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?

  • $\begingroup$ 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

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.


  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.
  • $\begingroup$ 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

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/


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.

  • $\begingroup$ 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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