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MHC restriction is the requirement to recognize an antigen in association with a self-MHC molecule; CD4+ cells can only respond to an antigen if it's presented with a self-MHC II molecule, and the same goes for CD8+ cells and self-MHC I.

Various sources say that super antigens require an MHCII+ antigen presenting cell to activate a T-cell, but they're not MHC-restricted. I've found one "clarification" on what this could mean, and it's that various MHC II molecules can present a superantigen. Does this mean that MHC II from different hosts can activate a clone of T-cells if a superantigen is involved? What's the significance of that in a single host, e.g., someone infected by a microbe that produces one of these things?

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    $\begingroup$ It means they bind outside the groove, and so bind nonspecifically. This is why they cause such a massive immune response. They activate indiscriminately (i.e., not a clone). I may have time to write this up in full later. $\endgroup$ – De Novo Dec 31 '19 at 20:20
  • $\begingroup$ By “non-specifically” do you mean in regards to the paratope the T-cell possesses or the MHC haplotypes/alleles that can present it? I think it can do both, but it’s not very clear to me yet. $\endgroup$ – Dahen Jan 1 at 14:18
  • $\begingroup$ What's your understanding of how a T cell clone is activated by a normal antigen? What binds to what? $\endgroup$ – De Novo Jan 1 at 16:39
  • $\begingroup$ A normal antigen must first get engulfed by an APC, processes then presented on the surface of the APC. To activate a T cell clone, TCR must bind to an antigen-MHC II complex, and some co-stimulation is also needed: CD4 and MHC II, CD28 and B7, LFA-1 and ICAM1. What I understand from superantigens is that they skip the whole engulfment thing (engulfment and processing makes them lose their "super", rather) and bind to the V-beta part of the TCR and the MHC II outside it's peptide-binding groove, so TCR antigen-specificity is rendered irrelevant. $\endgroup$ – Dahen Jan 1 at 17:46
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    $\begingroup$ Yep, you got it. I would suggest you convert to an answer and I'll upvote. $\endgroup$ – De Novo Jan 1 at 19:01
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Normal, "non-super" antigens activate T-cells in the following manner: they are first engulfed and processed by a professional antigen presenting cell (APC), e.g., a macrophage. The processed antigen is then presented along with an MHC class II molecule on the surface of this cell. The T-cell's T Cell Receptor (TCR) then binds this complex; it must be able to recognize both the MHC class II and the antigen, and in addition to this "main signal" other co-simulatory signals are also needed. The important thing to remember is that a T-cell will only react to a specific antigen it's specific with when it's present with an MHC class II molecule it can recognize. This is known as MHC restriction

A person has 3 genes (each having 2 alleles,for a total of 6 alleles) for MHC class I: HLA A, B and C, and 3 genes for MHC class II: HLA DR, DQ and DP. These alleles are highly polymorphic, i.e., varied, with each of these 6 genes having hundreds or thousands of different alleles, and the combination of alleles differs from individual to individual; it's very unlikely that two people who aren't identical twins would have the same combination of HLA alleles.

MHC molecules can only bind peptides, and in addition, they cant bind ALL peptides; of all the peptides that can possibly be bound by an MHC molecule, a particular MHC molecule can only bind a select number of those peptides. Different MHC molecular forms, be they class I or II, can bind, and thus present, a different set of peptides. Having different HLA alleles at your immune system's disposal means there's a larger pool of possible peptides your APCs can present with the different MHC class II isoforms they have, allowing defense against a larger pool of antigens.

A normal antigen has 2 "restrictions" on its ability to activate a T-cell clone: it must be presented by an MHC class II isoform that can bind it, and it must be recognized by a T-cell with a compatible TCR.

Superantigens activate T-cells in an unconventional manner: They have a domain that binds to the TCR, though not at the usual antigen binding site, and a domain that binds to the MHC class II molecule, but not in the usual peptide-binding site these molecules possess. Since it binds outside of these regions that are specific to particular molecules, they're not restricted by the antigen specificity of the TCR nor are they restricted by the MHC class II isoform they're utilizing. Hence why, even if they do need MHC class II-positive cells to be able to activate a T-cell clone, they're not MHC-restricted.

Readings:

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    $\begingroup$ Just add references and you're done! A general textbook level reference will suffice. $\endgroup$ – De Novo Jan 1 at 22:48

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