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TCRs are epitope-specific, and it has been estimated that 25 million T cells with unique epitope-binding TCRs are required to protect an individual against a wide range of microbial pathogens. Because the human genome only contains about 25,000 genes, we know that each specific TCR cannot be encoded by its own set of genes. This raises the question of how such a vast population of T cells with millions of specific TCRs can be achieved. The answer is a process called genetic rearrangement , which occurs in the thymus during the first step of thymic selection .

The genes that code for the variable regions of the TCR are divided into distinct gene segments called variable (V), diversity (D), and joining (J) segments . The genes segments associated with the α chain of the TCR consist 70 or more different V α segments and 61 different J α segments. The gene segments associated with the β chain of the TCR consist of 52 different V β segments, two different D β segments, and 13 different J β segments. During the development of the functional TCR in the thymus, genetic rearrangement in a T cell brings together one V α segment and one J α segment to code for the variable region of the α chain. Similarly, genetic rearrangement brings one of the V β segments together with one of the D β segments and one of thetJ β segments to code for the variable region of the β chain. All the possible combinations of rearrangements between different segments of V, D, and J provide the genetic diversity required to produce millions of TCRs with unique epitope-specific variable regions.

Drawing of a two bars spanning the T cell plasma membrane. On one side of the membrane is the intracellular domain. The transmembrane region spans the membrane. The constant region is outside the membrane; a disulfide bond holds these two bars together in the constant region. The variable region is at the top and contains the antigen binding sites.
A T-cell receptor spans the cytoplasmic membrane and projects variable binding regions into the extracellular space to bind processed antigens associated with MHC I or MHC II molecules.
  • What are the similarities and differences between TCRs and immunoglobulins?
  • What process is used to provide millions of unique TCR binding sites?

Activation and differentiation of helper t cells

Helper T cells can only be activated by APCs presenting processed foreign epitopes in association with MHC II . The first step in the activation process is TCR recognition of the specific foreign epitope presented within the MHC II antigen-binding cleft . The second step involves the interaction of CD4 on the helper T cell with a region of the MHC II molecule separate from the antigen-binding cleft. This second interaction anchors the MHC II-TCR complex and ensures that the helper T cell is recognizing both the foreign (“nonself”) epitope and “self” antigen of the APC; both recognitions are required for activation of the cell. In the third step, the APC and T cell secrete cytokines that activate the helper T cell. The activated helper T cell then proliferates, dividing by mitosis to produce clonal naïve helper T cells that differentiate into subtypes with different functions ( [link] ).

A native helper T cells binds to an antigen extracted from a pathogen sitting on the MCH Class II protein of an antigen presenting cell (dendritic cell). The portion of the helper T cell that binds is the T cell receptor and is stabilized by CD4. After this binding the helper T cell is activated and can become TH1 cell; TH2 cell or memory helper T cell.
This illustration depicts the activation of a naïve (unactivated) helper T cell by an antigen-presenting cell and the subsequent proliferation and differentiation of the activated T cell into different subtypes.
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Source:  OpenStax, Microbiology. OpenStax CNX. Nov 01, 2016 Download for free at http://cnx.org/content/col12087/1.4
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