You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells}
Article:
Abstract:
The global health burden due to sepsis and the associated cytokine storm is substantial. While early intervention has improved survival during the cytokine storm, those that survive can enter a state of chronic immunoparalysis defined by transient lymphopenia and functional deficits of surviving cells. Memory CD8 T cells provide rapid cytolysis and cytokine production following re-encounter with their cognate antigen to promote long-term immunity, and CD8 T cell impairment due to sepsis can pre-dispose individuals to re-infection. While the acute influence of sepsis on memory CD8 T cells has been characterized, if and to what extent pre-existing memory CD8 T cells recover remains unknown. Here, we observed that central memory CD8 T cells( TCM) from septic patients proliferate more than those from healthy individuals. Utilizing LCMV immune mice and a CLP model to induce sepsis, we demonstrated that TCM proliferation is associated with numerical recovery of pathogen-specific memory CD8 T cells following sepsis-induced lymphopenia. This increased proliferation leads to changes in composition of memory CD8 T cell compartment and altered tissue localization. Further, memory CD8 T cells from sepsis survivors have an altered transcriptional profile and chromatin accessibility indicating long-lasting T cell intrinsic changes. The sepsis-induced changes in the composition of the memory CD8 T cell pool and transcriptional landscape culminated in altered T cell function and reduced capacity to control L. monocytogenes infection. Thus, sepsis leads to long-term alterations in memory CD8 T cell phenotype, protective function and localization potentially changing host capacity to respond to re-infection.
Introduction:
Dysregulated systemic inflammatory responses define septic events and the associated cytokine storm, which is comprised of both pro- and anti-inflammatory cytokines( CDC, 2020; Singer et al., 2016). Sepsis leads to a substantial global health and economic burden wherein nine people develop sepsis every 6 s and two of those individuals die( Rudd et al., 2020). In the United States alone the cost to treat sepsis is >$20 billion with a mortality rate of ~20 %( CDC, 2020). While a 20 % mortality rate is high, it is also a vast improvement over the last 30 years where mortality had been at ~50 %( Dombrovskiy et al., 2007; Gaieski et al., 2013). This reduction in mortality rate has largely been through early intervention as the complexity of the cytokine storm has, dishearteningly, lead to the failure of >100 phase II and III clinical trials targeting the pro-inflammatory aspects of the cytokine storm( Marshall, 2014). Yet, even as survival of the cytokine storm has increased it has also become apparent that previously septic individuals are still at increased risk for mortality, this defines the sepsis-induced immunoparalysis state( Delano and Ward, 2016a; Delano and Ward, 2016b; Dombrovskiy et al., 2007; Donnelly et al., 2015). Sepsis-induced immunoparalysis is characterized by an increased susceptibility to both new and previously encountered unrelated infections and cancer( Danahy et al., 2019; Jensen et al., 2018a; Kutza et al., 1998; Walton et al., 2014). Alternately, sepsis-induced immunoparalysis reduces susceptibility to development of autoimmunity, cumulatively demonstrating immunologic impairment( Jensen et al., 2020). These profound impairments are sufficient to reduce the 5 year survival of septic cohorts, relative to non-septic cohorts; consequently, the majority of sepsis-associated mortality is late mortality secondary to the cytokine storm( Dombrovskiy et al., 2007; Donnelly et al., 2015; Gaieski et al., 2013). This immunologic impairment is typified by transient lymphopenia and reduced capacity of various surviving lymphocyte populations to perform effector function( Hotchkiss et al., 2016; Hotchkiss et al., 2013), including CD4( Cabrera-Perez et al., 2014; Cabrera-Perez et al., 2015; Chen et al., 2017; Jensen et al., 2020; Martin et al., 2020; Sjaastad et al., 2020b) and CD8 T cells( Condotta et al., 2013; Danahy et al., 2017; Danahy et al., 2019; Duong et al., 2014; Serbanescu et al., 2016; Xie et al., 2019), B cells( Hotchkiss et al., 2001; Sjaastad et al., 2018; Unsinger et al., 2010), NK cells( Hou et al., 2014; Jensen et al., 2021b; Jensen et al., 2018b; Souza-Fonseca-Guimaraes et al., 2012), and dendritic cells( DCs)( Poehlmann et al., 2009; Roquilly et al., 2017; Strother et al., 2016). We and others have characterized numerous impairments early after sepsis induction; however, the extent to which those cell populations recover in number and function remains largely unknown. Specifically, sepsis-induced lymphopenia impacts both memory and naïve CD8 T cells early after sepsis( Condotta et al., 2015; Condotta et al., 2013; Duong et al., 2014; Jensen et al., 2018a; Markwart et al., 2014). Additionally, those memory CD8 T cells that survive the cytokine storm are less capable of undergoing antigen-dependent effector function and responding to inflammatory cues( bystander activation). These intrinsic impairments, in conjunction with the numeric deficits imposed by the lymphopenic environment, reduce host capacity to control both infection( i. e. viral and bacterial) and cancer( Danahy et al., 2017; Danahy et al., 2019; Duong et al., 2014; Gurung et al., 2011). Additionally, extrinsic factors, such as reduced integrin expression on endothelia( Danahy et al., 2017) or altered monocyte/ macrophage activity( Jensen et al., 2021a; Roquilly et al., 2020), can influence CD8 T cell capacity to migrate into sites of infection. Even when T cells are spared from the cytokine storm by vascular exclusion( i. e. tissue residence) CD8 T cell-mediated protection can be hampered by inability of other cells( e. g. endothelia) to respond to the inflammatory cues provided by CD8 T cells( Danahy et al., 2017). Yet, these impairments are largely characterized proximal to the septic insult. However, sepsis-induced impairments are long-lasting and may not be consistent across time( Jensen et al., 2018a). Specifically, the lymphopenic environment is transient yet the ability to control cancer can remain reduced long after numeric recovery is complete( Danahy et al., 2019). Thus, while there does not appear to be preferential susceptibility to sepsis, if and how different subsets of memory CD8 T cells recover may dramatically shape how hosts respond to pathogen re-encounter and thereby contribute to the immunoparalysis state. Here, using samples from septic patients and well described experimental models we demonstrate increased proliferation of CD8 T cells( particularly central memory cells[TCM]) in septic patients and mice after cecal ligation and puncture( CLP)-induced sepsis, relative to non-septic controls. As a consequence of this increased proliferation, there is a remodeling of the memory CD8 T cell pool. This compositional change in turn leads to lasting changes in the localization, function, and protective capacity of pre-existing memory CD8 T cells.
Discussion:
In the present study, we demonstrate that sepsis leads to a lasting change in the composition of the memory CD8 T cell compartment in the sepsis survivors. This occurs as a result of proliferation in the lymphopenic environment that occurs after sepsis, seen in both patients and mice, wherein TCM have higher proliferative capacity than TEM. This biasing toward TCM alters the localization of memory CD8 T cells. Further, the memory CD8 T cell pool has an altered transcriptional landscape and chromatin accessibility, which is associated both with the transition toward TCM and functional alterations. The culmination of these sepsis-induced changes alters the function of the memory CD8 T cells and reduces their capacity to control virulent L. m. infection. There are several important implications of the present study, and the biasing toward TCM, that are relevant to our understanding of the immunoparalysis state. Among these is the relationship to tissue resident memory CD8 T cells( TRM), which provide sensing and alarm function at sites of prior infection( Masopust et al., 2001; Schenkel et al., 2013). The present study focuses on the influence of sepsis on circulating TEM and TCM CD8 T cells; however, the substantial population of TRM throughout the body may be an interesting source of future interrogation. Danahy et al. previously demonstrated that TRM were not susceptible to sepsis-induced lymphopenia, due to their exclusion from the vasculature( Danahy et al., 2017). In the present study, recovery in cellularity was observed with time after sepsis, but the biasing toward TCM may pose a particular problem for TRM. Specifically, Slütter et al. demonstrated that lung TRM are seeded from circulating TEM( Slütter et al., 2017). Thus, the challenge to the TRM may be twofold:( 1) the reduced seeding of cells during the lymphopenic state and( 2) reduced TEM pool from which to seed the TRM. This reduction may culminate in a more rapid waning of lung TRM and reinforce susceptibility to previously encountered infections. Moreover, the detrimental effects of sepsis on memory CD8 T cells may also be relevant to other major inflammatory events and poorly controlled infections( e. g. SARS-CoV-2) and should be considerations in the long-term consequences for similarly impacted individuals( Li et al., 2020; Sariol and Perlman, 2020). While the immunoparalysis state is often viewed directly through the lens of the detriments that may arise, it is also relevant to consider other means by which the host immune response may be shaped. The loss of TEM here demonstrates their critical role in fighting some infections( i. e. L. m.)( Nolz and Harty, 2011); however, TCM are also a potent population that can critically mediate control in other infection scenarios. Thus, infections for which TCM can provide critical control may be unimpaired or even enhanced in the post-septic environment. This is potentially complicated by intrinsic deficits that may be present in the memory cells, as observed in our GSEA analysis and by CD8 T cell extrinsic impairments. Therefore, future studies should consider additional interrogation of mechanisms by which the immune system is altered beyond detrimental aspects. Additionally, while our interrogation focused on a shift of pre-existing memory CD8 T cells toward a central memory phenotype, it remains possible that other T cell populations( e. g. different antigen specificities) may bias toward effector memory. This may be particularly relevant to memory T cell populations whose TCR has some low degree of cross reactivity with antigens present on microbes released during the septic event. These considerations may be important for future therapeutic interrogation in the specific targeting of the appropriate deficits. Additionally, it is relevant to consider that proliferation, as demarcated by Ki67, was also observed in naïve CD8 T cells of septic patients. While not the focus of the present study this is also observed in our mouse model. The proliferation by naïve CD8 T cells in septic hosts suggests that CD8 T cells are proliferating in response to the lymphopenic environment. Indeed, naive cells undergo antigen-independent proliferation in other lymphopenic environments, such as Rag-/- or irradiated hosts, wherein they adopt conventional markers of antigen experience along with some effector functionality( Cheung et al., 2009; Pribikova et al., 2018; Unsinger et al., 2009; White et al., 2017). Thus, it may be relevant to consider how the proliferation of these cells also alter the composition of the memory CD8 T cell compartment and shapes host response to subsequent infection for which they may be specific. Our novel characterization of how numeric recovery in the lymphopenic environment alters the composition of the memory CD8 T cell compartment demonstrates how sepsis can lead to lasting changes in host immunity. However, the implications of these changes may extend beyond the enhanced susceptibility to infection described here to potentially reframe our understanding of the immunoparalysis state. Future interrogation of these lasting effects will likely be required to best address the deficits that arise in the immunoparalysis state. Further understanding how sepsis shapes both naive and memory T cells may also alternately produce therapeutic interventions to benefit other diseases. One such example may be in the promotion of TCM over TEM, or vice versa, for specific vaccination strategies. Such outcomes and lines of investigation would be highly instructive for understanding how prior immune history shapes subsequent host immune responses.
A dirty cut , a nasty burn , a severe COVID infection; there are many ways for someone to develop sepsis . This life-threatening condition emerges when the immune system overreacts to a threat and ends up damaging the body . Even when patients survive , they are often left with a partially impaired immune system that cannot adequately protect against microbes and cancer; this is known as immunoparalysis . Memory CD8 T cells , a type of immune cell that is compromised by sepsis , are a long-lived population of cells that ‘remember’ previous infection or vaccination , and then react faster to prevent the same illness if the person ever encounters the same threat again . Yet it is unclear how exactly sepsis harms the function and representation of memory CD8 T cells , and the immune system in general . Jensen et al . investigated this question , first by showing that sepsis leads to a profound loss of memory CD8 T cells , but that surviving memory CD8 T cells multiply quickly – especially a subpopulation known as central memory CD8 T cells – to re-establish the memory CD8 T cell population . Since the central memory CD8 T cells proliferate better than the other memory T cells this alters the overall composition of the pool of memory CD8 T cells , with central memory cells becoming overrepresented . Further experiments revealed that this biasing toward central memory T cells , due to sepsis , created long-term changes in the distribution of memory CD8 T cells throughout the body . The way the genetic information of these cells was packaged had also been altered , as well as which genes were switched on or off . Overall , these changes reduced the ability of memory CD8 T cells to control infections . Together , these findings help to understand how immunoparalysis can emerge after sepsis , and what could be done to correct it . These findings could also be applied to other conditions – such as COVID-19 – which may cause similar long-term changes to the immune system .