Changes in MHC Terms in MF and CC

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Changes in MHC Terms in MF and CC

Terms relating to MHC class I and class II molecules in the molecular function and cellular component ontologies need to be revised to clarify their use and meaning and correct some misperceptions about the nature of these molecules.

In particular, a major misperception carried over into the GO from certain general texts concerning immunology is that MHC class I molecules only present endogenous antigens and that MHC class II molecules only present exogenous antigens. The experimental literature of the last 25 years clearly shows that both class I and class II can present antigens from both endogenous or exogenous sources.
Indeed the majority of peptides occupying class II binding grooves are endogenous in source, the products of both internalized membrane proteins and alternative intracellular pathways for class II antigen processing and presentation. Moreover, the cross-presentation pathway for presentation of exogenous antigens on MHC class I in dendritic cells is probably the most important pathway for the priming of immune responses involving CD8 T cells. I've eliminated all references to this false dichotomy in the BP ontology; it's time to do so for the CC and MF ontologies as well.

To correct this and other problems, I am proposing a series of changes to MHC related terms below to make it easier for annotators to pick the right terms and to provide a few missing terms.

In addition to other changes, I propose to obsolete and replace two terms. The MHC receptor activity terms, GO:0030106 and GO: 0045012 are defined poorly and have been misused by annotators for annotation of MHC proteins themselves, not the receptors for MHC proteins. These annotations are wrong, and therefore the terms need to be obsoleted, and replacement terms need to be made and defined according to GO standard definitions.

Important Note to Evelyn:

With this change the following Swiss-Prot to GO keywords should be corrected:

Existing mappings: SP_KW:KW-0490 MHC I > GO:MHC class I receptor activity ; GO: 0030106 SP_KW:KW-0490 MHC I > GO:antigen presentation, endogenous antigen ; GO:0019883 SP_KW:KW-0490 MHC I > GO:antigen processing, endogenous antigen via MHC class I ; GO:0019885 SP_KW:KW-0491 MHC II > GO:MHC class II receptor activity ; GO: 0045012 SP_KW:KW-0491 MHC II > GO:antigen presentation, exogenous antigen ; GO:0019884 SP_KW:KW-0491 MHC II > GO:antigen processing, exogenous antigen via MHC class II ; GO:0019886

Correct Mappings: SP_KW:KW-0490 MHC I > GO:MHC class I protein complex ; GO: 0042612 SP_KW:KW-0490 MHC I > GO:antigen processing and presentation of peptide antigen via MHC class I ; GO:0002474 SP_KW:KW-0491 MHC II > GO:MHC class II protein complex ; GO: 0042613 SP_KW:KW-0491 MHC II > GO:antigen processing and presentation of peptide or polysaccharide antigen via MHC class II ; GO:0002504

The terms below are in pseudo-OBO 1.0 format, with interspersed notes.

-- Alex

Obsoleted Terms

[Term] id: GO:0030106 name: MHC class I receptor activity namespace: molecular_function def: "OBSOLETE. A major histocompatibility complex class I receptor. These display processed antigens from the endocytosed bacteria. MHC class I proteins can form complexes with processed antigen peptides only if the antigen is synthesized in the same cell. As a consequence, T lymphocytes can only bind to class-I-positive cells that are synthesizing the antigen (e.g. virus-infected cells)." [ISBN:081533642X, ISBN:0879694971] comment: This term was made obsolete because the definition is ambiguous and contains incorrect information. To update annotations of gene products that act as receptors for MHC class I protein complexes, please use 'MHC class I receptor activity ; GO:NewTerm1' [below]; to update annotations of gene products which are components of MHC class I protein complexes, please use 'MHC class I protein complex ; GO:0042612'. related_synonym: "class I major histocompatibility complex antigen" [] exact_synonym: "major histocompatibility complex class I receptor" [] is_a: GO:0004888 ! transmembrane receptor activity is_obsolete: true

[Term] id: GO:0045012 name: MHC class II receptor activity namespace: molecular_function def: "OBSOLETE: A major histocompatibility complex class II receptor. These display processed antigens from virally-infected or transformed cells. Class-II-positive cells ('antigen-presenting cells') can take up antigens from outside by endocytosis, degrade them into small peptides, and re-export the peptides (now bound to MHC class II protein) to the cell surface. These peptide-MHC class II complexes can then be recognized by specific CD4+ lymphocytes." [ISBN: 081533642X, ISBN:0879694971] comment: This term was made obsolete because the definition is ambiguous. To update annotations of gene products that act as receptors for MHC class II protein complexes, please use 'MHC class II receptor activity ; GO:NewTerm3' [below]; to update annotations of gene products which are components of MHC class I protein complexes, please use 'MHC class II protein complex ; GO:0042613'. related_synonym: "class II major histocompatibility complex antigen" [] exact_synonym: "major histocompatibility complex class II receptor" [] is_a: GO:0004888 ! transmembrane receptor activity is_obsolete: true

New Terms

[Term] id: GO:NewTerm1 name: MHC class I receptor activity namespace: molecular_function def: "Combining with an MHC class I protein complex to initiate a change in cellular activity. Class I here refers to classical class I molecules." [GOC:add, ISBN:0781735149] comment: Note that this term is intended for annotation of gene products that act as receptors for MHC class I protein complexes, not for components of the MHC class I protein complexes themselves. related_synonym: "alpha-beta T cell receptor activity" [] related_synonym: "gamma-delta T cell receptor activity" [] related_synonym: "T cell receptor activity" [] is_a: GO:0004888 ! transmembrane receptor activity

[Term] id: GO:NewTerm2 name: MHC class Ib receptor activity namespace: molecular_function def: "Combining with an MHC class Ib protein complex to initiate a change in cellular activity. Class Ib here refers to non-classical class I molecules, such as those of the CD1 or HLA-E gene families." [GOC: add, ISBN:0781735149] comment: Note that this term is intended for annotation of gene products that act as receptors for MHC class Ib protein complexes, not for components of the MHC class Ib protein complexes themselves. related_synonym: "alpha-beta T cell receptor activity" [] related_synonym: "gamma-delta T cell receptor activity" [] related_synonym: "T cell receptor activity" [] is_a: GO:0004888 ! transmembrane receptor activity

[Term] id: GO:NewTerm3 name: MHC class II receptor activity namespace: molecular_function def: "Combining with an MHC class II protein complex to initiate a change in cellular activity." [GOC:add, ISBN:0781735149] comment: Note that this term is intended for annotation of gene products that act as receptors for MHC class II protein complexes, not for components of the MHC class II protein complexes themselves. related_synonym: "alpha-beta T cell receptor activity" [] related_synonym: "gamma-delta T cell receptor activity" [] related_synonym: "T cell receptor activity" [] is_a: GO:0004888 ! transmembrane receptor activity

Note that these definitions are not only written according to GO standard definition of receptor activity, but are also deliberately broad and cover TCRs, NK cell receptors, CD4, and CD8.

[Term] id: GO:NewTerm4 name: MHC class Ib protein complex namespace: cellular_component def: "A transmembrane protein complex composed of a MHC class Ib alpha chain and, in most cases, an invariant beta2-microglobin chain, and with or without a bound peptide or lipid antigen. Class Ib here refers to non-classical class I molecules, such as those of the CD1 or HLA-E gene families." [GOC:add, ISBN:0781735149, PMID:15928678] is_a: GO:0042611 ! MHC protein complex

[Term] id: GO:NewTerm5 name: inhibitory MHC class I receptor activity namespace: molecular_function def: "Combining with a MHC class I protein complex to mediate signaling that inhibits activation of a lymphocyte." [GOC:add, PMID: 9368779, PMID:11858820, PMID:9597134] is_a: GO:NewTerm1 ! MHC class I receptor activity

[Term] id: GO:NewTerm6 name: activating MHC class I receptor activity namespace: molecular_function def: "Combining with a MHC class I protein complex to mediate signaling that activates a lymphocyte." [GOC:add, PMID:11858820, PMID:9597134] is_a: GO:NewTerm1 ! MHC class I receptor activity

Terms with improved definitions and possibly changed links:

[Term] NOTE CHANGE IN DEFINITION, REFERENCE, AND LINK id: GO:0042611 name: MHC protein complex namespace: cellular_component def: "A transmembrane protein complex composed of an MHC alpha chain and, in most cases, either an MHC class II beta chain or an invariant beta2-microglobin chain, and with or without a bound peptide, lipid, or polysaccharide antigen." [GOC:jl, GOC:add, ISBN: 0781735149, PMID:15928678, PMID:16153240] is_a: GO:0043234 ! protein complex is_a: GO:0044459 ! plasma membrane part

PLEASE DELETE THIS LINK FOR GO:0042611, as it is not always true: relationship: part_of GO:0001772 ! immunological synapse

[Term] NOTE CHANGE IN DEFINITION AND REFERENCE id: GO:0042612 name: MHC class I protein complex namespace: cellular_component def: "A transmembrane protein complex composed of a MHC class I alpha chain and an invariant beta2-microglobin chain, and with or without a bound peptide antigen. Class I here refers to classical class I molecules." [GOC:jl, GOC:add, ISBN:0120781859, ISBN:0781735149] comment: See also the cellular component term 'MHC class I peptide loading complex ; GO:0042824'. is_a: GO:0042611 ! MHC protein complex

[Term] NOTE CHANGE IN DEFINITION AND REFERENCE id: GO:0042613 name: MHC class II protein complex namespace: cellular_component def: "A transmembrane protein complex composed of an MHC class II alpha and MHC class II beta chain, and with or without a bound peptide or polysaccharide antigen." [GOC:jl, GOC:add, ISBN:0120781859, PMID: 15928678] is_a: GO:0042611 ! MHC protein complex

[Term] NOTE CHANGE IN DEFINITION, REFERENCE, AND LINK id: GO:0030107 name: HLA-A specific inhibitory MHC class I receptor activity namespace: molecular_function def: "Combining with a MHC class I molecule of the HLA-A subclass to mediates signaling that inhibits activation of a lymphocyte." [GOC: mah, GOC:add, PMID:9368779, PMID:11929129] is_a: GO:NewTerm5 ! inhibitory MHC class I receptor activity

[Term] NOTE CHANGE IN DEFINITION, REFERENCE, AND LINK id: GO:0030108 name: HLA-A specific activating MHC class I receptor activity namespace: molecular_function def: "Combining with a MHC class I molecule of the HLA-A subclass to mediates signaling that activates a lymphocyte." [GOC:mah, GOC:add, PMID:9368779, PMID:11929129] is_a: GO:NewTerm6 ! activating MHC class I receptor activity

[Term] NOTE CHANGE IN DEFINITION, REFERENCE, AND LINK id: GO:0030109 name: HLA-B specific inhibitory MHC class I receptor activity namespace: molecular_function def: "Combining with a MHC class I molecule of the HLA-B subclass to mediates signaling that inhibits activation of a lymphocyte." [GOC:mah, GOC:add, PMID:9368779, PMID:11929129] is_a: GO:NewTerm5 ! inhibitory MHC class I receptor activity

[Term] NOTE CHANGE IN DEFINITION, REFERENCE, AND LINK id: GO:0030110 name: HLA-C specific inhibitory MHC class I receptor activity namespace: molecular_function def: "Combining with a MHC class I molecule of the HLA-C subclass to mediates signaling that inhibits activation of a lymphocyte." [GOC:mah, GOC:add, PMID:9368779, PMID:11929129] is_a: GO:NewTerm5 ! inhibitory MHC class I receptor activity

Previously obsolete terms with new comments:

[Term] id: GO:0003820 name: class I major histocompatibility complex antigen namespace: molecular_function def: "OBSOLETE (was not defined before being made obsolete)." [GOC: mah] comment: This term was made obsolete because it represents a gene product, and because describing something as an 'antigen' means that an organism can produce antibodies to it, which says nothing about the gene product activity. To update annotations, consider the molecular function term 'MHC class I protein complex ; GO:0042612'.
<<<<---- NOTE CHANGE IN RECOMMENDED TERM. is_obsolete: true

[Term] id: GO:0003821 name: class II major histocompatibility complex antigen namespace: molecular_function def: "OBSOLETE (was not defined before being made obsolete)." [GOC: mah] comment: This term was made obsolete because it represents a gene product, and because describing something as an 'antigen' means that an organism can produce antibodies to it, which says nothing about the gene product activity. To update annotations, consider the molecular function term 'MHC class II protein complex ; GO:0042613'.
<<<<---- NOTE CHANGE IN RECOMMENDED TERM. is_obsolete: true

[Term] id: GO:0004894 name: T cell receptor activity namespace: molecular_function def: "OBSOLETE (was not defined before being made obsolete)." [GOC: jl] comment: This term was made obsolete because it describes a receptor type, and not an activity. To update annotations, consider the molecular function terms 'MHC class I receptor activity ; GO:NewTerm1' [above], 'MHC class II receptor activity ; GO:NewTerm3' [above], or 'peptide antigen binding ; GO:0042605' or one of its children. <<<<---- NOTE CHANGE IN RECOMMENDED TERMS. is_obsolete: true

[Term] id: GO:0042096 name: alpha-beta T cell receptor activity namespace: molecular_function def: "OBSOLETE (was not defined before being made obsolete)." [GOC: jl] comment: This term was made obsolete because it describes a receptor type, and not an activity. To update annotations, consider the molecular function terms 'MHC class I receptor activity ; GO:NewTerm1' [above], 'MHC class II receptor activity ; GO:NewTerm3' [above], or 'peptide antigen binding ; GO:0042605' or one of its children.
<<<<---- NOTE CHANGE IN RECOMMENDED TERMS. is_obsolete: true

[Term] id: GO:0042099 name: gamma-delta T cell receptor activity namespace: molecular_function def: "OBSOLETE (was not defined before being made obsolete)." [GOC: jl] comment: This term was made obsolete because it describes a receptor type, and not an activity. To update annotations, consider the molecular function terms 'MHC class I receptor activity ; GO:NewTerm1' [above], 'MHC class II receptor activity ; GO:NewTerm3' [above], or 'peptide antigen binding ; GO:0042605' or one of its children.
<<<<---- NOTE CHANGE IN RECOMMENDED TERMS. is_obsolete: true

Changes in synonyms:

Contrary to my response to SF 1566423 "Add 'synonyms' for GO: 0042288" (but two days ago, sorry) I now think that the synonyms, "alpha-beta T cell receptor activity," "gamma-delta T cell receptor activity," and "T cell receptor activity," should be removed from MHC class I protein binding ; GO:0042288 and MHC class II protein binding ; GO:0042289 and be associated only with the new MHC receptor activity terms (GO:NewTerm1, GO:NewTerm2, and GO:NewTerm3), above, as the synonyms refer to "receptor activity" and not "binding."

Reported by: addiehl

Original Ticket: "geneontology/ontology-requests/3559":https://sourceforge.net/p/geneontology/ontology-requests/3559

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all this looks fine to me ... not that I really feel qualified to comment

m :}

Original comment by: mah11

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Logged In: YES user_id=865072

Midori,

Can you go ahead and implement this SF item. I'm currently making an immunology GO Slim and would like the new terms available for it.

If you don't have time, I can ask Harold.

Thanks,

Alex

Original comment by: addiehl

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Hi Alex,

Sorry, I've been away and didn't see your request until today. I think I'll be able to work on this later this week; if it turns out I won't have time this week, I'll get in touch with Harold.

Midori

Original comment by: mah11

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Logged In: YES user_id=436423

got started on this:

- sent obsoletion warning email for GO:0030106 & GO:0045012

- removed synonyms from GO:0042288 and GO:0042289

- opened new annotation SF item for the SP_KW mapping changes https://sourceforge.net/tracker/index.php? func=detail&aid=1588027&group_id=36855&atid=605890

I also have the new terms stashed in a separate file, ready to add once I get a reply to the email asking whether it's OK to add them before the other terms are made obsolete.

m

Original comment by: mah11

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• assigned_to: nobody --> gomidori

Original comment by: mah11

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Logged In: YES user_id=436423

all changes now done as requested (with a few small text corrections)

new terms: MHC class I receptor activity GO:0032393 (new def) MHC class Ib receptor activity GO:0032394 MHC class II receptor activity GO:0032395 (new def) inhibitory MHC class I receptor activity GO:0032396 activating MHC class I receptor activity GO:0032397 MHC class Ib protein complex GO:0032398

Original comment by: mah11

[gocentral]

• priority: 7 --> 5
• status: open --> closed-fixed

Original comment by: mah11