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ulty mentors her reaction was not what i expected she immediately launched into a story about how in graduate school she was convinced she could have had sex with peter doherty if she had really wanted to so apparently the immunology community contains its share of enthusiastic admirers but setting that aside the key scientific idea from those experiments is this t cells are restricted by mhc they only recognize a peptide when it s presented on the correct mhc molecule and once immunologists understood that principle they realized they could use it as an incredibly powerful experimental tool this is exactly what happens in the ctl assays used in papers like the one by hoerr and colleagues here s the basic idea first you immunize a mouse with your antigen in this case the antigen encoded by the rna vaccine then you isolate the cytotoxic t cells from that mouse those t cells have been trained to recognize a specific peptide presented on the mhc haplotype of that mouse strain now comes the test you grow target cells in culture that express the antigen and you mix them with those t cells to see if the targets get killed but here s the clever part you don t just use one kind of target cell you use two one target cell line carries the same mhc haplotype as the immunized mouse the other carries a different haplotype if the killing is truly antigen specific and mhc restricted then the t cells should kill the matched targets but leave the mismatched targets completely alone same antigen same peptide wrong mhc molecule and the t cells act like nothing happened so that mismatch becomes a beautiful negative control it proves that the t cells are responding exactly the way immunology predicts they should now of course we still need a way to measure whether those target cells are actually dying and that s where one of the most classic immunological assays comes in the chromium release assay in this assay the target cells are loaded with a radioactive isotope called 51 cr the chromium gets trapped inside the cells as long as the cells are alive the chromium stays inside but when cytotoxic t cells attack and rupture those cells the chromium leaks out into the surrounding media so after the t cells have had time to do their work researchers spin down the cells collect the supernatant and measure how radioactive it is more radioactivity means more cells were destroyed which means more t cells successfully found their target and if you want to extend the metaphor we started with earlier this is the moment when the investigators can tell that something terrible has happened inside the house because suddenly the evidence starts leaking out everywhere summary and takeaways so with that background in mind we can step back and look at what hoerr and colleagues actually showed in this paper the experiments themselves are fairly straightforward they generated messenger rna encoding a model antigen β galactosidase and delivered it to mice in a few different ways as naked rna as rna condensed with protamine and as rna packaged with liposomes they then asked a simple but important question what kind of immune response does this produce and the answer was surprisingly robust the rna was translated in vivo the antigen was expressed in the tissue where it was injected and the immune system responded in two major ways first the mice produced cytotoxic t lymphocytes capable of recognizing and killing target cells expressing the antigen second they produced class switched igg antibodies against that antigen so the immune response wasn t just weak or transient it included both arms of the adaptive immune system cellular immunity and humoral immunity and importantly the cytotoxic responses they measured were comparable to the responses generated by dna vaccination which at the time was the dominant nucleic acid vaccine platform so in many ways this paper answered a question that had been hanging over the field for years was messenger rna simply too fragile to function as a practical vaccine hoerr and colleagues showed that the answer was no even relatively simple rna constructs could be translated inside the body and generate a meaningful immune response stability and delivery were engineering problems but they weren t fundamental barriers but there s another lesson in this paper that has less to do with rna technology and more to do with basic immunology the experiments rely heavily on the principle of mhc restriction the cytotoxic t cells generated in these mice don t just recognize a peptide they recognize a peptide presented on a specific mhc molecule the haplotype carried by that strain of mouse and that s why immunologists pay such close attention to these haplotypes by comparing target cells that share the same mhc haplotype with cells that carry a different one researchers can prove that the killing they observe is truly antigen specific and mhc restricted rather than some nonspecific immune activation so the genetics of the mhc those tightly linked genes inherited together as a haplotype become a powerful tool for dissecting immune responses and that s one of the elegant things about immunology experiments the system itself provides the controls if you understand the genetics well enough now when we read this paper today it can feel almost quaint the formulations are simple the rna is unmodified the delivery methods are primitive compared to modern lipid nanoparticles but conceptually this study helped establish something that is now fundamental to modern vaccinology a strand of messenger rna delivered into a cell can turn that cell into a temporary antigen factory and the immune system will respond to it as if an infection were occurring which brings us back to the metaphor we started with for cytotoxic t cells danger isn t detected outside the cell it s detected when a cell begins displaying suspicious peptides on its mhc molecules signals that something inside the cell has gone wrong in other words the immune system realizes that the threat isn t outside anymore it s already inside the house and when a stranger comes calling sometimes the safest thing to do is eliminate the entire house teaser for ep6 next time we jump ahead to a 2012 nature biotechnology paper by petsch et al where mrna vaccines face the ultimate test protection against influenza a challenge leave a comment posted by downhousesoftware on march 8 2026 in uncategorized season 2 episode 4 08 mar some companion notes to supplement the reprogrammed podcast find the full episode at https spotifycreators web app link e x6kkjlq930b this week s paper was martinon et al eur j immunol 1993 23 1719 1722 induction of virus specific cytotoxic t lymphocytes in vivo by liposome entrapped mrna podcast intro hey and welcome back to reprogrammed the podcast where this year we ll be exploring the path that nucleic acid vaccines took from their first proof of concept work in the 90s to the mrna vaccines for covid19 that put an end to a pandemic and saved countless lives in the past several papers we ve been establishing that when you inject dna into muscle the muscle cells make a protein and somehow the immune system notices and reacts that gave us a conceptual breakthrough the body can become its own vaccine factory but there was still a huge open question was the immune system reacting because it saw a foreign protein or because it thought it was seeing a viral infection that distinction matters a lot because protection against many viruses can come in two flavors we can use soluble proteins or killed viruses as vaccines that we want to generate an antibody response to that acts prophylactically to prevent infection or we can find a way to generate killer t cells that can help fight established infections by killing infected cells and that s exactly what this week s paper tests instead of dna martinon and colleagues used mrna not inside a virus or encoded by a plasmid not replicating in any way just an rna message encoding influenza nucleoprotein np protected inside simple liposomes and injected into mice and what they were really asking was not can we make protein in an animal we already know the answer to that they were asking a much deeper immunology question if a cell makes a viral protein inside one of its own cells will the immune system treat that as an infection because if the answer is yes you don t just have tricked the immune system into believing a virus has already infected cell and that it needs to make a cellular response to combat it and to understand why this matters we need to take a short detour into immunology specifically the difference between antibody immunity and t cell immunity humoral vs cell mediated immunity when most people think about vaccines they think about antibodies you get a shot you make antibodies those antibodies block the virus before you ever get infected that s called humoral immunity antibodies work beautifully for to combat pathogens outside cells but once you get infected antibodies have to wait until new virus is made and buds from cells to bind and neutralize it even when viruses express their antigens on the cell surface antibodies are hampered in their ability to do much to those cells but the immune system has a second strategy to fight established infections instead of neutralizing the pathogen it eliminates the infected cell that s cell mediated immunity and the main players are cd8 cytotoxic t lymphocytes ctls ctls don t recognize whole proteins they recognize peptides displayed on mhc class i molecules luckily virtually all of our cells express mhc i and these molecules present portions of every protein made inside the cell and this is the thing that makes nucleic acid vaccines revolutionary a protein vaccine delivers antigen outside of cells dna or mrna vaccines force your own cells to manufacture the antigen internally in a way that looks a lot like a viral infection martinon et al are testing whether mrna vaccination activates that second pathway explaining mhc every cell in your body constantly displays samples of the proteins it is making as a way of helping the immune system know if a cell is sick mhc class i molecules present these sample peptides in a way that is engineered for t cells to see them cd8 cytotoxic t cell circulate around the body checking all of our cells to see what proteins they re making if the peptides look like self nothing happens if the peptides look like anything other than self the t cell kills the cell presenting those peptides there s an important consideration this paper looks into different individuals actually have different mhc molecules in much the same way that people have different hair or skin color each of these different mhc molecules can present different peptides from the same protein because of their slight differences in structure that s why the authors immunized multiple mouse strains they were testing what happens with animals with different mhcs presenting antigens if the same mrna works across different mhc haplotypes then the immune system itself is doing the epitope selection automatically that is the modern idea of a platform vaccine the vaccine does not need to be customized for each genotype the immune system customizes it for you the ctl assay so how did they actually know they made killer t cells looking for antibodies is fairly easy looking for t cells is a bit harder instead they ran what used to be the gold standard immunology experiment a cytotoxic t lymphocyte killing assay here s the setup they immunize a mouse they isolate t cells from its spleen they grow target cells in a dish they infect those target cells with influenza or load them with the specific viral peptide then they mix the t cells with the targets if ctls exist the targets die but here s the clever part the target cells are loaded with a radioactive label historically chromium 51 when the t cell kills the target cell the cell membrane ruptures and releases the radioactive contents into the medium so instead of counting dead cells directly they measure radioactivity in the supernatant more radioactivity more killing stronger ctl response this is not a molecular assay it is a functional immune assay they are not asking did t cells activate they are asking can these t cells find and destroy infected cells and the remarkable thing about this paper is what they found the t cells induced by mrna vaccination killed virus infected cells the same way infection induced t cells do to the immune system the mrna vaccine was indistinguishable from influenza infection at least at the level of cytotoxic t cell recognition experimental setup in a nutshell antigen in vitro transcribed mrna encoding influenza a nucleoprotein np formulation np mrna was encapsulated in simple liposomes made of cholesterol phosphatidylcholine phosphatidylserine using a detergent removal technique in vivo immunization mice were immunized with mrna containing liposomes and the authors systematically examined how the route of administration affected ctl induction readouts balb c virus specific ctls from spleen after immunization cytotoxicity against np peptide sensitized targets and influenza virus infected target cells mhc restriction haplotype breadth they did this in three mouse strains with different mhc haplotypes each known to present a different np peptide no dna no viral vector just in vitro transcribed the article uses the abbrev ivt mrna protected in liposomes injected in vivo then ctl readouts key findings figure 1 induction of virus specific ctl activity by immunization of balblc mice with liposome entrapped mrna encoding the npof influenza a ntvirus liposome entrapped mrna can prime virus specific ctls in vivo mice immunized with np mrna liposomes developed anti influenza ctls in vivo those ctls lysed np peptide pulsed targets lysed influenza infected target cells in other words the response wasn t just peptide like it was indistinguishable from ctls generated by real infection in terms of specificity n on replicating mrna if delivered correctly can drive mhc i antigen presentation and robust ctl responses mice were immunized as described in sect 2 2 with mrna a c empty liposomes g mrna f empty liposomes and mrna e or influenza virus b d splenocytes from primed a g or unprimed h mice were stimulated in vitro either with influenza a ntvirus a b or with np147 158 peptide c h the targets were p815 cells 0 p 815 cells incubated with np147 158 peptide o p815 cells infected with influenza a nt w p815 cells infected with the control influenza bmamagata bmam virus o el4 cells incubated with np147 158 synthetic peptide a and el4 cells infected with influenza alnt virus a table 1 dependence on the route of administration of liposome entrapped mrna on the induction of ctl route of administration matters early biodistribution lesson some routes were clearly better for splenic ctl priming than others this foreshadows a now familiar theme where the ...