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When a cytotoxic T cell (CTL) recognizes a peptide presented in the MHC-1 of a dendritic cell (APC), why it doesn't kill this cell?

I know that initially, in the lymph node, the T cell is inactivated. But eventually it becomes activated and travels to the tissue, where it again finds APCs presenting the offending antigen. So why doesn't the CTL kill the APC at this point?

Moreover, not all MHC-1's of the dendritic cell present antigens from phagocytized cells. Some MHC-1's present peptides coming from the dendritic cell itself, so that if the dendritic cell itself becomes infected with virus or bacteria, it can be killed by a CTL that recognizes the peptide. So in this case, the CTL does indeed kill the dendritic cell.

So my question is, when exactly does the CTL kill the APC? How does the CTL knows that should or shouldn't kill the APC?

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  • $\begingroup$ Afaik. if the CTL is not activated yet, it requires a verification signal from a HTL or a very strong stimuli from the APC. Now I don't know yet what happens when it is already activated and meets with an APC presenting the same peptide. Afaik APCs do present the antigens on MHC2 and MHC1 as well, and it does not depends on whether the cell is infected, so I guess there is a way to prevent cell death in these cases. It probably depends on the amount of TCRs activated and other signals as well e.g. stress signals of the APC or cytokins. $\endgroup$ – inf3rno Nov 21 '14 at 16:56
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    $\begingroup$ Effector T cells have lower TCR stimuli threshold for proliferation than naive T cells. I haven't found any article about killing TCR stimuli threshold and about what environment is required for successful effector function by cytotoxic T cells. I found that by HIV not infected CD4+ T cells can be killed accidentally by effector T cells so I think the APC can be accidentally killed by the T cells too and the outcome depends on the strength of the TCR stimuli, and other environmental factors (costimulation). It is not clear for me yet how naive and effector T cells differ by activation. $\endgroup$ – inf3rno Dec 1 '14 at 1:00
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The presentation of antigens on the cell surface is done by two different molecule complexes: The MHCI and the MHCII complexes. These are coupled to different pathways and are recognized by different T cell populations.

The MHCI molecule presents all proteins which are present in the cell on the surface. To do so, peptides coming from the proteasome (where long proteins are digested) are transported in the the endoplasmatic reticulum (ER) by a special transporter called Transporter associated with Antigen Processing (TAP). By doing so, a profile of all proteins expressed in the cell is presented on its surface, including proteins which arise due to an infection of the cell. MHCI is recognized by cytotoxic (or CD8 positive) T cells which subsequently kill all cells which show foreign antigens on their surface (since this is a sign for an infection).

The MHCII complex only presents proteins on its surface which have been taken up by phagocytosis (so here only external proteins are presented). To prevent binding of cellular proteins in the ER (like for MHCI), the binding pocket of the receptor is blocked by the invariant chain. This chain dissociates only when the MHCII complex enter the phagolysosome with its acidic conditions. This makes sure that only proteins which have been taken up by phagocytosis are presented. MHCII complexes are recognized by helper (or CD4 positive) T cells, which in turn can activate B cells to raise a proper immune response.

In theory this should prevent all problems. In the practical life this is different for dendritic cells in a mechanism called "cross presentation". In this mechanism antigens which are taken up by phagocytosis are exported from the phagolysosme and imported into the ER. This pathway also involves the TAP protein. By choosing this way, APC can activate naive CTL which will kill all cells which present this antigen. See references 1 and 2 for more details.

This pathway is important for the immune response to a number of viruses as well as tumors which evade the MHCII mediated immune response by suppressing the MHCII antigen presentation. See references 3 and 4.

It is also important for the stability of the self-tolerance by the deletion of auto-reactive CTL. See reference 5 for details.

References:

  1. Outside looking in: the inner workings of the crosspresentation pathway within dendritic cells
  2. Cross-talk between the endocytic pathway and the endoplasmic reticulum in cross-presentation by MHC class I molecules
  3. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens.
  4. Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen.
  5. Exogenous class I-restricted cross-presentation of self antigens can lead to deletion of autoreactive CD8+ T cells.
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  • $\begingroup$ The question was about what happens if an effector CTL meets with an APC, which presents a peptid from the proper pathogen. Why does the CTL not kill the APC? Note that APC can present pathogen peptides both on MHC1 and MHC2 without becoming infected by the pathogen. So I don't think this answers the question... $\endgroup$ – inf3rno Nov 24 '14 at 18:45
  • $\begingroup$ I agree with @inf3rno. I don't see how this answers my question. $\endgroup$ – becko Nov 24 '14 at 18:54
  • $\begingroup$ I misunderstood the question and have adapted it now. Thanks for the notification. $\endgroup$ – Chris Nov 24 '14 at 21:45
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You might find this paper helpful in answering your question. It proposes that Memory CD8+ T-cells protect dendritic cells, with TNF-alpha playing a major role in the molecular mechanism of doing so

Watchmaker, P. B., Urban, J. A., Berk, E., Nakamura, Y., Mailliard, R. B., Watkins, S. C., … Kalinski, P. (2008). Memory CD8+ T Cells Protect Dendritic Cells from CTL Killing. Journal of Immunology (Baltimore, Md. : 1950), 180(6), 3857–3865.

It can be found at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905219/

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Major reason – Helper T-cells induce APCs to produce an endogenous granzyme inhibitor (serpin SPI) by APCs. So APC's are protected from being killed (which normally involves granzyme-induced apoptosis due to perforin release by the cytotoxic T-cell)

Also, downregulation of cell surface expression of the CCR7 homing receptor on activated cytotoxic T-cell. Not attracted to APC.

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  • $\begingroup$ I presume these things (overexpression of the SPI and downregulation of the CCR7) can also be performed by clever malignant cells. Are there examples of this? $\endgroup$ – becko Oct 18 '18 at 16:33
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Here's couple links explaining this:

  1. Allison himself talks about the role of CTLA-4:
    https://www.researchgate.net/publication/327062074_Fundamental_Mechanisms_of_Immune_Checkpoint_Blockade_Therapy

  2. Clear explanation of what happens (see Figures 1&2):
    https://www.researchgate.net/publication/329214140_CTLA-4_and_PD-1_Control_of_T-Cell_Motility_and_Migration_Implications_for_Tumor_Immunotherapy

Briefly, CTLA-4 is expressed shortly after T cell activation and serves to protect APCs (and everything else) from excessive T cell activation and proliferation. Also CTLA-4 makes T cell detach from APC and travel to where it's action is needed - into inflammatory sites.

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  • $\begingroup$ Welcome and thanks for your answer. We generally encourage more elaborate answers, but because of the referencing a +1 nonetheless :) $\endgroup$ – AliceD Mar 13 at 14:53
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Here is some exciting textbook reference (Janeway 5th ed.): https://www.ncbi.nlm.nih.gov/books/NBK27118/

Try to read Figure 8.14 and compare with text. Whereas the figure shows some presentation of antigen at the site of infection, the text elaborates on this actually happening only after (or during) movement of APCs to lymph nodes. It seems to be only there that presentation - and do not think of "priming" at this time, as the question to be answered is on presentation only, not on priming in lymph nodes. The point is that presentation does NOT happen at peripher sites of infection, so no killing there. It's a different question why there is no killing when or after priming in lymph nodes, it's a different question if the second signal next to presentation induces tolerance. On the other hand, only in the case that the assumption of no presenting at sites of infection is false, it would be relevant to know if there is a second signal (to assumed presentation at sites of infection) necessary for activation. It's not explicitely stated as it might be evident that the second signal - B7 - protects the presenter from the one he's activated and "turned(!)" to an aggressive killer, although it's named "activation" (if the t-cell would be actived towards the presenting APC there would be no activation, priming, though :-), sorry for being so "cumbersome"). Hence, your question does refer to the problem of inducing tolerance. Second signaling might activate, thus causing killing, and inducing tolerance - to be more precise and refering to your question - in respect of the activating presenting cell. "Nothing goes without saying", once again, why should activation exclude the activator? In that case, to my mind, because "activation" in lymph nodes in a first step and in timing does only refer to mitosis of t-cells, it is a licencing the t-cell to multiply and does not imply the killing that comes with differentiation only. However, the problem thus just seems to have been put on a bench.

Another reference on APCs presenting only and first time in lymph nodes would be Chen/Wang https://pubmed.ncbi.nlm.nih.gov/20636805: "..., DCs undergo a complex process of maturation into antigen-presenting cells. This happens while the DCs migrate from the periphery into the draining lymph node through the lymphatics." In case dendritic cells did present at sites of infection, however, that should, as a matter of fact, make them prone to be killed by friendly fire which is counterintuitive. Best of all, Janeway says, without explaining, that after priming t-killer cells the B-cells as well as the macrophages "become targets" of TCLs (t8-killer-cells, it's not about the T4-helper cells targeting, to my understanding - that might even have been some reason for bringing up your question), the dendritic apcs not mentioned in that context.

You say "it can be killed by a CTL that recognizes the peptide. So in this case, the CTL does indeed kill the dendritic cell". It seems unclear (they "can") if that is a conclusion of yours or empirical knowledge. Explaining the very mechanism of inducing self-tolerance parallels answering your question. In other words, what is so "local" about killing friendly fire in lymph nodes when setting up self-tolerance that couldn't be done at sites of infection?

There is some illustration in Roitt et al, Immunology,"Dual signaling is necessary for full t-cell activation" The B7-Receptor is not expressed constitutively, so logically, there is an option for dendrictic cells not to express the "fully activating" receptor, i.e. B7, at the site of infection - thus not being protectes in their role as priming cells. Interestingly, "CTLA4" has been discussed here, which is in fact a ligand to B7 - a question on which side it's on. Being able to refrain from expressing B7, thus causing "anergy" and survival of the "expressor" (APC) is a decision on the side of the APC (who might not want to get killed), whereas CTLA4 as "dampening" an activation hat has been started, is on the side of the aggressorm, the cytotoxic t-cells.

Interestingly, you finish your question with asking about the exact timing and regulation. As a matter of fact, there is some event! As soon as a "clone is born" any other APC still at the site of infection and not in lymph node might rightly be killed as it may be considered as some down regulation, no need for any more clones of proliferation. Compare other answer above: it might be a matter of "growth", i.e. proliferation (cp. role of mentioned CTLA4 in cancer) and its regulation by sheer timing and amounts. (The latter seems to settle a paradoxon: no B7 yet at site of infection, so killing of friendly APCs should undergo - and it does, for the reason of down regulation). With the B-7 receptor of APCs being termed "stimulatory", "activating" (proliferation of T-cells) it is counterintuitive to consider "anergy" as the other side of the same medal, i.e. to recognize ACPS in lymph nodes being protected in spite of their stimulating activity, leading to proliferation. Nontheless, just the opposite, non-expression of B/ leads to anergy. So my very point refers to the ending of your question: there is a point of expression of B7 in lymph nodes that turns the APC from "anergy" to "stimulation", however at the site of infection an APC not expressing, refraining from B/, just presenting antigen, would not "anergically be spared", it should be treated just like any other self-cell that's being killed by a clone of some T8-cell that has already, maybe first of all, been activated. This seems plausible within a regulation of proliferation stated above which fits into the context of CTL4 discussed in this thread.

"Anergy" (i.e. no killing of APCs) refers to t-cells (T8) that have not been primed yet. Anergy because of lack of B7 to my understanding refers to naive T-cells, it does not refer to the role of non-naive T8-cells that have been primedbefore meeting any dendritic APCs at the site of infection. It's my speculation that at site of infection any APC that "primaturely" presents antigen does get killed by primed T-cells in a concept of self-regulation which limits the proliferation of cytotocic t-cells in the sense and direction of downregulating B7-ligands that are being discussed here.

Edited: My answer has probably been inspired by having read the question of S. Oncosuresh at researchgate at https://www.researchgate.net/post/Why-Dendritic-cell-are-not-killed-by-T-cells-when-they-present-antigen It is the "speculative" answer by Ye Tian from the University of Chicago which I feel inclined most to: cp. "... if by then" (they will kill the DC's presenting).

You say, quote: "... and travels to the tissue, where it again finds APCs presenting the offending antigen."

After all and to sum up, it's a possibility that either the assumption that there is presentation by dendritic APCs at site of infection is wrong, or, that indeed, if there should be presentation, presenting dendritic cells in fact are being killed by t-cells that are members of a clone derived from activated t-cells which are specific for that antigen - as they are not needed for activation which is "priming" that had already, earlier, in time, been undertaken, as the presence of non anergic t-cells at site of infection shows.

As an answer, I'd prefer the second alternativ based on the empirical assumption that there is presentation of antigen by APC already at site of infection which might not be known yet.

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    $\begingroup$ Welcome to Biology.SE! This may be a good answer, but answers are much more likely to receive a favorable response if you include supporting references (primary literature is best). Without that support, your answer is indistinguishable from opinion. This is a good example of how to format references. In addition, your post would be improved by formatting (e.g. paragraphs) and focusing on being concise. ——— Please also take the tour and then consult the help pages for additional advice on How to Answer effectively on this site. Thank you! 😊 $\endgroup$ – tyersome Oct 29 at 4:20
  • $\begingroup$ @Peter - thanks for your answer - but it would really improve the readability if you included paragraphs. $\endgroup$ – user438383 Nov 6 at 13:08

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