Antigen receptor

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Antigen receptors are lymphocyte cell surface proteins that these cells use to identify the target that the immune response is supposed to be directed at. A distinction is made between the antigen receptors of B-lymphocytes ( B-cell receptors ), which are membrane-bound antibodies , and the antigen receptors of T-lymphocytes ( T-cell receptors ), which do not show any similarity to antibodies.

Formation of the antigen receptors

Antigen receptors arise within the maturation processes of the lymphocyte progenitor cells, in which the DNA of the progenitor cells undergoes changes that are referred to as recombination .

  • During recombination in the course of cell division, two DNA recognition motifs are joined by an RAG (recombination-activating gene) enzyme complex and the DNA between them is cut out together with the recognition motifs, while the DNA outside the recognition motifs is linked. So there are deletions . This is where pieces of genes are put together that were previously apart.
  • The pieces of genes that are put together appear not just once on the DNA, but several times. Some gene pieces occur up to 100 times. The recognition motifs with which the RAG protein recognizes these pieces are located behind or in front of each gene piece that can be joined together.
  • Which gene piece in a given lymphocyte is used in the recombination is random.
  • With the loss of the DNA between the gene pieces, a new state of the lymphocyte precursor cell is fixed, the cell has matured somewhat.
  • The gene pieces are referred to as V (variable), D (diversity) or J (joining) elements. For the heavy chain of an antigen receptor, first a DJ recombination and in a later division a V-DJ recombination must be carried out. For the light chains, only one VJ recombination is necessary, the D elements are missing in the genes of the light chains. For the successful formation of antigen receptor genes, which can then be transcribed into RNA and formed as proteins , at least three recombination events are necessary in a precursor cell: two recombinations for the heavy chain, one for the light chain.
  • The human immunoglobulin heavy chain gene has about 50 V elements, 25 D elements and 6 J elements. This makes about 7500 different heavy chain proteins possible. There are two genes for light chains, each with 40 or 30 V elements and 5 or 4 J elements, i.e. 200 or 120 light chains. Combined freely, this results in 7500 × 200 + 7500 × 120 = 2,400,000 different immunoglobulin receptors on B-lymphocytes . For the antigen receptor of the T lymphocytes , the T cell receptor, this number is roughly similar.
  • Another element of diversity arises from the fact that during the enzymatic process of the RAG complex, the ends of the cut DNA are not immediately linked again, but are free for some time. During this time, the enzyme terminal deoxyribonucleotidyl transferase (TdT) can attach any nucleotides to the ends.

If exactly three or multiples of three DNA bases have been added during this process , a protein with variable amino acid (s) can later be formed. It is estimated that more than a billion different receptor proteins can be formed in this way. If these proteins were encoded as individual genes in the human genome , they would burst the genome, which so far (after almost complete DNA sequencing ) has around 30,000 independent genes.

  • If a recombination fails, the lymphocyte progenitor cell has the opportunity to recombine the gene on the other chromosome. If both recombination options have failed in the case of heavy chains or all four have failed in the case of light chains, the precursor cell is destroyed from within; it is apoptotically and eaten by phagocytes .
  • The same thing happens if exactly three bases or multiples of three have not been incorporated. The protein cannot be read because the front part of the protein chain is in a different reading frame than the rear part. A cell with such a recombination is also apoptotic and disposed of. Most of the progenitor cells that undergo recombination of an antigen receptor gene die prematurely. Only every sixth cell at most can produce the two RNAs for light and heavy chains with the correct reading frames.

Consequences from the recombination

  • A precursor cell that has successfully recombined two genes for the light and heavy chain forms the two proteins for the light and heavy chain, joins these chains together to form the antigen receptor and brings it to the cell surface . This turns the precursor cell into a lymphocyte.
  • As early as the 1960s and 1970s, it was estimated and experimentally researched that 1 billion different immunoglobulin receptors could recognize all chemically possible structures of immunoglobulins. Therefore, the immunoglobulin repertoire is considered complete.
  • As a direct consequence of this fact, immunoglobulins must also be directed against the body's own substances, since they can react to everything, including their own proteins, sugar or nucleic acids, vitamins, fats, etc.
  • When the T-lymphocyte receptor was known, which has a similarly high variability, it could be assumed that the T-cell receptor can also recognize its own substances.
  • The big question was how is it prevented that the lymphocytes, whose receptors recognize their own, trigger an immune response against the individual himself?
  • For B lymphocytes, the following solution was explored:

B lymphocytes, which recognize their own substances with their antigen receptor, are not activated because they lack a second stimulation signal. The B cell is only activated if the B cell antigen receptor recognizes its antigen together with the costimulatory signal. Otherwise it will be irreversibly inactivated, apoptotic and disposed of.

T-lymphocyte education in the thymus

In T lymphocytes, the elimination of cells that carry self-reactive antigen receptors takes place in the thymus , an organ under the upper part of the sternum . The antigen receptor of the T lymphocytes does not recognize a substance, but this substance must be shown to him, presented. This antigen presentation is carried out by the molecules of the major histocompatibility complex .

Of every protein that is formed in a cell, there are also degradation products, peptides that are formed during the degradation of proteins in the proteasome and that are around eight to 10 amino acids long. The molecules of the histocompatibility protein class I ( MHC-I ) can incorporate some of these peptides into a special binding pocket and then present them in the peptide binding pocket on the cell surface. The T-antigen receptor recognizes exactly such a complex of peptide and MHC-I, but only a certain combination.

There are three genes for the MHC-I proteins in humans: HLA-A , HLA-B and HLA-C, of ​​which up to a hundred different alleles exist with different frequencies in the entire human population . A single T cell receptor recognizes a peptide with a certain sequence in a certain MHC-I protein.

So that the T-cell does not z. B. recognizes a kidney peptide in a self-MHC-I and reacts to it by triggering an immune response, the genes of the human genome are randomly converted into RNA and protein in the thymus of medullary epithelial cells (MTEC), digested in proteasomes, resulting peptides stored in MHC-I and presented to the fresh T lymphocytes. In each medullary epithelial cell, up to 5% of the human genes are switched on

A T cell whose antigen receptor now binds to some peptide in self-MHC is eliminated - as we have already seen with B cells. Only T lymphocytes that have survived the selection process for non-self MHC plus peptide in the thymus are allowed to leave the thymus. In the thymus, the T lymphocytes also acquire additional surface proteins that are necessary for the activation of the T lymphocytes.

literature

  • Thomas J. Kindt, J. Donald Capra: The Antibody Enigma. Plenum Press, New York NY u. a. 1984, ISBN 0-306-41581-X .
  • Charles A. Janeway , Paul Travers, Mark Walport: Immunobiology. Garland Science Publishing, 6th edition. Garland Science, New York et al. a. 2005, ISBN 0-8153-4101-6 .

Web links

Individual evidence

  1. ↑ L. Klein, B. Kyewski: Promiscuous expression of tissue antigens in the thymus: a key to t-cell tolerance and autoimmunity? In: J Mol Med , 78 (9), 2000, pp. 483-494, PMID 11140374 .
  2. ↑ B. Kyewski, L. Klein: A central role for central tolerance. In: Annu. Rev. Immunol. , 24, 2006, pp. 571-606, PMID 16551260 .