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My understanding of acute transplant rejection is that donor dendritic cells present donor antigens on MHC1 to host naive CD8+ T-cells resulting in an immune response against the graft. If you match MHC1 complexes between donor and host, wouldn't t-cell activation actually be more likely than the case where MHC1 complexes between donor and host are different?

Reasoning: I imagine in the case where MHC1 complexes between donor and host are different that the t-cell receptor is unable to bind the MHC1 complex in the first place..making the transplant essentially invisible. In the case where MHC1 complex between donor and host are the same, the t-cell receptor would bind the MHC1 complex, and increase the likelihood of an immune response. Given that HLA mismatch is a major cause of transplant rejection, something is wrong with my reasoning. Thoughts?

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  • $\begingroup$ 1. There are no T cells in a host that attack foreign MHC1? $\endgroup$ Oct 24 '21 at 8:51
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Cells with low MHC1 or non-recognizable MHC1 are destroyed by NK cells, so e.g. viral infections, intracellular bacterial infections and cancer cells cannot hide with their "abnormal" proteins...

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  • $\begingroup$ I seem to remember from my (far behind) immunology that such is also the case with T CD8+ cells. Is that not the case? $\endgroup$
    – Raoul
    Oct 27 '14 at 12:57
  • $\begingroup$ @Raoul I don't think so, but I am not sure. Afaik TCR-MHC1 connection is required to activate CD8+ T-cells, and TCR does not necessary connect to non matching MHC1. Afaik anergy happens when it is connected to the MHC1, it recognizes the oligopeptide pattern with the TCR, but it does not have enough stimulus for activation. It needs costimulation e.g. B7 protein from an APC or cytokin from a CD4+ T-cell to lower the activation threshold. If it does not get it, it will die after a while. I'll check what happens when a CD8+ T-cell meets with a non MHC1 cell. $\endgroup$
    – inf3rno
    Oct 27 '14 at 13:13
  • $\begingroup$ @Raoul It seems like much more complicated than we both thought. I'll edit my answer later. $\endgroup$
    – inf3rno
    Oct 27 '14 at 14:00
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    $\begingroup$ @Raoul Still reading articles in the topic. ;-) Just a short report: it seems like there are multiple cell types with NK ability, e.g. NK cells, NKT cells (subgroup of T-lymphocites), etc... (possibly more). These cells can kill other cells if they don't recognize the MHC1 (MHC1 does not exist or not compatible). Regular T-cells (without NK receptor) seems like having the same ability by not compatible MHC1, but I am not sure yet about the mechanism. I think I'll need a weak more to read all articles I opened and come to a conclusion about how the immune response works in this case. $\endgroup$
    – inf3rno
    Oct 31 '14 at 1:12
  • $\begingroup$ @Raoul Have you finished this work? I've been citing you at biology.stackexchange.com/questions/104879/… $\endgroup$ Oct 23 '21 at 9:17
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In short, if a T cell does not find its corresponding MHC 1 complex on a particular cell, its default behavior will be to attack it. Binding to the MHC complex will cause a period of anergy in the bound T cell.

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  • $\begingroup$ "Binding to the MHC complex will cause a period of anergy in the bound T cell." - I think this refers to T cells that encounter their specific antigen while strolling in the blood without having been primed/immunisized before by APC/dendritic cells, cp. Janeway's. $\endgroup$ Oct 24 '21 at 8:48
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T-cells are selected against self reactivity so those that react to self-MHC are selected against and die by anergy. That's why they try to match the donor and the recipient's MHC molecules, to diminish the immune response.

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  1. On activation of host cells by foreign APC/dendritic cells with non identical MHC1

It cannot be ruled out that there do exist host T cells that do not bind to host MHC1 and have not been sorted out by so called positive or negative selection. They would not be activated by any presentation of antigen on host type MHC1 (conversely, presentation on foreign, non identical MHC1 might acitvate them, and there would be no sorting out of non-tolerant cells). Cp. comment above
inf3rno: "it seems like there are multiple cell types with NK ability, e.g. (...) NKT cells (subgroup of T-lymphocites), etc... (possibly more)."

To sum up: assuming that there are T cells that react to foreign, not host MHC, there is no need for antigens being presented on (identical) host MHC1

  1. On presentation on (identical) host MHC1

a. in case some antigen is presented on host MHC1 that there has been a process of inducing tolerance for there would be no specific host T cells "left" to mount a reaction, as they would have been sorted out. Apart from pre-tolerance, your reasoning should apply, as there is no process of tolerization after a certain period of "youth".

"Given that HLA mismatch is a major cause of transplant rejection, something is wrong with my reasoning." - To sum up, nothing's wrong, as there is rejection with identical MHC1 too, according to my reasoning above (with the exceptio of "tolerance").

However, refering to first part of my answer, this (rejection with self MHC1) does not imply that there is no rejection with non-identical MHC1. There is no either/or. Both situations know rejection. From "self MHC1 has rejection" does not follow "foreign MHC1 doesn't".

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