receptor gene organization;

n  describe the strategies for diversification of T cell receptors;

n  describe how a T cell Receptor recognizes an antigen;

n  describe the TCR-Antigen-MHC complex.

Required Reading

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

 

P Key Words

•           CD2

•           CD4

•           CD8

•           CD28

•           CD54

•           CD58

•           integrins

•           T cell receptors

•           alpha beta TCR

•           gamma delta TCR

•           Transcription factor NF-KB

P Key Concepts

n  T-cell receptors do not react with soluble antigen but rather with processed antigen associated with a self-MC molecule on an antigen presenting cell or a target cell.

n  Formation of TCR-antigen-MHC complex, which is essential for an immune response, depends on several interactions and also includes interactions between accessory membrane molecules.

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  The TCR is closely associated with CD3, a complex of five different polypeptide chains that associate to form three dimers.

DID YOU KNOW?

One Cell-One Receptor?

It has been generally accepted that each T cell (and B cell) carries antigen receptors specific for a single epitope.  This is the “one cell-one receptor” rule.  However, it has also been recognized that each cell actually has the potential to produce two receptor chains of two types.  This occurs because in diploid cells there are two copies of each gene.  Thus, for example, any T cell is theoretically capable of producing two different T   chains.  This does not normally occur because of a process called allelic exclusion that permits only one chain to be expressed.  Thus the presence of a rearranged V  chain prevents rearrangement of the other V  chain. 

In contrast, both V  alleles rearrange simultaneously.  Recent studies by Elisabetta Padovan and her colleagues have now shown that up to one third of TCR    T cells can express two different V  chains simultaneously.  These cells may therefore be specific for more epitopes that cells with only single receptor and may play an important role in immunity.

As appeared in: Immunology an Introduction, 4th edition.   Ian R. Tizard, Saunders College Publishing, Harcourt Brace College Publishing 1995.

Review Questions

1. Textbook Study Questions

Review questions at the end of the Chapter 11.  The answers with explanations are available at the end of the textbook.

2.  Multiple Choice Questions

1.  A key difference between the generation of diversity TCR and immunoglobulin variable regions is the use of

A) sister chromatid exchange

B)  class switching

C)  looping out

D) N-region addition

E)  somatic mutation

2.  How many constant region genes are found in each TCR gene family?

A) one

B)  two

C)  three

D) four

E)  five

3.  Which TCR gene product can express two diversity (D) gene segments?

A) a chain

B)  B chain

C)  y chain

D) S chain

E)  u chain

4.  At least one of the functions of CD8 on the surface of lymphocytes interacting  with another cell is to

A) bind antigen

B)  bind to MHC class I molecules

C)  bind to MHC class II molecules

D) bind to Fc receptors

E)  bind surface immunoglobulin

5.  Superantigens are molecules that

A) are nonspecific T cell mitogens

B)  bind to specific TCR VB regions

C)  bind to immunoglobulin Fc regions

D) bind to specific antigens

E)  bind to complement receptors

3. Definitions/Short Answer Questions.

1.  Hedrick and Davis used the technique of subtractive hybridization to isolate cDNA clones encoding for the T cell receptor.

2.  Briefly explain the method of subtractive hybridization.

3.  State why this method was so important in the characterization of the TCR.

4.  What does it mean to say that TCRs belong to the Ig supergene family? Briefly describe the heterodimeric structure of the TCR.

5.  TCR genes use the same strategies as antibody genes to develop receptor diversity; however, TCR genes do not exhibit somatic hypermutation. Why?

6.  The TCR is closely associated with another surface protein complex. What is its name and function?

7.  Describe the three way complex that occurs during antigenic recognition by T cells.

8.  T cells can react only with protein fragments. What is this process called? How does it occur?

9.  Which pathway leads to antigen interaction with MHC-I molecules?

10.   Which pathway leads to interaction with MHC-II molecules?

11.   What are accessory molecules? Give some examples. Briefly discuss how they may be involved in antigen recognition by T cells.

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 and Information for assignments and due dates for completing them.

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