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Antigen-specific T cells: analyses of the needles in the haystack.

Slansky JE - PLoS Biol. (2003)

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology at the University of Colorado Health Sciences Center in Denver, Colorado, USA. Jill.Slansky@UCHSC.edu

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If there were only two TCRs, like the ERs, or even 350 TCRs, like the ORs, then how would the T cells distinguish what is a viral protein versus a cellular protein, and how would immunity develop to a virus that was not recognized by one of those TCRs? Many T cells are deleted in the process of T cell development... This process of negative selection greatly reduces the number of TCRs that recognize self-proteins; 95%–98% of all T cells are deleted... Unlike the ERs and ORs that recognize molecules in solution, TCRs recognize a cell-bound complex that includes a protein known as an MHC (major histocompatibility complex) molecule and a short peptide of less than 20 amino acids (Figure 1)... The molecular partner, or, in this case, T cells bearing potential cognate TCR, is passed over the array in solution phase... Binding results in a detectable signal... Since the ligand is immobilized, high concentrations of peptide–MHC monomer might achieve the same goal as the multimers... When bound to MHC, these “mimotopes” activate T cells that may cross-react with the peptide–MHC expressed on the tumor... Currently, about 10%–20% of melanoma patients given vaccines that include these mimotopes have a clinical response to their tumors... The efficacy of these treatments needs to be improved... Which T cells to specifically target with the vaccine and what is required to activate those T cells could be determined using the peptide–MHC and antibody microarrays... The ability of tumor-derived T cells to bind to a panel of mimotope–MHC complexes and the corresponding tumor-associated antigens would indicate whether the patients had T cells to react with the mimotope or whether these T cells were deleted during development... With a simple, economical method to screen the available T cell repertoire to tumor antigens and mimotopes, individual treatments could be easily formulated and clinical response to tumors could be improved... In addition to cancer, the peptide–MHC microarray technology could also improve the analysis of the T cells responding to infectious diseases, autoimmune diseases, and transplants... A more advanced understanding of the available T cells will be beneficial for each of these conditions.

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MHC Class I and MHC Class II Bind to Specific TCRsMHC class I and MHC class II bind to specific TCRs on the surface of the MHC molecule that is facing you. The peptide is presented by the MHC to the TCR like a hotdog in a bun; the peptide typically constitutes approximately 15% and the MHC molecule constitutes approximately 85% of the surface that the TCR binds. (A) shows a molecular structure of the human MHC class I, HLA-A2, bound to a tumor antigen, MAGE-4 (Hillig et al. 2001). This structure is distinct from (B), which shows the human MHC class II molecule HLA-DR1 bound to a peptide derived from the Epstein–Barr virus gp42 protein (Mullen et al. 2002) in three ways. (1) The MHC class I peptide is shorter (average of nine amino acids versus 15 amino acids). (2) The ends of the peptide-binding grooves are closed in the MHC class I. (3) Although it is not evident in the structures shown, the binding groove from MHC class II is produced from two distinct molecules; the groove from MHC class I forms from one protein. The class I and II molecules can be found in animals from jawed vertebrates on up the evolutionary tree. (Figure produced with Cn3D version 4 from the National Center for Biotechnology Information.)
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pbio.0000078-g001: MHC Class I and MHC Class II Bind to Specific TCRsMHC class I and MHC class II bind to specific TCRs on the surface of the MHC molecule that is facing you. The peptide is presented by the MHC to the TCR like a hotdog in a bun; the peptide typically constitutes approximately 15% and the MHC molecule constitutes approximately 85% of the surface that the TCR binds. (A) shows a molecular structure of the human MHC class I, HLA-A2, bound to a tumor antigen, MAGE-4 (Hillig et al. 2001). This structure is distinct from (B), which shows the human MHC class II molecule HLA-DR1 bound to a peptide derived from the Epstein–Barr virus gp42 protein (Mullen et al. 2002) in three ways. (1) The MHC class I peptide is shorter (average of nine amino acids versus 15 amino acids). (2) The ends of the peptide-binding grooves are closed in the MHC class I. (3) Although it is not evident in the structures shown, the binding groove from MHC class II is produced from two distinct molecules; the groove from MHC class I forms from one protein. The class I and II molecules can be found in animals from jawed vertebrates on up the evolutionary tree. (Figure produced with Cn3D version 4 from the National Center for Biotechnology Information.)

Mentions: The molecular ligand recognized by the TCR is unique. Unlike the ERs and ORs that recognize molecules in solution, TCRs recognize a cell-bound complex that includes a protein known as an MHC (major histocompatibility complex) molecule and a short peptide of less than 20 amino acids (Margulies 1999) (Figure 1). These complexed ligands, or antigens, are on the surface of nearly all healthy cells. MHC class I predominantly binds peptides from inside the cell. These peptides can be derived from viruses, which are recognized by T cells as foreign. The consequence of this recognition is destruction of the infected cells by the T cells. Bacteria or cell debris brought into the cell from outside is degraded and the peptides bind to MHC class II molecules. The function of the T cells that recognize these antigens is different from those that bind MHC class I. These T cells typically respond by producing cytokines, proteins that bind to receptors on other cells that augment immunity. The MHC class I– and class II–bound peptides also include fragments of self-proteins. Most of the T cells specific for these peptides are deleted during development. The T cells that are not deleted are controlled by other mechanisms so that these T cells do not kill healthy cells resulting in autoimmunity.


Antigen-specific T cells: analyses of the needles in the haystack.

Slansky JE - PLoS Biol. (2003)

MHC Class I and MHC Class II Bind to Specific TCRsMHC class I and MHC class II bind to specific TCRs on the surface of the MHC molecule that is facing you. The peptide is presented by the MHC to the TCR like a hotdog in a bun; the peptide typically constitutes approximately 15% and the MHC molecule constitutes approximately 85% of the surface that the TCR binds. (A) shows a molecular structure of the human MHC class I, HLA-A2, bound to a tumor antigen, MAGE-4 (Hillig et al. 2001). This structure is distinct from (B), which shows the human MHC class II molecule HLA-DR1 bound to a peptide derived from the Epstein–Barr virus gp42 protein (Mullen et al. 2002) in three ways. (1) The MHC class I peptide is shorter (average of nine amino acids versus 15 amino acids). (2) The ends of the peptide-binding grooves are closed in the MHC class I. (3) Although it is not evident in the structures shown, the binding groove from MHC class II is produced from two distinct molecules; the groove from MHC class I forms from one protein. The class I and II molecules can be found in animals from jawed vertebrates on up the evolutionary tree. (Figure produced with Cn3D version 4 from the National Center for Biotechnology Information.)
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC300688&req=5

pbio.0000078-g001: MHC Class I and MHC Class II Bind to Specific TCRsMHC class I and MHC class II bind to specific TCRs on the surface of the MHC molecule that is facing you. The peptide is presented by the MHC to the TCR like a hotdog in a bun; the peptide typically constitutes approximately 15% and the MHC molecule constitutes approximately 85% of the surface that the TCR binds. (A) shows a molecular structure of the human MHC class I, HLA-A2, bound to a tumor antigen, MAGE-4 (Hillig et al. 2001). This structure is distinct from (B), which shows the human MHC class II molecule HLA-DR1 bound to a peptide derived from the Epstein–Barr virus gp42 protein (Mullen et al. 2002) in three ways. (1) The MHC class I peptide is shorter (average of nine amino acids versus 15 amino acids). (2) The ends of the peptide-binding grooves are closed in the MHC class I. (3) Although it is not evident in the structures shown, the binding groove from MHC class II is produced from two distinct molecules; the groove from MHC class I forms from one protein. The class I and II molecules can be found in animals from jawed vertebrates on up the evolutionary tree. (Figure produced with Cn3D version 4 from the National Center for Biotechnology Information.)
Mentions: The molecular ligand recognized by the TCR is unique. Unlike the ERs and ORs that recognize molecules in solution, TCRs recognize a cell-bound complex that includes a protein known as an MHC (major histocompatibility complex) molecule and a short peptide of less than 20 amino acids (Margulies 1999) (Figure 1). These complexed ligands, or antigens, are on the surface of nearly all healthy cells. MHC class I predominantly binds peptides from inside the cell. These peptides can be derived from viruses, which are recognized by T cells as foreign. The consequence of this recognition is destruction of the infected cells by the T cells. Bacteria or cell debris brought into the cell from outside is degraded and the peptides bind to MHC class II molecules. The function of the T cells that recognize these antigens is different from those that bind MHC class I. These T cells typically respond by producing cytokines, proteins that bind to receptors on other cells that augment immunity. The MHC class I– and class II–bound peptides also include fragments of self-proteins. Most of the T cells specific for these peptides are deleted during development. The T cells that are not deleted are controlled by other mechanisms so that these T cells do not kill healthy cells resulting in autoimmunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology at the University of Colorado Health Sciences Center in Denver, Colorado, USA. Jill.Slansky@UCHSC.edu

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

If there were only two TCRs, like the ERs, or even 350 TCRs, like the ORs, then how would the T cells distinguish what is a viral protein versus a cellular protein, and how would immunity develop to a virus that was not recognized by one of those TCRs? Many T cells are deleted in the process of T cell development... This process of negative selection greatly reduces the number of TCRs that recognize self-proteins; 95%–98% of all T cells are deleted... Unlike the ERs and ORs that recognize molecules in solution, TCRs recognize a cell-bound complex that includes a protein known as an MHC (major histocompatibility complex) molecule and a short peptide of less than 20 amino acids (Figure 1)... The molecular partner, or, in this case, T cells bearing potential cognate TCR, is passed over the array in solution phase... Binding results in a detectable signal... Since the ligand is immobilized, high concentrations of peptide–MHC monomer might achieve the same goal as the multimers... When bound to MHC, these “mimotopes” activate T cells that may cross-react with the peptide–MHC expressed on the tumor... Currently, about 10%–20% of melanoma patients given vaccines that include these mimotopes have a clinical response to their tumors... The efficacy of these treatments needs to be improved... Which T cells to specifically target with the vaccine and what is required to activate those T cells could be determined using the peptide–MHC and antibody microarrays... The ability of tumor-derived T cells to bind to a panel of mimotope–MHC complexes and the corresponding tumor-associated antigens would indicate whether the patients had T cells to react with the mimotope or whether these T cells were deleted during development... With a simple, economical method to screen the available T cell repertoire to tumor antigens and mimotopes, individual treatments could be easily formulated and clinical response to tumors could be improved... In addition to cancer, the peptide–MHC microarray technology could also improve the analysis of the T cells responding to infectious diseases, autoimmune diseases, and transplants... A more advanced understanding of the available T cells will be beneficial for each of these conditions.

Show MeSH
Related in: MedlinePlus