Questions from Last Time:
1. What does the interaction time between a T Cell and an APC look like for T Cells that bind the antigen the cell is presenting as opposed to those that do not bind?
1a. How long does it take the T Cell to kill the APC if it is a match?
2. What kinds of chemicals go back and forth between the T Cell and the APC during this process and how are they released (transcriptional response/some other signaling cascade)?
- Cytotoxic T Cells Release perforin and granzymes. Perforin makes holes in cell membrane through which the other proteins can enter, granzymes trigger caspase cascade resulting in apoptosis
- Perforin and granzymes are stored in small cytoplasmic granules that can be released from a small region of the cell membrane by exocytosis. (immunological synapse)
- (semi-related) It takes roughly 50 TCR-MHC pairings to activate the T Cell -> implies that MHC molecules could be close enough for some kind of interaction between fusion proteins
- Vesicles in Helper T Cells store lymphokines that stimulate further immune response when released
3. What kinds of chemicals are released by the Tregs to suppress Teffs?
- (alt. modes of of action) It has been reported that Foxp3+ Treg cells exert suppression by cell contact–dependent mechanisms (for example, functional modulation by means of CD39, CD73 and LAG-3, or killing of APCs or responder T cells by means of granzyme and perforin) as well as mechanisms mediated by soluble factors (for example, secretion of immunosuppressive cytokines such as IL-10, TGF-β, IL-35 and galectin-1, or deprivation of cytokines (for example, IL-2) necessary for the expansion and/or survival of responder T cells65, 66, 67). It is thus likely that several mechanisms or modes of suppression may operate synergistically and in a complementary manner and that each mechanism contributes to suppression to a particular extent and under a certain condition. "
- IL-10, IL-9
- TGFβ
- Granzyme B?
- CTLA-4 (protein receptor on surface) http://www.nature.com/ni/journal/v11/n1/fig_tab/ni.1818_F2.html (highly expressed narturally; suppression directly leads to autoimmune disorder)
4. How can we modify MHC (or other APC surface protein) to release the chemicals normally released by Tregs when a Teff successfully binds MHC?
Other New, Relevant Information:
-Engineering the pathway that leads to secretion of the appropriate chemicals by Tregs seems like it could be a pain in the ___. Maybe it would be more feasible to engineer Tregs to express endocytotic behavior/MHC and somehow work it so that their TCRs are stimulated when MHC is bound that way the original exocytotic pathway can be preserved
- This could also be a good idea because the exact molecular nature of Treg-mediated suppression is not particularly well characterized
- MHC Class I presents peptides from proteins produced by the cell (viral or self) whereas MHC Class II presents endocytosed antigens, If we plan to engineer the production of MHC into a cell that typically does not produce it, we'll probably want both for the most adaptability
Just a pretty picture I found ...
