Infection of HLA-DR1 Transgenic Mice with a Human Isolate of Influenza A Virus (H1N1) Primes a Diverse CD4 T-Cell Repertoire That Includes CD4 T Cells with Heterosubtypic Cross-Reactivity to Avian (H5N1) Influenza Virus

ABSTRACT The specificity of the CD4 T-cell immune response to influenza virus is influenced by the genetic complexity of the virus and periodic encounters with variant subtypes and strains. In order to understand what controls CD4 T-cell reactivity to influenza virus proteins and how the influenza virus-specific memory compartment is shaped over time, it is first necessary to understand the diversity of the primary CD4 T-cell response. In the study reported here, we have used an unbiased approach to evaluate the peptide specificity of CD4 T cells elicited after live influenza virus infection. We have focused on four viral proteins that have distinct intracellular distributions in infected cells, hemagglutinin (HA), neuraminidase (NA), nucleoprotein, and the NS1 protein, which is expressed in infected cells but excluded from virion particles. Our studies revealed an extensive diversity of influenza virus-specific CD4 T cells that includes T cells for each viral protein and for the unexpected immunogenicity of the NS1 protein. Due to the recent concern about pandemic avian influenza virus and because CD4 T cells specific for HA and NA may be particularly useful for promoting the production of neutralizing antibody to influenza virus, we have also evaluated the ability of HA- and NA-specific CD4 T cells elicited by a circulating H1N1 strain to cross-react with related sequences found in an avian H5N1 virus and find substantial cross-reactivity, suggesting that seasonal vaccines may help promote protection against avian influenza virus.

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Peptide Epitope Hot Spots of CD4 T Cell Recognition Within Influenza Hemagglutinin During the Primary Response to Infection

Pathogens ◽

10.3390/pathogens8040220 ◽

2019 ◽

Vol 8 (4) ◽

pp. 220 ◽

Cited By ~ 1

Author(s):

Zackery A. G. Knowlden ◽

Katherine A. Richards ◽

Savannah A. Moritzky ◽

Andrea J. Sant

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Cd4 T Cells ◽

H1n1 Influenza ◽

Primary Response ◽

Cd4 T Cell ◽

T Cell Epitopes ◽

Peptide Epitope ◽

Ha Protein

Antibodies specific for the hemagglutinin (HA) protein of influenza virus are critical for protective immunity to infection. Our studies show that CD4 T cells specific for epitopes derived from HA are the most effective in providing help for the HA-specific B cell responses to infection and vaccination. In this study, we asked whether HA epitopes recognized by CD4 T cells in the primary response to infection are equally distributed across the HA protein or if certain segments are enriched in CD4 T cell epitopes. Mice that collectively expressed eight alternative MHC (Major Histocompatibility Complex) class II molecules, that would each have different peptide binding specificities, were infected with an H1N1 influenza virus. CD4 T cell peptide epitope specificities were identified by cytokine EliSpots. These studies revealed that the HA-specific CD4 T cell epitopes cluster in two distinct regions of HA and that some segments of HA are completely devoid of CD4 T cell epitopes. When located on the HA structure, it appears that the regions that most poorly recruit CD4 T cells are sequestered within the interior of the HA trimer, perhaps inaccessible to the proteolytic machinery inside the endosomal compartments of antigen presenting cells.

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Suppression of Cytotoxic T Cell Functions and Decreased Levels of Tissue-Resident Memory T Cells during H5N1 Infection

Journal of Virology ◽

10.1128/jvi.00057-20 ◽

2020 ◽

Vol 94 (9) ◽

Cited By ~ 2

Author(s):

Matheswaran Kandasamy ◽

Kevin Furlong ◽

Jasmine T. Perez ◽

Santhakumar Manicassamy ◽

Balaji Manicassamy

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Memory T Cells ◽

Viral Clearance ◽

Virus Infections ◽

Cell Functions ◽

Resident Memory T Cells

ABSTRACT Seasonal influenza virus infections cause mild illness in healthy adults, as timely viral clearance is mediated by the functions of cytotoxic T cells. However, avian H5N1 influenza virus infections can result in prolonged and fatal illness across all age groups, which has been attributed to the overt and uncontrolled activation of host immune responses. Here, we investigate how excessive innate immune responses to H5N1 impair subsequent adaptive T cell responses in the lungs. Using recombinant H1N1 and H5N1 strains sharing 6 internal genes, we demonstrate that H5N1 (2:6) infection in mice causes higher stimulation and increased migration of lung dendritic cells to the draining lymph nodes, resulting in greater numbers of virus-specific T cells in the lungs. Despite robust T cell responses in the lungs, H5N1 (2:6)-infected mice showed inefficient and delayed viral clearance compared with H1N1-infected mice. In addition, we observed higher levels of inhibitory signals, including increased PD-1 and interleukin-10 (IL-10) expression by cytotoxic T cells in H5N1 (2:6)-infected mice, suggesting that delayed viral clearance of H5N1 (2:6) was due to the suppression of T cell functions in vivo. Importantly, H5N1 (2:6)-infected mice displayed decreased numbers of tissue-resident memory T cells compared with H1N1-infected mice; however, despite the decreased number of tissue-resident memory T cells, H5N1 (2:6) was protected against a heterologous challenge from H3N2 virus (X31). Taken together, our study provides mechanistic insight for the prolonged viral replication and protracted illness observed in H5N1-infected patients. IMPORTANCE Influenza viruses cause upper respiratory tract infections in humans. In healthy adults, seasonal influenza virus infections result in mild disease. Occasionally, influenza viruses endemic in domestic birds can cause severe and fatal disease even in healthy individuals. In avian influenza virus-infected patients, the host immune system is activated in an uncontrolled manner and is unable to control infection in a timely fashion. In this study, we investigated why the immune system fails to effectively control a modified form of avian influenza virus. Our studies show that T cell functions important for clearing virally infected cells are impaired by higher negative regulatory signals during modified avian influenza virus infection. In addition, memory T cell numbers were decreased in modified avian influenza virus-infected mice. Our studies provide a possible mechanism for the severe and prolonged disease associated with avian influenza virus infections in humans.

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CD32+and PD-1+Lymph Node CD4 T Cells Support Persistent HIV-1 Transcription in Treated Aviremic Individuals

Journal of Virology ◽

10.1128/jvi.00901-18 ◽

2018 ◽

Vol 92 (20) ◽

Cited By ~ 18

Author(s):

Alessandra Noto ◽

Francesco A. Procopio ◽

Riddhima Banga ◽

Madeleine Suffiotti ◽

Jean-Marc Corpataux ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hiv Infection ◽

Cell Population ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Cell Populations ◽

Latently Infected ◽

Infected Cells ◽

Hiv 1

ABSTRACTA recent study conducted in blood has proposed CD32 as the marker identifying the “elusive” HIV reservoir. We have investigated the distribution of CD32+CD4 T cells in blood and lymph nodes (LNs) of HIV-1-uninfected subjects and viremic untreated and long-term-treated HIV-1-infected individuals and their relationship with PD-1+CD4 T cells. The frequency of CD32+CD4 T cells was increased in viremic compared to treated individuals in LNs, and a large proportion (up to 50%) of CD32+cells coexpressed PD-1 and were enriched within T follicular helper (Tfh) cells. We next investigated the role of LN CD32+CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32+and PD-1+CD4 T cells compared to CD32−and PD-1−cells in both viremic and treated individuals, but there was no difference between CD32+and PD-1+cells. There was no enrichment of latently infected cells with inducible HIV-1 in CD32+versus PD-1+cells in antiretroviral therapy (ART)-treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32+PD-1+CD4 T cells were significantly enriched in cell-associated HIV RNA compared to CD32−PD-1−(averages of 5.2-fold in treated individuals and 86.6-fold in viremics), CD32+PD-1−(2.2-fold in treated individuals and 4.3-fold in viremics), and CD32−PD-1+(2.2-fold in ART-treated individuals and 4.6-fold in viremics) cell populations. Similar levels of HIV-1 transcription were found in CD32+PD-1−and CD32−PD-1+CD4 T cells. Interestingly, the proportion of CD32+and PD-1+CD4 T cells negatively correlated with CD4 T cell counts and length of therapy. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and coexpression of CD32 and PD-1, the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals.IMPORTANCEThe existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication-competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells coexpressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription.

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Anti-apoptotic clone 11 derived peptides induce in vitro death of CD4+ T cells susceptible to HIV-1 infection

10.1101/2020.04.06.028860 ◽

2020 ◽

Author(s):

Anastassia Mikhailova ◽

José Carlos Valle-Casuso ◽

Annie David ◽

Valérie Monceaux ◽

Stevenn Volant ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

T Cell Subsets ◽

Cd4 T Cell ◽

T Cell Memory ◽

Target Cells ◽

Cell Memory ◽

Infected Cells ◽

Hiv 1

ABSTRACTHIV-1 successfully establishes long-term infection in its target cells despite viral cytotoxic effects. We have recently shown that cell metabolism is an important factor driving CD4+ T-cell susceptibility to HIV-1 and the survival of infected cells. We show here that expression of anti-apoptotic clone 11 (AAC-11), an anti-apoptotic factor upregulated in many cancers, increased with progressive CD4+ T cell memory differentiation in association with the expression of cell cycle, activation and metabolism genes and correlated with susceptibility to HIV-1 infection. Synthetic peptides based on the LZ domain sequence of AAC-11, responsible for its interaction with molecular partners, were previously shown to be cytotoxic to cancer cells. Here we observed that these peptides also blocked HIV-1 infection by inducing cell death of HIV-1 susceptible primary CD4+ T-cells across all T-cell subsets. The peptides targeted metabolically active cells and had the greatest effect on effector and transitional CD4+ T cell memory subsets. Our results suggest that AAC-11 survival pathway is potentially involved in the survival of HIV-1 infectable cells and provide a proof of principle that some cellular characteristics can be targeted to eliminate the cells offering the best conditions to sustain HIV-1 replication.IMPORTANCEAlthough antiretroviral treatment efficiently blocks HIV multiplication, it cannot eliminate the cells already carrying integrated proviruses. In the search for a HIV cure the identification of new potential targets to selectively eliminate infected cells is of the outmost importance. We show here that peptides derived from the anti-apoptotic clone 11 (AAC-11), which expression levels correlated with susceptibility to HIV-1 infection of CD4+ T-cells, induced cytotoxicity in CD4+ T-cells showing the highest levels of activation and metabolic activity, conditions known to favor HIV-1 infection. Accordingly, CD4+ T-cells that survived the cytotoxic action of the AAC-11 peptides were resistant to HIV-1 replication. Our results identify a new potential molecular pathway to target HIV-1 infection.

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Memory CD4 T Cells Direct Protective Responses to Influenza Virus in the Lungs through Helper-Independent Mechanisms

Journal of Virology ◽

10.1128/jvi.01069-10 ◽

2010 ◽

Vol 84 (18) ◽

pp. 9217-9226 ◽

Cited By ~ 117

Author(s):

John R. Teijaro ◽

David Verhoeven ◽

Carly A. Page ◽

Damian Turner ◽

Donna L. Farber

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Cd4 T Cells ◽

Natural Infection ◽

Influenza Virus Infection ◽

Cd4 T Cell ◽

Virus Challenge ◽

Specific Memory ◽

Memory Cd4 T Cells

ABSTRACT Memory CD4 T cells specific for influenza virus are generated from natural infection and vaccination, persist long-term, and recognize determinants in seasonal and pandemic influenza virus strains. However, the protective potential of these long-lived influenza virus-specific memory CD4 T cells is not clear, including whether CD4 T-cell helper or effector functions are important in secondary antiviral responses. Here we demonstrate that memory CD4 T cells specific for H1N1 influenza virus directed protective responses to influenza virus challenge through intrinsic effector mechanisms, resulting in enhanced viral clearance, recovery from sublethal infection, and full protection from lethal challenge. Mice with influenza virus hemagglutinin (HA)-specific memory CD4 T cells or polyclonal influenza virus-specific memory CD4 T cells exhibited protection from influenza virus challenge that occurred in the presence of CD8-depleting antibodies in B-cell-deficient mice and when CD4 T cells were transferred into lymphocyte-deficient RAG2−/− mice. Moreover, the presence of memory CD4 T cells mobilized enhanced T-cell recruitment and immune responses in the lung. Neutralization of gamma interferon (IFN-γ) production in vivo abrogated memory CD4 T-cell-mediated protection from influenza virus challenge by HA-specific memory T cells and heterosubtypic protection by polyclonal memory CD4 T cells. Our results indicate that memory CD4 T cells can direct enhanced protection from influenza virus infection through mobilization of immune effectors in the lung, independent of their helper functions. These findings have important implications for the generation of universal influenza vaccines by promoting long-lived protective CD4 T-cell responses.

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Intranasal nanoparticle vaccination elicits a persistent, polyfunctional CD4 T cell response in the murine lung specific for a highly conserved influenza antigen that are sufficient to mediate protection from influenza virus challenge

Journal of Virology ◽

10.1128/jvi.00841-21 ◽

2021 ◽

Author(s):

Sean A. Nelson ◽

Thamotharampillai Dileepan ◽

Amy Rasley ◽

Marc K. Jenkins ◽

Nicholas O. Fischer ◽

...

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Cd4 T Cells ◽

Critical Role ◽

Influenza Virus Infection ◽

T Cell Response ◽

Cd4 T Cell ◽

Vaccine Platform

Lung-localized CD4 T cells play a critical role in the control of influenza virus infection and can provide broadly protective immunity. However, current influenza vaccination strategies primarily target influenza hemagglutinin (HA) and are administered peripherally to induce neutralizing antibodies. We have used an intranasal vaccination strategy targeting the highly conserved influenza nucleoprotein (NP) to elicit broadly protective lung localized CD4 T cell responses. The vaccine platform consists of a self-assembling nanolipoprotein particle (NLP) linked to NP with an adjuvant. We have evaluated the functionality, in vivo localization and persistence of T cells elicited. Our study revealed that intranasal vaccination elicits a polyfunctional subset of lung-localized CD4 T cells that persist long term. A subset of these lung CD4 T cells localize to the airway, where they can act as early responders following encounter with cognate antigen. Polyfunctional CD4 cells isolated from airway and lung tissue produce significantly more effector cytokines IFNγ and TNFα as well as cytotoxic functionality. When adoptively transferred to naïve recipients, CD4 T cells from NLP:NP immunized lung were sufficient to mediate 100% survival from lethal challenge with H1N1 influenza virus. Importance Exploiting new, more efficacious strategies to potentiate influenza-specific immune responses is important, particularly for at-risk populations. We have demonstrated the promise of direct intranasal protein vaccination to establish long-lived immunity in the lung with CD4 T cells that possess features and positioning in the lung that are associated with both immediate and long-term immunity, as well as demonstrating direct protective potential.

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Suppression of Cytotoxic T Cell Functions and Decreased Levels of Tissue Resident Memory T cell During H5N1 infection

10.1101/2020.01.09.901132 ◽

2020 ◽

Cited By ~ 1

Author(s):

Matheswaran Kandasamy ◽

Kevin Furlong ◽

Jasmine T. Perez ◽

Santhakumar Manicassamy ◽

Balaji Manicassamy

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Cytotoxic T Cells ◽

Influenza Viruses ◽

Viral Clearance ◽

Virus Infections ◽

Cell Functions

AbstractSeasonal influenza virus infections cause mild illness in healthy adults, as timely viral clearance is mediated by the functions of cytotoxic T cells. However, avian H5N1 influenza virus infections can result in prolonged and fatal illness across all age groups, which has been attributed to the overt and uncontrolled activation of host immune responses. Here we investigate how excessive innate immune responses to H5N1 impair subsequent adaptive T cell responses in the lungs. Using recombinant H1N1 and H5N1 strains sharing 6 internal genes, we demonstrate that H5N1 (2:6) infection in mice causes higher stimulation and increased migration of lung dendritic cells to the draining lymph nodes, resulting in higher numbers of virus specific T cells in the lungs. Despite robust T cell responses in the lungs, H5N1 (2:6) infected mice showed inefficient and delayed viral clearance as compared to H1N1 infected mice. In addition, we observed higher levels of inhibitory signals including increased PD1 and IL-10 expression by cytotoxic T cells in H5N1 (2:6) infected mice, suggesting that delayed viral clearance of H5N1 (2:6) was due to suppression of T cell functions in vivo. Importantly, H5N1 (2:6) infected mice displayed decreased numbers of tissue resident memory T cells as compared to H1N1 infected mice; however, despite decreased number of tissue resident memory T cells, H5N1 (2:6) were protected against a heterologous challenge from H3N2 virus (X31). Taken together, our study provides mechanistic insight for the prolonged viral replication and protracted illness observed in H5N1 infected patients.ImportanceInfluenza viruses cause upper respiratory tract infections in humans. In healthy adults, seasonal influenza virus infections result in mild disease. Occasionally, influenza viruses endemic in domestic birds can cause severe and fatal disease even in healthy individuals. In avian influenza virus infected patients, the host immune system is activated in an uncontrolled manner and is unable to control infection in a timely fashion. In this study, we investigated why the immune system fails to effectively control a modified form of avian influenza virus. Our studies show that T cell functions important for clearing virally infected cells are impaired by higher negative regulatory signals during modified avian influenza virus infection. In addition, memory T cell numbers were decreased in modified avian influenza virus infected mice. Our studies provide a possible mechanism for the severe and prolonged disease associated with avian influenza virus infections in humans.

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Avian and Human Seasonal Influenza Hemagglutinin Proteins Elicit CD4 T Cell Responses That Are Comparable in Epitope Abundance and Diversity

Clinical and Vaccine Immunology ◽

10.1128/cvi.00548-16 ◽

2017 ◽

Vol 24 (3) ◽

Cited By ~ 5

Author(s):

Anthony DiPiazza ◽

Katherine Richards ◽

Nicholas Poulton ◽

Andrea J. Sant

Keyword(s):

T Cells ◽

T Cell ◽

Avian Influenza ◽

Cd4 T Cells ◽

Influenza Viruses ◽

Cd4 T Cell ◽

T Cell Epitopes ◽

Avian Influenza Viruses ◽

Influenza Hemagglutinin ◽

Unbiased Manner

ABSTRACT Avian influenza viruses remain a significant concern due to their pandemic potential. Vaccine trials have suggested that humans respond poorly to avian influenza vaccines relative to seasonal vaccines. It is important to understand, first, if there is a general deficiency in the ability of avian hemagglutinin (HA) proteins to generate immune responses and, if so, what underlies this defect. This question is of particular interest because it has been suggested that in humans, the poor immunogenicity of H7 vaccines may be due to a paucity of CD4 T cell epitopes. Because of the generally high levels of cross-reactive CD4 T cells in humans, it is not possible to compare the inherent immunogenicities of avian and seasonal HA proteins in an unbiased manner. Here, we empirically examine the epitope diversity and abundance of CD4 T cells elicited by seasonal and avian HA proteins. HLA-DR1 and HLA-DR4 transgenic mice were vaccinated with purified HA proteins, and CD4 T cells to specific epitopes were identified and quantified. These studies revealed that the diversity and abundance of CD4 T cells specific for HA do not segregate on the basis of whether the HA was derived from human seasonal or avian influenza viruses. Therefore, we conclude that failure in responses to avian vaccines in humans is likely due to a lack of cross-reactive CD4 T cell memory perhaps coupled with competition with or suppression of naive, HA-specific CD4 T cells by memory CD4 T cells specific for more highly conserved proteins.

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CD32+and PD-1+Lymph Node CD4 T Cells Support Persistent HIV-1 Transcription in Treated Aviremic Individuals

10.1101/329938 ◽

2018 ◽

Cited By ~ 1

Author(s):

Alessandra Noto ◽

Francesco A. Procopio ◽

Riddhima Banga ◽

Madeleine Suffiotti ◽

Jean-Marc Corpataux ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hiv Infection ◽

Cell Population ◽

Cd4 T Cells ◽

Cd4 T Cell ◽

Cell Populations ◽

Latently Infected ◽

Infected Cells ◽

Hiv 1

ABSTRACTA recent study conducted in blood has proposed CD32 as the marker identifying the ‘elusive’ HIV reservoir. We have investigated the distribution of CD32+CD4 T cells in blood and lymph nodes(LNs) of healthy HIV-1 uninfected, viremic untreated and long-term treated HIV-1 infected individuals and their relationship with PD-1+CD4 T cells. The frequency of CD32+CD4 T cells was increased in viremic as compared to treated individuals in LNs and a large proportion(up to 50%) of CD32+cells co-expressed PD-1 and were enriched within T follicular helper cells(Tfh) cells. We next investigated the role of LN CD32+CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32+and PD-1+CD4 T cells as compared to CD32-and PD-1-cells in both viremic and treated individuals but there was no difference between CD32+and PD-1+cells. There was not enrichment of latently infected cells with inducible HIV-1 in CD32+versus PD-1+cells in ART treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32+PD-1+CD4 T cells were significantly enriched in cell associated HIV RNA as compared to CD32-PD-1-(average 5.2 fold in treated and 86.6 fold in viremics), to CD32+PD-1-(2.2 fold in treated and 4.3 fold in viremics) and to CD32-PD-1+cell populations(2.2 fold in ART treated and 4.6 fold in viremics). Similar levels of HIV-1 transcription were found in CD32+PD-1-and CD32-PD-1+CD4 T cells. Interestingly, the proportion of CD32+and PD-1+CD4 T cells negatively correlated with CD4 T cell counts and length of therapy while positively correlated with viremia. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and CD32 and PD-1 co-expression the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals.ImportanceThe existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells co-expressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription.

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Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

Immunity & Ageing ◽

10.1186/s12979-021-00217-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Stephanie M. Dillon ◽

Tezha A. Thompson ◽

Allison J. Christians ◽

Martin D. McCarter ◽

Cara C. Wilson

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Older Persons ◽

Age Groups ◽

T Cell Immunity ◽

Cd4 T Cell ◽

Cell Immunity ◽

Memory Cd4 T Cells

Abstract Background The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons. Results Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults. Conclusions Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.

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