Lecture 9: "Immunology: T cells"Jun 08, 2021
hi i'm richard young your host with facundo batista and lennon feyen for the mit course on covin 19 sars go v2 and the pandemic now we've heard experts talk about the pandemic, the coronavirus and what happens to the covid patient , we have also heard an overview of the immune response but have not fully explored the critical functions of the key cell type that regulates the immune response the t cell today we are pleased to hear from one of the world's leading t cell experts dr arlene sharp dr sharp is the george fabian professor of comparative pathology at harvard medical school he is also chair of the department of
immunologyat harvard a member of the department of pathology at brigham and women's hospital a member of the broad institute of mit and harvard a leader in cancer
immunologyprogram at the dana farber harvard cancer center co-director of the evergren center for immunological diseases at the faculty d of harvard medicine and brigham hospital for women dr sharp has been elected to is a member of the national academy of sciences and the national academy of medicine, is co-leader of the massachusetts consortium on pathogen preparedness established this march by the harvard medical school to respond to the sars cov2 pandemic and prepare for the emerging pathogens of the future arlene thank you thank you for joining us today well my real pleasure thank you for inviting me to this wonderful course to preserve my bandwidth , I'm going to stop my video for this presentation and let me see, I'm going to share my screen here, um, can you see my slides and put them in slide mode here? of T cell responses, essentially what turns T
cellson and off and why that's important and then we'll talk a little bit about the roles of T
cellsin defending against pathogenic microbes that cause disease and then I'll focus on what we're learning about T cell responses to covid19 which is a work in progress so I know you've had
lectures on a lot of topics and had an overview of the immune system but a lot of you have a variety of backgrounds, So first I want to remind you of some terms, first, an individual's immune system is really amazing, it has the ability to recognize between 10 million and 1 billion different substances which are called in immunology parlance as antigens now these antigens are recognized by lymphocytes and lymphocytes have on their receptors on their receptor surfaces to recognize these antigens l b cells have b cell receptors t cells have t cell receptors there are several classes of lymphocytes that are summarized on this slide there are b cells which are cells that become antibody producing cells and they are going to have a whole
lectureon the b cells today we are going to focus on t cells and these t cells come in several types, the There are so called helper T cells and these cells produce cytokines small proteins that can help other types of immune cells to activate that are important in defense of the host There are also killer T cells.
These lymphocytes are capable of recognizing infected cells that express microbial antigens. and then kill these infected cells there are also regulatory T cells that suppress immune responses so I'd like to start by talking a little bit about regulation of responses and why we need regulation so just to talk a little bit more about these types of T cells that kill infected cells, we have a very limited number of T cells that could recognize a specific antigen and so when we encounter a pathogen and you have an antigen specific T cell, this cell needs to be activated and then it can expand many times over studies have shown that a T-lymphocyte can expand more than fifty thousand times in just one week, such a rapid response is needed to defend against infections, it also means that this response must be carefully regulated to get activation proper immune response in response to a virus at the right time and not indeterminately to when we think of an immune response these active lymphocytes these specific antigens must become activated these cells proliferate and can differentiate into cells that carry out effector functions for example for t cells these killer t cells once the immune response is removed pathogen, there's a decline known as homeostasis and then one of the features that's very special about the immune system is that it remembers this encounter with the pathogen, so the next time it encounters, for example, a virus, it can respond more quickly because it has these memory T cells so there are passive mechanisms that control these phases once the microbe lights up the infection is over and the stimulus is gone but there are also active mechanisms and we're going to have a while I'm Speaking of these active mechanisms, then why are these mechanisms important?
We need to have control of the T cell responses to control the activation of these T cells in order for the cells to fire properly, but you also want to control the duration of the response and have proper response resolution, otherwise there may be tissue damage, in addition, there are certain situations, for example, certain chronic viral infections such as hiv, where antigens can persist for a long period of time, in addition, one of the most amazing aspects of the immune system is the wallet can defend us against diversity of the microbial world and the normal immune system does not respond to itself so we tolerate ourselves and a break in tolerance can lead to autoimmunity so we need to have these appropriate control mechanisms so we don't develop immunity . mediated diseases, first we're going to talk about costimulation, which is an important regulator of this balance between T-lymphocyte activity ation so that you get the right response against pathogens and control so that we don't get our own response to the cells in our own bodies and get a controlled response to the pathogen, so first we'll talk about costimulation and activation of T cells.
In order for T cells to become activated, they need to receive two signals that are sent by antigen-presenting cells, such as dendritic cells. The first signal confers specificity to an immune response and involves the recognition of antigens. Antigenic peptides are presented by mhc molecules expressed on antigen-presenting cells to the T cell receptor for full T cell activation, a co-signal is needed, a second signal known as the costimulatory signal, and when the T cell receives both signals, it can be activated and differentiated into effector T cells which can then deal with the pathogen and therefore these two signals are optimal for T cell activation.
There has been a lot of research in this area and our understanding of costimulation h as it evolved over time, so we now appreciate that not only are there positive second signals that work with the T cell receptor to promote T cell activation, but there are also negative second signals that attenuate signals through the receptor of T cells. We have learned that many of these negative these second inhibitory signals are important in mediating the tolerance that protects us against autoimmunity these costimulatory signals control a variety of T cells at different stages of their lives we have naive T cells that are controlled by costimulatory signals effector cells memory T cells and regulatory T cells that I mentioned inhibit T cell responses and there are many T cell costimulatory pathways and co-inhibitory pathways and today we'll just focus on two pathways that are key immunoregulatory pathways.
The first is the pathway involving the b7 b71 and b72 molecules and their receptors cd28 and ctla4, whereby the b7 molecules, also known as cd80 and cd86, are upregulated in an antigen-presenting cells, such as dendritic cells. , when the immune system detects its danger, for example, microbes or components of microbes, such as bacterial cell wall components, such as lipopolysaccharides, can lead to the expression of these b7 molecules in dendritic cells. These two b7 molecules have overlapping functions but differ in their expression kinetics and these molecules can interact with cd28 which is constitutively expressed on the surface of T cells and can also interact with ctla-4 now cd28 is expressed constitutively but in contrast , ctla4 is upregulated in T cells upon activation whereas cd28 is expressed on the cell surface ctla4 is mainly expressed in the cytoplasm and transported to the cell surface, thus ctla4 is expressed and reaches the surface of activated T cells and studies have shown that ctla 4 is the high affinity receptor for b71 and b72 so first we will talk about the function of cd28 cd28 is the main stimulatory receptor that activates naive t cells when a t cell receives signals through from the t-cell receptor or through the antigen and by binding the b7 molecules through cd28, the t-cell receives these two s signals and signals through cd28 provide growth factors, survival factors, and bioenergetics that allow these t cells to be able to divide and proliferate and then differentiate into effector cells so that signals through cd28 lead to factor synthesis growth factors like il2 by t cell survival factors like bcl2 and then glucose metabolism which provides the energy for these cells to divide what about ctla4 ctla-4 has structural similarities to cd28 and is adjacent to cd -28 on the chromosome in early studies it was a debate whether ctla4 was a stimulatory molecule like cd28 or if it could be an inhibitory molecule my lab together with tacmac's lab made ctla-4 knockout mice and the phenotype of these mice convinced the field that ctla-4 was a key inhibitory molecule, these animals die at three to four weeks of age develop massive spleens enlarged cells known as splenomegaly and in large lymphocytes known as lymphadenopathy the T cells in these animals spontaneously activate and infiltrate many different tissues and lead to tissue destruction so here on the left we are looking at the heart of one of these animals all these little purple cells are lymphocytes and when we have inflammation we refer to it as itis then there is myocarditis inflammation and destruction of the heart and also here on the right we are seeing a pancreas here there has been complete destruction of the eyelids which are important to produce insulin, so we have pancreatitis, so this phenotype showed that ctla-4 had a pivotal role in inhibiting T cell responses and downregulating T cell activation, thus that this pathway then when you think about this pathway, there is a balance between activation mediated by participation of b7 at cd 28 and inhibition mediated by b7 involvement at ctla -4 It is not fully understood how this occurs, but differences in timing and kinetics help us understand this: first, when we have a quiescent situation , there are very few b7 molecules, but then when dangerous signals are found, like a bacterial pathogen, there is an upregulation of these b7 molecules then it can involve cd28 which will lead to T cell activation as a result of T cell activation ctla4 is upregulated in these cells ctla4 is the high affinity receptor and when things get involved they are involved by b7 this can then downregulate the T cell response how ctla-4 exerts its inhibitory functions ctla-4 se can be expressed in a variety of T cell types and this cartoon illustrates two ways that ctla4 can inhibit T cell functions first ctla4 has what is known as a intrinsic function of the cell, which means that cells expressing ctla4 send signals to those cells, and therefore within cells expressing ctla4 signals ctla4 can block signals through the t-cell receptor and through cd28 and therefore inhibit the activation of T cells.
Regulatory T cells. Those suppressor T cells also highly express ctla4 and ctla4 on these regulatory cells. They can extract b7 molecules from the membrane of antigen-presenting cells such as dendritic cells. these b7 molecules and are not present to interact with 28 so there is reduced costimulation via cd 28 and that also downregulates T cell function. What is the significance of the role of ctla-4 and these immune responses? the phenotype of ctla because knockout mice resembled an autoimmune disease and led us and others to wonder if ctla-4 had a role in regulating tolerance and autoimmunity and therefore first when we think of the immune response, returning towhat I mentioned at the beginning of this lecture, shutting down Immune responses are important for the proper functioning of the immune system.
We need to activate these cells, but once the pathogen is removed, we need to go back. To bring the immune system back to its baseline state, which is again referred to as homeostasis, we also need to avoid an inappropriate response to self antigens, which is known as tolerance and, as you may have heard before, when the immune receptors are generated. antigens and T cells are born in the thymus. these receptors are on developing lymphocytes the expression of these antigen receptors is random without any specificity as to whether these T cells can recognize themselves or foreign substances, so all individuals can produce lymphocytes whose receptors can see the antigens self and these self antigens do not hide from the immune system so there is a way to deal with them first in the thymus where the T cells are born some of these lymphocytes that recognize themselves are eliminated however some of these lymphocytes enter the periphery and there are also peripheral mechanisms that can kill or inactivate these cells to prevent autoimmunity so just a little more terminology here I've used the term autoimmunity and so I mean by this are immune responses against autoantigens or autoantigens and, by implication, these responses are what cause disease and there are diseases that are classified into these immune mediated inflammatory diseases and when we think of autoimmunity this can be systemic throughout the body such as systemic lupus erythematosus or specific organs such as type 1 diabetes and autoimmune disease that occurs in the pancreas, so people have studied the function of ctla4 and autoimmunity and we've learned that in fact ctla-4 regulates tolerance and ctla-4 autoimmunity can control the function of these is regulatory T cells suppressors and also limit the function of autoreactive effector cells long before we had whole genome sequencing when we had genome-wide association studies by John Todd and Linda Wicker that identified polymorphisms in the ctla-4 gene and associated them with autoimmune diseases human diseases such as type 1 diabetes.
We also learned that there are mutations that occur naturally but are rare. ras in ctla-4, such as those listed here. mike leonardo and gulbu uzel work in the nih called chai and latte. which are mutations, the first is a mutation in ctla4 which is associated with autoimmunity and the second is a mutation in the protein that transports ctla-4 into the cell. urface lrba and these individuals will develop autoimmune characteristics as well as this understanding of ctla-4 as an inhibitory molecule has been translated into the therapy work of jim allison who was a nobel prize winner last year appreciated that since ctla 4 inhibits t c cell activation and blocking ctla4 may enhance T cell responses it might be possible to block ctla4 and enhance T cell responses against tumors and this is illustrated in this cartoon there are therapeutic antibodies to see tla4 that these antibodies have been developed bind to ctla4 so that b7 molecules can no longer interact with ctla4 and therefore there is unopposed stimulation of b7 molecules that interact with cd28 and this can promote immune responses and this has resulted in fact, in anti-ctla 4 therapy for cancer there are many costimulatory and coinhibitory pathways and I would like to talk about another pathway that also it's a key inhibitory pathway, the pathway that involves pd1 and I'll use this cartoon to introduce the pd1 pathway for the pd1 receptor to increase on T cells upon its ctla4-like activation and when pd-1 mates with either of its ligands pdl1 or pdl2 is phosphorylated on tyrosine motifs in its cytoplasmic domain and this can lead to the association of protein tyrosine phosphatases such as ship 2 which can then dephosphorylate kinases downstream of the T-cell receptor or cd28 as a result there is reduced signaling through the pdl2 receptor.
T cells on cd28 and reduced T cell responses reduced cytokine production by T cells and reduced death by those cytolytic T cells now one of the fascinating aspects of this pathway lies in the expression pattern of its ligands and in particular the expression of pdl1 really caught our attention when we first discovered that pdl1 and pdl2 were binding partners for pd1 and that these molecules can be expr esar on a variety of hematopoietic cell types, such as antigen-presenting cells, but pdl1 in particular can be expressed. It relies on a number of non-hematopoietic cell types, such as blood vessels.
A variety of epithelial cell types. muscle cells. liver cells. Cells from the eyelids in the pancreas. they control T cell responses locally within tissues, and indeed that is the case. We've learned that interferons are potent stimuli for upregulation of pdl1 and pdl2, so this is one way the immune system can downregulate immune responses naturally once it gets the cells activated, these cytokines are made and part of the counterpoint and the counterbalance here is that these cytokines will regulate these ligands which can then also serve to fine-tune immune responses when I think about the pd-1 pathway it's really an example of why we have somewhat inhibitory signals in the immune system, this pathway is a counterbalance to positive signals via T cell receptor and cd28 pd1 like ctla4 these inhibitory signals are also important in mediating tolerance and furthermore, expression of pdl1 in tissues has a role important, since it allows these pathways to play an important role in the resolution of pdl1 inflammation in cells of non-hematopoietic tissue, thus so cells in tissues express pdl-1 and this can control the resolution of inflammation and also protect tissues from autoimmune attack; moreover, they are the smartest immunologists, the microbes and tumors that have time and again exploited this pathway to evade eradication by the immune system.
This pathway contributes to T cell dysfunction, a known process. like depletion that can develop during chronic viral infection and also cancer now, what is T cell depletion? This is a dysfunctional state that is defined by poor effector T cell function, so the cells do not kill as well. They do not produce cytokines as well as these cells. they express high levels of pd1 and other inhibitory receptors and this is a unique transcriptional and epigenetic state only for c Let's compare acute versus chronic infection. Here we have a viral infection. Let's say, like the influenza virus, the immune system encounters the virus and the naive T cells are activated. infected cells and then the virus is cleared and then we get a memory response in contrast there are some infections like hiv hepatitis b hepatitis c a mouse model is widely used as well known lymphocytic choreomingitis virus like lcmv and the situation in cancer where you have tumor antigens that are chronic is quite similar in this situation where you have persistent anagen that these chronically stimulated cells go into as they sink progressively into states of T cell depletion , first the cells lose the ability to make IL-2 and then they lose the ability to make cytokines and become poorer killers and these cells some of them can disappear we are now learning that there are distinct populations of these e cells this understanding of pd- 1 and t cell depletion was first described in this model of lcmv infection and here what we are seeing do is there is a form of lcmv that causes an acute infection like influenza the infection occurs but then it is cleared and so here if we look at the black circles what you can see is that during the acute infection the expression of pd- 1 goes up, but then as the virus is cleared, pd-1 expression will go down again during chronic infection, pd-1 goes up but stays high and what we've learned is that these cells that express a lot of pd1 are depleted and they are less functional and the work of rafael john weary dan barber and gordon freeman showed that blocking this pathway could revive the function of these depleted cells so that chronic infection could reduce the viral load in many registries and what i want that The take away from this is that both activated T cells and exhausted cells can express pd1, so you can't tell if a cell was recently activated or exhausted.
Due to the expression of pd-1 alone, it is necessary to observe these cells and study them further. This part of the pathway has also been translated into therapy. tissue cells can express pdl1 and antibody drugs have been developed to pd-1 or pdl-1 that blocks this interaction and this can trigger a potent antitumor response so these ctls these cd8 t cells can now kill and make a more cytokines and this has translated into therapy as well, as pd1 blockers have been approved for 22 different types or for 22 different types of cancer. I would now like to move on to a discussion of the role of T cells in defense against infection.
So when we think about the immune response to an acute viral infection, we can think of it in phases, so we have the infection, and then as a result of the stimulation, the immune cells are activated, the T cells are activated. they expand, they differentiate, then they can deal with the virus, so the viral load will go down and the virus will be shed, then we have what's known as a contraction phase and a transition to memory, so we're looking at the time here this can take a period typically of weeks and these memory cells can last for years so when we think about the sequence events for the development of these effector T cell responses we have antigen recognition as we've mentioned and these naive T cells or B cells can become activated and these cells will then proliferate and then differentiate into effector cells and two memory cells so first we'll talk about cd4 effector cells and what they can do and then affect your cd8 cells, which are the cells that become killer. cells and what they're capable of doing first these naive cd4 cells are able to differentiate into different subsets and these subsets can recruit and activate different types of cells that the can collaborate to fight different types of infections so like shown on this slide, there are effector cells which are the cells that produce the cytokine.
Interferon is the cytokine that defines these cells that the main target of gamma interferon is macrophages and as a result of interferon. these cells, the macrophages will have a receptor to be able to bind to the gamma interferon and then there are signals that go into these macrophages that activate these macrophages so that they can deal with intracellular microbes and kill them. Th2 cells produce different cytokines il4 il5 and il13 and these cytokines are capable of activating different types of immune cells eosinophils mast cells and certain types of macrophages and this type of immune defense is important in particular for certain types of parasites and worms these hulls we also have th17 cells that produce il-17 and il-22 and these can recruit neutrophils and activate them and these neutrophils can deal with ext racellular bacteria and fungi finally there are t follicular helper cells abbreviated tfh these cells can produce cytokines that they include il-21 and they can also produce interferon or il-4 and these target b cells and tfh cells work together with b cells and can lead to the production of antibodies and antibodies are very important in dealing with extracellular pathogens or extracellular forms of for example For example, a virus, so antibodies are important in dealing with viral particles. s and prevent antibodies can prevent the virus from attaching to a cell and infecting and I think your next lesson is to speak.
We're going to talk a lot more about the properties of antibodies, but we also have shapes in the ctl that we'll talk about next. They are important to kill the cells that become infected, but first us. I'll talk a little more. I'm going to focus here on the time that only allows me to talk in depth about one set of these cells and I'm going to talk about follicular helper T cells because in Interactions between helper cells, T helper cells, and B cells are important for the antibody defense and then we'll continue talking about cytotoxic T cells, so in this cartoon what we're doing is outlining the steps and stages for cd4 t helper cell interactions. cells with b cells that are needed for antibody production, so initially we have activation of these helper t cells with antigen and costimulation, as we've already discussed, that allow these cells to differentiate into theirt cells and this initial activation occurs in the t cell zone and thus you get antigen recognition and costimulation at the same time in the follicles the antigen is carried to the same antigen that is carried there and these b cells are activated as a result of the activation of t cells into b cells are capable of migrating with each other and interacting, so when these cells interact, it is the interactions between these cells and the signals between them that allow the initial signals to initiate the antibody resp.
As a result, outside of the follicle we have these short-lived plasma cells that develop, but then some of these cells migrate back into the follicle where they form the germinal center and these specialized follicular helper cells can interact with the b cells there and allow these The b cells then become long-lived plasma cells and memory b cells. I know michel bummer talked in depth about these cells, but I just want to focus on one aspect of these cells and talk about the collaboration of tb and helping our cd4-mediated activation of these B-cell lymphocytes that when these cells interact, as we've discussed, these activated helper T cells will express a molecule called cd40 ligand which is upregulated on the surface of these activated cells and they also produce cytokines and then the B cells when they interact have receptors where they can receive signals through these cytokines and also cd40 will activated when the sligand of the t cell binds to cb40 on the b cell as a result of these signals, these interactions between cd40 and the cd40 ligand are very important for the proliferation and differentiation of b cells and we know this because there are diseases , there are mutations in the cd40 or cd40 ligand gene and this can lead to hyper igm syndrome. mutations in the cd40 ligand gene result in a disease characterized by defects in antibody production in which isotypes such as igg are not switched and maturation of the immunoglobulin response is not obtained and we also know this from studies in mice that have mutations in the cd40 or cd40 ligand, so these interactions between these cd4 cells and b lymphocytes are critical to the maturation and activation of the b cell response that occurs.
Now I would like to move on to the cd8 cells. These are the cells. those are the ones that can develop to kill infected cells and so giving you an overview first of these responses cd4 and cd8 T cell responses occur within a lymphoid organ such as a lymph node it has presenting cells of anagens, such as dendritic cells that are to transport the viral antigens to the lymph node, where interactions between um, the t cell receptor, and the b7 molecules on these dendritic cells with naïve cd8 t cells will lead to their activation, their proliferation, and then their differentiation in effector cells and these differentiated effector cells then enter the circulation and can migrate back to the sites of initial infection where these ctls can kill the infected cells which are called target cells so it is important that you know that these cd8 t cells naive cells do not kill infected cells which these cells need to differentiate into effective cells and when this differentiation process occurs, these mature killer T cells acquire the machinery that allows these cells to lyse and kill infected cells now killing cells is antigen specific is the same mhc peptide antigen that caused these cd8 cells to become differentiate into these killer cells which is required to trigger death by these mature differentiated ctl.
Now these cytolytic T cells have two main functions, the first is direct destruction of infected cells and the second is secretion. of inflammatory cytokines these inflammatory cytokines are important in the function of the ctl but they can also work to activate macrophages so there is an association of different types of cells to defend us against microbes how do these cells exert their functions and this cartoon shows that when there is antigen recognition of an infected target cell here by a ctl that these cells bind very tightly there are integrins on the surface of these cells that lead to a stable interaction like the interactions between lfa 1 and i cam for example these ctl then get activated and have that leads to excessive exocytosis of granules in these cells and these granules contain granzymes and front perforin creates pores in the membranes of the target cell of the infected cell and then these granzymes can enter to the cell and can cause the death of these cells, a process that leads to cell death death d e cells infected by these activated ctl finally I would like to move on to T cell responses in covid19 this is a work in progress the type of work being done Work is being done on characterizing cd4 cells and specific cd8 cells of the virus across the spectrum of disease in hospitalized patients in recovering patients both in convalescent and asymptomatic people, work is underway to define the specificities of t cells, what does the virus have that cb4 t cells and cd8 ven and work is underway to correlate the phenotypes of these t cells with the spectrum of disease. but this is resolved when the patients recover.
Lymphopenia has been reported to affect cd4 t cells, cd8 t cells, b cells, and natural killer cells. The mechanisms are still unclear. could be due to hyperactivation hyperstimulation of t cells or high levels of expression of molecules that can cause the death of these t cells work from one of the previous ious lectures dr schiff pillai has been studying seriously ill patients who had coven 19 who unfortunately succumbed to the disease and when they studied the cells of these individuals they found that in contrast to the individuals who were not infected there was a marked decrease in the number of b and t cells, the number of cells in the lymph nodes of these people who died, as well as the reduced number of cells b and t cells in the spleen, another thing that was found and I think Dr. pillai talked about this a little bit last time from an innate immunity perspective is that in these In individuals who died from severe infection, found that there was an attenuation of the germinal center response and this probably leads to a dis decreased generation of long-lasting antibodies.
What was found is that there was a complete loss of the germinal centers in the lymph nodes and spleens of these people with severe covin19 and that there was a blockage in the development of these follicular helper T cells that are important for the generation of these responses. from the germinal center in the b cells there was an increase in these th1 cells which produce cytokines and there was also a lot of tnf production and macrophage secretion which may contribute to this faulty response more work is needed but this is certainly enlightening and helping us understand some of defects seen in patients with very serious illnesses.
There is other work in progress from people with less severe disease and the types of studies are illustrated here where people are asking what cd8 t cells are. and cd4 c t cells that t cells are taken from patients which, in this case, patients who have recovered from a disease, patients who are asymptomatic for example, and they can take these t cells and then see what portions of the virus proteins are seen and identify them and this kind of work that just came online this last month in immunity, for example, has shown that about 90% of the proteins that are epitopic That means the anagen portions that you see are not the protein spike, but it appears that other proteins, such as the nucleocapsid protein, as well as membrane and other open reading frames, are the targets and found that cd8 t cells from these individuals do not show cross-reactivity with seasonal coronaviruses;
Also, a recent article that was just published and was online last week in Cell was looking at a variety of patients or people who were infected, those with very severe illness who died, those who recovered, those with mild illness illness those who recovered from mild illness exposed family members some of whom were asymptomatic and then also observed blood donors and observed in various ways using flow cytometry to observe phenotype using ellie dot to looking at some of the functions of these cells and correlating this with um types of disease and what and and disease phenotype and what they found is that in acute infection there are t cells that can display an activated cytotoxic phenotype and that in convalescent individuals when they study these t cells and stimulate them in vitro can produce for example multiple cytoq uines and on their surface have memory markers interestingly they have found specific cyrus cov2 specific T cells and people who do not have antibodies suggesting that antibodies alone may underestimate the extent of infected people so as I mentioned this is a work in progress, more and more articles are being published every day, literally, um, I have here two recent reviews. which I think are very thoughtful one from corolla venusa that was published in cell in october one from john weary in his lab that was published in nature also reviews immunology and to sum it up we are really at a very early stage of understanding immunology t cell responses to coven 19 we are detecting cd4 and cd8 t cells with memory markers these have been detected in one hundred percent of cd4 or f cells people who have recovered and seventy percent cd of uh cd8 cells are seen in these patients and individuals who recovered um memory t cells responding to multiple sars cov2 proteins not only the spike protein but also, for example, the nucleoprotein and membrane protein have been detected in different studies which appears to be cd8 t cell responses it is mainly to the internal proteins rather than the spike protein what has been observed is a particularly high frequency of cd4 cells that can see the protein ina of the viral spike in patients who have recovered but we need more work to understand if the presence of how to interpret the presence of these cells is not yet clear if these cells provide protective immunity and that work will take time also as I mentioned there has been work recent with virus-specific T cells being detected in antibodies in negative individuals and these were relatives of people who developed sars cov2 infection and in convalescence More work is needed to understand how to interpret this and eventually as one reads the articles some studies show from the early days that you see a lot of cells expressing high levels of these inhibitory receptors like pd1 and ctla4 and some people refer to these cells as depletion in preparation for this conference i talked to one of the experts who has been studying these cells because and I asked him how he interprets that these cells, as I mentioned onee, they are newly activated or dysfunctional and your feeling is that these cells are predominantly highly activated cells as I mentioned during activation there may be high levels of these inhibitory receptors that are upregulated but more work is needed he said that as has done transcriptional profiling on some of these cells that have some characteristics of depleted cell transcriptional profiling, so this is really a work in progress, but I think this work gives us hope that memory T cells will develop and we need to understand more about the functions of these cells so i will stop sharing my screen now and turn on my video again happy to answer questions i think i have a few minutes left thank you very much dr sharp we have some questions uh the vaccines as you noticed they are developing cells focus on the spike protein and you noted that t cells often recog They don't know extra bits of the virus, right?
I think this is a problem so I think vaccines are going to be very important in building up protective immunity because as work from the Shiv Pillai lab has indicated that in critically ill patients we won't be able to build up a good antibody response it seems as though most cd4 cells are directed against spike proteins, so that's good news, but I think this also tells us that in order to build a broader response, we may want to think more broadly about developing responses. to ot their proteins you also think that T cell responses could contribute to the rogue immune response cytokine storm, for example, which is seen in a subset of patients that's a very good question is it possible that T cells could contribute the innate immune system certainly has an important role in this as well that we know thatthe cytokines produced by the cells of the innate immune system make a lot of interferons and tnf very early, so it could be that those cells are the predominant drivers of the cytokine storm, but I think that T cells also have the potential to contribute to that some patients who are infected with this virus also get cancer and there is some curiosity as to whether we know anything about the response to viral infection when patients receive therapies that modulate the immune response in cancer, so it is a very good question if has published very little on that, as the current work that has been published has indicated that cancer patients still can't respond to immunotherapies in some of the patients that I mentioned where there are high levels of these inhibitory receptors that have been seen in certain patients, especially with haematological malignancies, suggesting that it may be different in ci Certain types of cancer patients may be some of the most vulnerable to this infection, so more work is needed as we begin to understand how different types of comorbidities, cancer, age, obesity, others things will affect the immune response to copine 19. and one more question, you talked about depletion of T cells, but why not?
Pathogens that directly suppress ctla-4 or pd1 do not evolve. Yeah, so, I think this is part of an answer that's playing out because we know that if we don't have ctla4 or pd1, these pathogens can upregulate pdl1 ligands for tumors. smart in the sense that they can regulate the ligands and defend themselves as well but if we lack pd1, the pd1 pathway and mouse models when you give the animal an infection with the form of lcmv causing chronic infection they die trying to clear the infection so it has balanced pathogenicity if you will the virus can survive and find another host to replicate so there is limited damage to the host's immune system arlene thank you so much for being with us today truly a pleasure Thanks again
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