 | This is a user sandbox of Immcarle8. You can use it for testing or practicing edits. This is not the sandbox where you should draft your assigned article for a dashboard.wikiedu.org course. To find the right sandbox for your assignment, visit your Dashboard course page and follow the Sandbox Draft link for your assigned article in the My Articles section. |
MHC restriction
editMHC-restricted antigen recognition, or MHC restriction, refers to the fact that a given T cell can interact with both the self-MHC molecule and the foreign peptide that is bound to it, and will recognize the peptide antigen only when it is bound to a host body's own MHC molecule. As T cells are stimulated by peptide antigens only in the presence of self-MHC molecules, MHC restriction adds another dimension to the specificity of TCR so that an antigen is recognized only as peptide-MHC complexes.[1]
MHC restriction in T cells occurs after its development in the thymus, specifically after positive selection.[2] Only the thymocytes (developing T cells in the thymus) that are capable of binding, with an appropriate affinity, with the MHC molecules can receive a survival signal and go on to the next level of selection. MHC restriction is significant for T cells to function properly when it leaves the thymus because it allows T cell receptors to bind to MHC and detect cells that are infected by intracellular pathogens, viral proteins and bearing genetic defects. Two models explaining how restriction arose are the germline model and the selection model.
The germline model suggests that MHC restriction is a result of evolutionary pressure favoring T cell receptors that are capable of binding to MHC.[3] The selection suggests that not all T cell receptors show MHC restriction, however only the T cell receptors with MHC restriction are expressed after thyme selection.[4] In fact, both hypothesis are reflected in the determination of TCR restriction, such that both germline-encoded interactions between TCR and MHC and co-receptor interactions with CD4 or CD8 to signal T cell maturation during selection. [5]
Introduction to MHC Restriction
editThe αβ TCRs of T lymphocytes recognize linear peptide epitopes only if coupled with a MHC molecule. In other words, the antigenic ligands of TCRs are specific peptide-MHC complexes.[6] MHC restriction is particularly important when primary lymphocytes are developing and differentiating in the thymus or bone marrow. It is at this stage that T cells die by apoptosis if they express high affinity for self-antigens presented by an MHC molecule or express too low affinity for self MHC.[7]
T cell maturation involves two distinct developmental stages: positive selection and negative selection. Positive selection ensures that any cells with a high enough affinity for peptide bound MHC survive, while negative selection induces death in cells which bind MHC too strongly. Ultimately, the T cells differentiate and mature to express either CD4 and TcR or CD8 and TcR. At this point the T cells leave the primary lymphoid organ and enter the blood stream.[8]
The interaction between TCRs and peptide-MHC complex is significant in maintaining the immune system against foreign antigens. MHC restriction allows TCRs to detect host cells that are infected by pathogens, contains non-self proteins and bears foreign DNA. However, MHC restriction is also responsible for chronic autoimmune diseases and hypersensitivity.[6]
Structural Specificity
editThe peptide-MHC complex presents a surface that looks like an altered self to the TCR.[9] The surface consisting of two α helices from the MHC and a bound peptide sequence is projected away from the host cell to the T cells, whose TCRs are projected away from the T cells towards the host cells. In contrast with T cell receptors which recognize linear peptide epitopes, B cell receptors recognize a variety of conformational epitopes (including peptide, carbohydrate, lipid and DNA) with specific three-dimensional structures.[6]
Imposition of MHC Restriction
editThe imposition of MHC restriction on the highly variable TCR repertoire has caused heated debate. Two models have been proposed to explain the imposition of MHC restriction. The Germline model proposes that MHC restriction is hard-wired in the TCR Germline sequence due to co-evolution of TCR and MHC to interact with each other. The Selection model suggests that MHC restriction is not a hard-wired property in the Germline sequences of TCRs, but imposed on them by CD4 and CD8 co-receptors during positive selection. The relative importance of the two models are not yet determined.[10]
Germline Model
editThe Germline hypothesis suggests that the ability to bind to MHC is intrinsic and encoded within the Germline DNA coding for TCRs. This is because of evolutionary pressure selects for TCRs that are capable of biding to MHC and selects against those that are not capable of binding to MHC. [11] Since the emergence of TCR and MHC ~500 million years ago [12], there is opportunity for TCR and MHC to coevolve to recognize each other. Evolutionary pressure would lead to conserved amino acid sequences at regions of contact with MHCs on TCRs[10].
Evidence from X-ray crystallography shows comparable binding topologies between various TCR and MHC-peptide complexes.[13] In addition to conserved interactions between TCR variable regions and specific MHCs supports the hypothesis that MHC restriction is related to the co-evolution of TCR and MHC to some extent. However it has also been shown that T cell selection in the thymus and periphery T cell repertoire is independent of germline TCR sequence, arguing against the hypothesis that MHC restriction is intrinsic to germline TCR sequences.[14]
Selection Model
editThe selection hypothesis argues that instead of being an intrinsic property, MHC restriction is imposed during positive thymic selection after random TCRs are produced.[15] According to this model, T cells in the form of double positive thymocytes are capable of recognizing a variety of peptide epitopes independent of MHC molecules before undergoing thymic selection. During thymic selection, only the T cells with affinity to MHC are signaled to survive after the CD4 or CD8 co-receptors bind to the MHC molecule. This is called positive selection.[16]
During positive selection, co-receptors CD4 and CD8 initiate a signaling cascade following MHC binding.[17] This involves the recruitment of Lck, a tyrosine kinase essential for T cell maturation that is associated with the cytoplasmic tail of the co-receptors. Selection model argues that Lck is directed to TCRs by co-receptors CD4 and CD8 when they recognize MHC molecules.[2] Since TCRs only interact wtih Lck when they are binding to the MHC molecules that are binding to the co-receptors, T cells that can interact with MHCs bound to by the co-receptors can activate the Lck kinase and receive a survival signal.[10]
Supporting this argument, genetically modified T cells without CD4 and CD8 co-receptors express MHC-independent TCRs.[16] It follows that MHC restriction is imposed by CD4 and CD8 co-receptors during positive selection of T cell selection.
Reconciliation
editA reconciliation of the two models was offered later on.[5] Co-receptor and Germline predisposition to MHC binding both play significant roles in imposing MHC restriction. Since T cells with the ability to bind MHC are selected for during positive selection in the thymus, evolutionary pressure acts on the germline TCR sequence selecting for MHC binding TCRs. MHC restriction also requires for TCRs to bind with the same MHC molecules as the CD4 or CD8 co-receptor to deliver a maturation signal to double-positive thymocytes during T cell selection.[10]
- ^ Charles A Janeway, Jr; Travers, Paul; Walport, Mark; Shlomchik, Mark J. (2001-01-01). "Antigen Recognition by B-cell and T-cell Receptors".
{{cite journal}}: Cite journal requires|journal=(help) - ^ a b Van Laethem, François; Tikhonova, Anastasia N.; Singer, Alfred (2012-01-09). "MHC restriction is imposed on a diverse T cell receptor repertoire by CD4 and CD8 co-receptors during thymic selection". Trends in Immunology. 33 (9): 437–441. doi:10.1016/j.it.2012.05.006. ISSN 1471-4906. PMC 3427466. PMID 22771139.
- ^ Christopher Garcia, K; Adams, Jarrett J; Feng, Dan; Ely, Lauren K (2009-01-16). "The molecular basis of TCR germline bias for MHC is surprisingly simple". Nature Immunology. 10 (2): 143–147. doi:10.1038/ni.f.219. PMC 3982143. PMID 19148199.
- ^ Collins, Edward J.; Riddle, David S. (2008-08-26). "TCR-MHC docking orientation: natural selection, or thymic selection?". Immunologic Research. 41 (3): 267–294. doi:10.1007/s12026-008-8040-2. ISSN 0257-277X.
- ^ a b Garcia, K. Christopher (2012-09-01). "Reconciling views on T cell receptor germline bias for MHC". Trends in Immunology. 33 (9): 429–436. doi:10.1016/j.it.2012.05.005. PMC 3983780. PMID 22771140.
- ^ a b c Parham, Peter (2005-01-01). "Putting a face to MHC restriction". Journal of Immunology (Baltimore, Md.: 1950). 174 (1): 3–5. ISSN 0022-1767. PMID 15611221.
- ^ B Adkins; C Mueller; C Y Okada; R A Reichert; I L Weissman; Spangrude, G. J. (1987-01-01). "Early Events in T-Cell Maturation". Annual Review of Immunology. 5 (1): 325–365. doi:10.1146/annurev.iy.05.040187.001545. PMID 3109456.
- ^ Klein, Ludger; Kyewski, Bruno; Allen, Paul M.; Hogquist, Kristin A. "Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)". Nature Reviews Immunology. 14 (6): 377–391. doi:10.1038/nri3667.
- ^ Bjorkman, P. J.; Saper, M. A.; Samraoui, B.; Bennett, W. S.; Strominger, J. L.; Wiley, D. C. (1987-10-08). "The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens". Nature. 329 (6139): 512–518. doi:10.1038/329512a0.
- ^ a b c d Rangarajan, Sneha; Mariuzza, Roy A. (2014-03-17). "T cell receptor bias for MHC: co-evolution or co-receptors?". Cellular and Molecular Life Sciences. 71 (16): 3059–3068. doi:10.1007/s00018-014-1600-9. ISSN 1420-682X.
- ^ Yin, Lei; Scott-Browne, James; Kappler, John W.; Gapin, Laurent; Marrack, Philippa (2012-11-01). "T cells and their eons-old obsession with MHC". Immunological Reviews. 250 (1): 49–60. doi:10.1111/imr.12004. ISSN 1600-065X. PMC 3963424. PMID 23046122.
- ^ Flajnik, Martin F.; Kasahara, Masanori. "Origin and evolution of the adaptive immune system: genetic events and selective pressures". Nature Reviews Genetics. 11 (1): 47–59. doi:10.1038/nrg2703. PMC 3805090. PMID 19997068.
- ^ Scott-Browne, James P.; White, Janice; Kappler, John W.; Gapin, Laurent; Marrack, Philippa. "Germline-encoded amino acids in the αβ T-cell receptor control thymic selection". Nature. 458 (7241): 1043–1046. doi:10.1038/nature07812. PMC 2679808. PMID 19262510.
- ^ Deng, Lu; Langley, Ries J.; Wang, Qian; Topalian, Suzanne L.; Mariuzza, Roy A. (2012-09-11). "Structural insights into the editing of germ-line–encoded interactions between T-cell receptor and MHC class II by Vα CDR3". Proceedings of the National Academy of Sciences. 109 (37): 14960–14965. doi:10.1073/pnas.1207186109. ISSN 0027-8424. PMC 3443186. PMID 22930819.
- ^ Van Laethem, François; Tikhonova, Anastasia N.; Pobezinsky, Leonid A.; Tai, Xuguang; Kimura, Motoko Y.; Le Saout, Cécile; Guinter, Terry I.; Adams, Anthony; Sharrow, Susan O. (2013-09-12). "Lck Availability during Thymic Selection Determines the Recognition Specificity of the T Cell Repertoire". Cell. 154 (6): 1326–1341. doi:10.1016/j.cell.2013.08.009. ISSN 0092-8674. PMC 3792650. PMID 24034254.
{{cite journal}}: no-break space character in|last6=at position 3 (help); no-break space character in|last=at position 4 (help) - ^ a b Tikhonova, Anastasia N.; Van Laethem, François; Hanada, Ken-ichi; Lu, Jinghua; Pobezinsky, Leonid A.; Hong, Changwan; Guinter, Terry I.; Jeurling, Susanna K.; Bernhardt, Günter (2012-01-27). "αβ T Cell Receptors that Do Not Undergo Major Histocompatibility Complex-Specific Thymic Selection Possess Antibody-like Recognition Specificities". Immunity. 36 (1): 79–91. doi:10.1016/j.immuni.2011.11.013. ISSN 1074-7613. PMC 3268851. PMID 22209676.
{{cite journal}}: no-break space character in|last2=at position 4 (help) - ^ Merwe, P. Anton van der; Cordoba, Shaun-Paul (2011-01-28). "Late Arrival: Recruiting Coreceptors to the T Cell Receptor Complex". Immunity. 34 (1): 1–3. doi:10.1016/j.immuni.2011.01.001. ISSN 1074-7613. PMID 21272780.