Hello,
Can someone explain me the MLR(MHC alloantigens in mixed leukocyte reactions) test?
I know the MLR means APC co-culture with heterogous CD4+ T cells, and can promote T cells proliferation. But I am confused that where is the antigen peptide which present by MHC-II to TCR? Can the APCs with co-stimulation molecule alone(without antigen) stimulate T cell efficiently?
Hope someone could explain to me, much thanks!!
Miao,
Typical antigen reactivity is based on the cells selection on self peptide/MHC during thymic development. However, in the presence of a mixed leukocyte reaction (MLR), T cells are being exposed to peptides and MHC to which they have NEVER been "educated". This can lead to two possible effects.
1 - MHC dominant recognition - where the peptide does not mater but the binding of foreign MHC is sufficiently strong to drive T cell activations
2 - peptide dominant recognition - the foreign cell processes a novel peptide which is independently high affinity despite the absence of allo-MHC recognition. The peptide-only recognition is sufficiently strong to drive T cell activation.
These two ideas are summarized in this Nature review image (see link below).
Check out the review by Felix et. al in nature immunology, Dec 2007. http://www.nature.com/nri/journal/v7/n12/full/nri2200.html.
For a more brief review: See Janeway Immunobiology section 5-14. Freely available in PubMed (Books)
http://www.ncbi.nlm.nih.gov/books/NBK27156/
http://www.nature.com/nri/journal/v7/n12/images/nri2200-f1.jpg
Dear Miao Lee,
TCRs are molecules designed to interact with different MHC molecules. Due to negative selection in thymus, T cells slightly react to self MHC molecules associated with self peptides, but can develop strong response to foreign MHC molecules in the MLR, because they never seen them before. In this case both the structure of MHC molecules itself and associated peptides are foreign for responder T cells, because foreign allelic forms of MHC proteins bind different sets of peptides. As a rule, these peptides are endogenously synthesized in APC in case of MHC class I molecules, and they are exogenously engulfed from extracellular milieu in case of MHC class II molecules. Expression of both types of MHC molecules on APC is peptide-dependent. As result, recognition by T cells also requires the presence of peptides, associated with MHC molecules. You should especially take into account that peptides presented by different allelic forms of MHC molecules are also different. This difference is determined by allele-specific MHC-binding motifs, which should be presented in peptides for effective binding with MHC molecule.
Just some practical considerations. MHC molecules are never "empty", so strictly speaking no recognition can occur to MHC without peptide. To the best of my knowledge, T cell activation always involves MHC recognition, constimulation alone cannot trigger it, even if we are talking about so called polyclonal stimulation (to ConA, for example). One of the tricks about MLR is that you normally do not have 100% pure responding T cell population, and even 1-5% percent of "other" cells can present allogeneic antigens to T cells. That's what we see in our practice. Besides, human T cells (not mouse) can also present antigens. Of course, when you try to explain very very pure experiment you will look for the other explanations.
Dear Natalie, not so strictly. TAP KO bm3 mice develop CD8 T cells, in contrast to TAP KO on parent genetic background (C57BL/6).
I don't see what is likely to be the correct answer in any of the explanations posted so far. Have a look at a 1977 paper in Cellular Immunology by Matzinger and Bevan for the best explanation of alloreactivity. The peptides presented by allo MHC need not be different to be seen as foreign, the peptides can be the same as self, but when presented in an allo MHC their 3D conformation will be different. Thus every peptide is seen as foreign when presented by allo MHC.