Liisa Kaarina Selin - Academia.edu (original) (raw)

Papers by Liisa Kaarina Selin

The Journal of Immunology

Anti-viral CTL were induced in vitro using a particle bombardment device or "gene-gun" ... more Anti-viral CTL were induced in vitro using a particle bombardment device or "gene-gun" to deliver plasmid DNA encoding the nucleoprotein of the lymphocytic choriomeningitis virus (LCMV). Using this plasmid we were able to study T cell-mediated immunity in the absence of a neutralizing Ab response. Upon a single DNA immunization, a nearly 2 log10 reduction in splenic viral titers was observed 3 days after LCMV infection. After two or three immunizations a greater than 3 log10 inhibition of viral titers in the spleen was observed, with most animals having no detectable virus. C57BL/6 mice immunized with DNA encoding the nucleoprotein gene were also challenged with LCMV intracranially. Upon intracranial challenge, vaccinated animals displayed either protection or enhanced immunopathology leading to accelerated kinetics of death. Using limiting dilution analysis it was possible to detect LCMV-specific CTL precursors in both the spleen and lymph nodes of vaccinated animals. C57...

Frontiers in Immunology

Older people have difficulty controlling infection with common viruses such as influenza A virus ... more Older people have difficulty controlling infection with common viruses such as influenza A virus (IAV), RNA virus which causes recurrent infections due to a high rate of genetic mutation, and Epstein Barr virus (EBV), DNA virus which persists in B cells for life in the 95% of people that become acutely infected. We questioned whether changes in epitope-specific memory CD8 T cell receptor (TCR) repertoires to these two common viruses could occur with increasing age and contribute to waning immunity. We compared CD8 memory TCR alpha and beta repertoires in two HLA-A2+ EBV- and IAV-immune donors, young (Y) and older (O) donors to three immunodominant epitopes known to be cross-reactive, IAV-M158-66 (IAV-M1), EBV-BMLF1280-288 (EBV-BM), and EBV-BRLF1109-117 (EBV-BR). We, therefore, also designed these studies to examine if TCR cross-reactivity could contribute to changes in repertoire with increasing age. TCR high throughput sequencing showed a significant difference in the pattern of TR...

The Journal of Immunology

IAV is a common human respiratory pathogen with a strong association with heterotypic and heterol... more IAV is a common human respiratory pathogen with a strong association with heterotypic and heterologous immunity. IAV-immune mice challenged with LCMV develop detrimental effects with both increased virus titers and immunopathology. Crossreactive CD8 T cell responses between these two viruses mediate the enhanced lung pathology. Here, we questioned whether crossreactive CD4 memory cells in IAV-immune mice could play a role in increasing viral titers during the subsequent LCMV infection. Preferential depletion of memory CD4 but not CD8 cells in IAV-immune mice prevented the increase in LCMV titers. In IAV+LCMV mice there was an early increase in CD4 cells with a shift in the CD4/CD8 ratio. Luminex cytokine assays suggested that there was an increase in Th2 cytokines, IL-4 and IL-5, in the spleen of IAV+LCMV mice, which was IAV CD4 memory cell dependent, as IL-4 decreased in the CD4 depleted mice. Depleting IL-4 or IL-5 returned LCMV titers to naïve levels while adding rIL-4 and rIL-5 ...

The Journal of Immunology

During EBV-associated infectious mononucleosis (IM) influenza A-specific crossreactive memory T c... more During EBV-associated infectious mononucleosis (IM) influenza A-specific crossreactive memory T cells are highly activated and play a role in disease severity. In HLA-A2+ IM patients, influenza M158 (IAV-M1)-specific CD8 memory T cell responses cross-reacted with two different EBV lytic epitopes, BRLF-1(190) (19/20) and BMLF-1(280) (17/29). Furthermore, 11/22 IM patients demonstrated some intra-viral cross-reactivity between EBV-BRLF-1 and -BMLF-1 responses. Disease severity of IM did not correlate with viral load, but instead directly correlated with the percentage of IAV-M1, EBV-BMLF-1 and crossreactive IAV-M1/EBV-BMLF-1-specific CD8 T cells. This was associated with altered TCR Vbeta usage. In all IM patients cross-reactive T cell responses were observed but different patterns of cross-reactivity were seen in each individual. A number of unique features of the TCR of the highly cross-reactive BRLF-1 epitope were noted. BRLF-1 T cell responses were of very high avidity. There was ...

The Journal of Immunology

Cross-reactive memory T cells specific to previously encountered influenza A contribute to the ch... more Cross-reactive memory T cells specific to previously encountered influenza A contribute to the characterisitic lymphoproliferation of EBV-associated infectious mononucleosis (IM). In HLA-A2+ IM patients, influenza M158 (IAV-M1)-specific CD8 memory T cell responses cross-reacted with two different EBV lytic epitopes, BRLF-1190 (10/10) and BMLF-1280 (14/26). Disease severity of IM did not correlate with viral load. Interestingly, instead disease severity directly correlated with the percentage of Flu-M1-specific CD8 T cells but not with either EBV-BMLF-1, or -BRLF-1-specific responses. In addition, 8/19 IM patients demonstrated some intra-viral cross-reactivity between EBV-BRLF-1 and -BMLF-1 responses. These cross-reactive T cell responses were observed in all IM patients but different patterns of cross-reactivity occurred in each individual concerning the specific epitopes involved and their time of appearance after infection. A number of unique features of the TCR of the highly cros...

The Journal of Immunology

Respiratory viral infection can cause subclinical to severe lung disease. As hosts are continuous... more Respiratory viral infection can cause subclinical to severe lung disease. As hosts are continuously exposed to environmental pathogens, a history of past infection might alter the immune response to a subsequent infection. This concept termed heterologous immunity has been largely overlooked. Prior immunity to influenza A (FLU) was shown to have a profound impact on acute infection with LCMV increasing virus titers and immunopathology, a phenomenon that we have called deranged immunity. We observed that LCMV infected FLU-immune mice displayed an alteration of the kinetics of their immune response with increased and more activated CD8 T cells. This is consistent with the activation of cross-reactive memory T cells. We showed that the FLU-induced memory CD8 and/or CD4 T cells played a role in enhancing lung immunopathology, and virus titers. We also identified a cross-reactive CD8 T cell response between the two viruses that maybe playing a role in modulating disease. Consistent with ...

The Journal of Immunology

Alterations in memory CD8 T cell responses may contribute to the high morbidity and mortality cau... more Alterations in memory CD8 T cell responses may contribute to the high morbidity and mortality caused by seasonal influenza A virus (IAV) infections in older individuals. We questioned whether memory CD8 responses changed overtime with increasing age. Here, for the first time we show that the HLA-A2-restricted IAV M158-66-specific Vα T cell repertoire was significantly narrowed leading to oligoclonal expansions including the usage of a single identical VA12 clonotype. This was the case for all 8 older donors. The VA repertoire of older individuals also had longer CDR3 regions with increased usage of alanine/glycine runs which may enhance TCR promiscuity. Collectively these results suggest that CD8 memory responses in humans to non-persistent viruses like IAV are dynamic, and become narrower with preferential retention of T cell repertoires with features of enhanced promiscuity with age.

The Journal of Immunology

Natural killer (NK) cells directly control virus replication during some infections and are postu... more Natural killer (NK) cells directly control virus replication during some infections and are postulated to indirectly regulate antiviral immunity during other infections through modulation of antiviral T cell responses, but the consequences and mechanisms of this regulation remain largely unexplored. Using the relatively NK cell-resistant lymphocytic choriomeningitis virus (LCMV), we identified a crucial role for NK cells in repression of antiviral T cell responses to a degree that alters the balance between virus clearance and immune pathology. Depletion of NK cells prior to infection of mice with a LCMV clone 13 dose (2 x 105 PFU) normally associated with fatal T cell-mediated immunopathology completely prevented virus-associated morbidity and promoted rapid viral clearance. In contrast, mice depleted of NK cells succumbed to a higher viral dose (2 x 106 PFU) normally associated with non-lethal persistent infection and clonal exhaustion of T cells. During the first three days of in...

The Journal of Immunology

Previously we have reported that cross-reactive memory CD8 T cells specific for the Flu-M158-66 e... more Previously we have reported that cross-reactive memory CD8 T cells specific for the Flu-M158-66 epitope (GILGFVFTL) respond to the EBV-BMLF1280-288 epitope (GLCTLVAML) during the course of EBV infection and contribute to the onset of infectious mononucleosis. Recently we have found that the memory CD8 T cells specific for the Flu-M158-66 are also cross-reactive to an additional EBV epitope, EBV-BRLF1109-117 (YVLDHLIVV). Here we sought to determine the cross-reactive properties of the Flu-M158-66 specific cells in EBV sero-negative individuals. CD8 T cells cultured in the presence of the cross-reactive EBV epitopes preferentially expanded the Flu-M158-66 specific cells. Although these expanded cells did not stain with EBV pentamers they were able to produce cytokine in response to EBV peptides. Additionally these cells were capable of killing autologous EBV infected targets. Interestingly the T cell repertoire demonstrated unique characteristics including nearly complete domination b...

The Journal of Immunology

During EBV-associated infectious mononucleosis (IM) IAV-specific crossreactive memory T cells are... more During EBV-associated infectious mononucleosis (IM) IAV-specific crossreactive memory T cells are activated and play a role in disease severity. In HLA-A2+ IM patients, influenza M158 (IAV-M1)-specific CD8 memory T cell responses crossreacted with two different EBV lytic epitopes, BMLF1280 (17/29) and BRLF1109 (19/20). Disease severity of IM directly correlated with significantly increased frequencies of crossreactive IAV-M1/EBV-BMLF1, IAV-M1, and EBV-BMLF1 specific CD8 cells, and with mean viral load over the first 5 weeks of infection. Disease severity did not correlate with BRLF1 or M1/BRLF1 crossreactive responses. When severity of IM was scored and patients were assigned to either mild or severe groups, disease severity correlated with specific TCR Vb usage in IAV-M1 population suggesting that TcR selection is driving disease outcome. Consistent with crossreactive responses driving increased immunopathology was the observation that tetramer-sorted crossreactive responses had co...

The Journal of Immunology

Generally, it has been assumed that memory T cells are dormant and inactive cells in the absence ... more Generally, it has been assumed that memory T cells are dormant and inactive cells in the absence of their specific Ag. Recent work has challenged this assumption by showing that a portion of the CD8+ memory T cell pool is in cycle. In this study, we demonstrate that a significant number of blast-size memory CD8+ T cells in mice, long after lymphocytic choriomeningitis virus (LCMV) infection, mediate cytolysis against highly sensitive targets without any in vivo or in vitro restimulation and expansion with Ag. Peptide-coated RMA-S targets were sufficiently sensitive to detect low but significant cytolytic activity in bulk 51Cr release assays in nonstimulated LCMV-specific splenic memory CTL populations. Most of the directly cytotoxic activity was against the GP33 epitope, and this persisted throughout the lifetime of the mouse following infection. The cytotoxic activity was not inhibited by cyclosporin A, indicating that these cells were already in an active state and not dependent o...

The Journal of Immunology

The gamma-herpes Epstein-Barr virus (EBV) infects ~90% of individuals globally, establishing a li... more The gamma-herpes Epstein-Barr virus (EBV) infects ~90% of individuals globally, establishing a life-long infection. The clinical presentation of EBV infection can range from asymptomatic to severe, occasionally fatal, acute infectious mononucleosis (IM). There is also a strong causal relationship between EBV infection and common malignancies, including carcinoma’s, and Burkitt’s lymphoma. However it is unknown why 5-10% of adults remain EBV-sero-negative (EBV-SN), despite the fact the virus infects the vast majority of the population and is actively shed at high titers even during chronic infection. Here, we show that EBV-SN HLA-A2+ adults possess cross-reactive IAV-GIL/EBV-GLC memory CD8 T-cells that show highly unique properties. These IAV-GIL crossreactive cells preferentially expand, and produce cytokines to, EBV antigens with high avidity. Additionally they are capable of lysing EBV-infected targets and show the potential to enter the mucosal epithelial tissue where infection i...

The Journal of Immunology

Heterologous immunity may help explain why any respiratory infection can cause a wide range of di... more Heterologous immunity may help explain why any respiratory infection can cause a wide range of disease from asymptomatic to extremely severe, even resulting in death. Prior immunity to influenza A led to significantly increased viral load and lung pathology upon LCMV infection, the severity of which varied between genetically identical mice, but did not correlate with viral load. Flu-specific memory CD8 T cells mediated this increased pathology as evidenced by CD8 depletion studies and the observation that disease severity directly correlated with the expansion of two cross-reactive Flu-epitope specific memory CD8 T cell responses during LCMV infection. H2-Kb-restricted IAV-PB1703 and H2-Db-restricted IAV-PA224 responses cross-reacted with LCMV-GP34, and -GP276, respectively. Functionally inactivating these memory populations by peptide tolerization or blocking IFNγ activity greatly decreased lung pathology demonstrating novel therapeutic interventions. Flu-specific memory CD4 T cel...

Viruses

Immunological memory to a previously encountered pathogen can influence the outcome of a sequenti... more Immunological memory to a previously encountered pathogen can influence the outcome of a sequential infection, which is called heterologous immunity. Lymphocytic choriomeningitis virus (LCMV) immune mice develop a NP205-specific T cell response that is cross-reactive to Pichinde virus infection (PICV). So far, limited data are available if cross-reactive T cell responses appear also during chronic infections with exhausted T cell responses. Exhaustion in chronic viral infections can be treated with checkpoint inhibitors, which might affect heterologous outcomes unexpectedly. The aim of this study was to investigate the cross-reactive immune response in chronic LCMV clone 13 (LCMVcl13) infection during primary PICV infection at phenotypic, functional, and T cell receptor (TCR) level. Moreover, the influence of checkpoint inhibitor therapy with αPD-L1 was investigated. Cross-reactive NP205-specific responses were present and functional in the chronic environment. Additionally, chronic...

The T cell receptor (TCR) repertoire is an essential component of the CD8 T-cell immune response.... more The T cell receptor (TCR) repertoire is an essential component of the CD8 T-cell immune response. Here, we seek to investigate factors that drive selection of TCR repertoires specific to the HLA-A2-restricted immunodominant epitope BRLF1109-117 (YVLDHLIVV) over the course of primary Epstein Barr virus (EBV) infection. Using single-cell paired TCRalphabeta sequencing of tetramer sorted CD8 T cells ex vivo, we show at the clonal level that recognition of the HLA-A2-restricted BRLF1 (YVL-BR, BRLF-1109) epitope is mainly driven by the TCRalpha chain. For the first time, we identify a CDR3alpha (complementarity determining region 3 alpha) motif, KDTDKL, resulting from an obligate AV8.1-AJ34 pairing that was shared by all four individuals studied. This observation coupled with the fact that this public AV8.1-KDTDKL-AJ34 TCR pairs with multiple different TCRbeta chains within the same donor (median 4; range: 1-9), suggests that there are some unique structural features of the interaction b...

Journal of Immunology, May 1, 2014

This article was submitted to

doi: 10.3389/fimmu.2013.00229 Immune parameters to consider when choosingT-cell receptors for the... more doi: 10.3389/fimmu.2013.00229 Immune parameters to consider when choosingT-cell receptors for therapy

Journal of Immunology, 2014

During EBV-associated IM IAV-specific crossreactive memory T cells are activated and play a role ... more During EBV-associated IM IAV-specific crossreactive memory T cells are activated and play a role in disease severity. In HLA-A2+ IM patients, influenza M1-58 (IAV-M1)-specific CD8 memory T cell responses crossreacted with two different EBV lytic epitopes, BMLF1-280 (17/29) and BRLF1-109 (19/20). Furthermore, 11/22 IM patients demonstrated some intra-viral crossreactivity between EBV-BRLF1 and -BMLF1 responses. Disease severity of IM directly correlated with significantly increased frequencies of crossreactive IAV-M1/EBV-BMLF1, IAV-M1, and EBV-BMLF1 specific CD8 cells, and with mean viral load over the first 5 weeks of infection. Disease severity did not correlate with BRLF1 or M1/BRLF1 crossreactive responses. When severity of IM was scored and patients were assigned to either mild or severe groups, disease severity correlated with specific TCR Vb usage in IAV-M1 population suggesting that TcR selection is driving disease outcome. Consistent with IAV-M1 and EBV-BMLF1 responses drivi...

The Journal of Immunology

Anti-viral CTL were induced in vitro using a particle bombardment device or "gene-gun" ... more Anti-viral CTL were induced in vitro using a particle bombardment device or "gene-gun" to deliver plasmid DNA encoding the nucleoprotein of the lymphocytic choriomeningitis virus (LCMV). Using this plasmid we were able to study T cell-mediated immunity in the absence of a neutralizing Ab response. Upon a single DNA immunization, a nearly 2 log10 reduction in splenic viral titers was observed 3 days after LCMV infection. After two or three immunizations a greater than 3 log10 inhibition of viral titers in the spleen was observed, with most animals having no detectable virus. C57BL/6 mice immunized with DNA encoding the nucleoprotein gene were also challenged with LCMV intracranially. Upon intracranial challenge, vaccinated animals displayed either protection or enhanced immunopathology leading to accelerated kinetics of death. Using limiting dilution analysis it was possible to detect LCMV-specific CTL precursors in both the spleen and lymph nodes of vaccinated animals. C57...

Frontiers in Immunology

Older people have difficulty controlling infection with common viruses such as influenza A virus ... more Older people have difficulty controlling infection with common viruses such as influenza A virus (IAV), RNA virus which causes recurrent infections due to a high rate of genetic mutation, and Epstein Barr virus (EBV), DNA virus which persists in B cells for life in the 95% of people that become acutely infected. We questioned whether changes in epitope-specific memory CD8 T cell receptor (TCR) repertoires to these two common viruses could occur with increasing age and contribute to waning immunity. We compared CD8 memory TCR alpha and beta repertoires in two HLA-A2+ EBV- and IAV-immune donors, young (Y) and older (O) donors to three immunodominant epitopes known to be cross-reactive, IAV-M158-66 (IAV-M1), EBV-BMLF1280-288 (EBV-BM), and EBV-BRLF1109-117 (EBV-BR). We, therefore, also designed these studies to examine if TCR cross-reactivity could contribute to changes in repertoire with increasing age. TCR high throughput sequencing showed a significant difference in the pattern of TR...

The Journal of Immunology

IAV is a common human respiratory pathogen with a strong association with heterotypic and heterol... more IAV is a common human respiratory pathogen with a strong association with heterotypic and heterologous immunity. IAV-immune mice challenged with LCMV develop detrimental effects with both increased virus titers and immunopathology. Crossreactive CD8 T cell responses between these two viruses mediate the enhanced lung pathology. Here, we questioned whether crossreactive CD4 memory cells in IAV-immune mice could play a role in increasing viral titers during the subsequent LCMV infection. Preferential depletion of memory CD4 but not CD8 cells in IAV-immune mice prevented the increase in LCMV titers. In IAV+LCMV mice there was an early increase in CD4 cells with a shift in the CD4/CD8 ratio. Luminex cytokine assays suggested that there was an increase in Th2 cytokines, IL-4 and IL-5, in the spleen of IAV+LCMV mice, which was IAV CD4 memory cell dependent, as IL-4 decreased in the CD4 depleted mice. Depleting IL-4 or IL-5 returned LCMV titers to naïve levels while adding rIL-4 and rIL-5 ...

The Journal of Immunology

During EBV-associated infectious mononucleosis (IM) influenza A-specific crossreactive memory T c... more During EBV-associated infectious mononucleosis (IM) influenza A-specific crossreactive memory T cells are highly activated and play a role in disease severity. In HLA-A2+ IM patients, influenza M158 (IAV-M1)-specific CD8 memory T cell responses cross-reacted with two different EBV lytic epitopes, BRLF-1(190) (19/20) and BMLF-1(280) (17/29). Furthermore, 11/22 IM patients demonstrated some intra-viral cross-reactivity between EBV-BRLF-1 and -BMLF-1 responses. Disease severity of IM did not correlate with viral load, but instead directly correlated with the percentage of IAV-M1, EBV-BMLF-1 and crossreactive IAV-M1/EBV-BMLF-1-specific CD8 T cells. This was associated with altered TCR Vbeta usage. In all IM patients cross-reactive T cell responses were observed but different patterns of cross-reactivity were seen in each individual. A number of unique features of the TCR of the highly cross-reactive BRLF-1 epitope were noted. BRLF-1 T cell responses were of very high avidity. There was ...

The Journal of Immunology

Cross-reactive memory T cells specific to previously encountered influenza A contribute to the ch... more Cross-reactive memory T cells specific to previously encountered influenza A contribute to the characterisitic lymphoproliferation of EBV-associated infectious mononucleosis (IM). In HLA-A2+ IM patients, influenza M158 (IAV-M1)-specific CD8 memory T cell responses cross-reacted with two different EBV lytic epitopes, BRLF-1190 (10/10) and BMLF-1280 (14/26). Disease severity of IM did not correlate with viral load. Interestingly, instead disease severity directly correlated with the percentage of Flu-M1-specific CD8 T cells but not with either EBV-BMLF-1, or -BRLF-1-specific responses. In addition, 8/19 IM patients demonstrated some intra-viral cross-reactivity between EBV-BRLF-1 and -BMLF-1 responses. These cross-reactive T cell responses were observed in all IM patients but different patterns of cross-reactivity occurred in each individual concerning the specific epitopes involved and their time of appearance after infection. A number of unique features of the TCR of the highly cros...

The Journal of Immunology

Respiratory viral infection can cause subclinical to severe lung disease. As hosts are continuous... more Respiratory viral infection can cause subclinical to severe lung disease. As hosts are continuously exposed to environmental pathogens, a history of past infection might alter the immune response to a subsequent infection. This concept termed heterologous immunity has been largely overlooked. Prior immunity to influenza A (FLU) was shown to have a profound impact on acute infection with LCMV increasing virus titers and immunopathology, a phenomenon that we have called deranged immunity. We observed that LCMV infected FLU-immune mice displayed an alteration of the kinetics of their immune response with increased and more activated CD8 T cells. This is consistent with the activation of cross-reactive memory T cells. We showed that the FLU-induced memory CD8 and/or CD4 T cells played a role in enhancing lung immunopathology, and virus titers. We also identified a cross-reactive CD8 T cell response between the two viruses that maybe playing a role in modulating disease. Consistent with ...

The Journal of Immunology

Alterations in memory CD8 T cell responses may contribute to the high morbidity and mortality cau... more Alterations in memory CD8 T cell responses may contribute to the high morbidity and mortality caused by seasonal influenza A virus (IAV) infections in older individuals. We questioned whether memory CD8 responses changed overtime with increasing age. Here, for the first time we show that the HLA-A2-restricted IAV M158-66-specific Vα T cell repertoire was significantly narrowed leading to oligoclonal expansions including the usage of a single identical VA12 clonotype. This was the case for all 8 older donors. The VA repertoire of older individuals also had longer CDR3 regions with increased usage of alanine/glycine runs which may enhance TCR promiscuity. Collectively these results suggest that CD8 memory responses in humans to non-persistent viruses like IAV are dynamic, and become narrower with preferential retention of T cell repertoires with features of enhanced promiscuity with age.

The Journal of Immunology

Natural killer (NK) cells directly control virus replication during some infections and are postu... more Natural killer (NK) cells directly control virus replication during some infections and are postulated to indirectly regulate antiviral immunity during other infections through modulation of antiviral T cell responses, but the consequences and mechanisms of this regulation remain largely unexplored. Using the relatively NK cell-resistant lymphocytic choriomeningitis virus (LCMV), we identified a crucial role for NK cells in repression of antiviral T cell responses to a degree that alters the balance between virus clearance and immune pathology. Depletion of NK cells prior to infection of mice with a LCMV clone 13 dose (2 x 105 PFU) normally associated with fatal T cell-mediated immunopathology completely prevented virus-associated morbidity and promoted rapid viral clearance. In contrast, mice depleted of NK cells succumbed to a higher viral dose (2 x 106 PFU) normally associated with non-lethal persistent infection and clonal exhaustion of T cells. During the first three days of in...

The Journal of Immunology

Previously we have reported that cross-reactive memory CD8 T cells specific for the Flu-M158-66 e... more Previously we have reported that cross-reactive memory CD8 T cells specific for the Flu-M158-66 epitope (GILGFVFTL) respond to the EBV-BMLF1280-288 epitope (GLCTLVAML) during the course of EBV infection and contribute to the onset of infectious mononucleosis. Recently we have found that the memory CD8 T cells specific for the Flu-M158-66 are also cross-reactive to an additional EBV epitope, EBV-BRLF1109-117 (YVLDHLIVV). Here we sought to determine the cross-reactive properties of the Flu-M158-66 specific cells in EBV sero-negative individuals. CD8 T cells cultured in the presence of the cross-reactive EBV epitopes preferentially expanded the Flu-M158-66 specific cells. Although these expanded cells did not stain with EBV pentamers they were able to produce cytokine in response to EBV peptides. Additionally these cells were capable of killing autologous EBV infected targets. Interestingly the T cell repertoire demonstrated unique characteristics including nearly complete domination b...

The Journal of Immunology

During EBV-associated infectious mononucleosis (IM) IAV-specific crossreactive memory T cells are... more During EBV-associated infectious mononucleosis (IM) IAV-specific crossreactive memory T cells are activated and play a role in disease severity. In HLA-A2+ IM patients, influenza M158 (IAV-M1)-specific CD8 memory T cell responses crossreacted with two different EBV lytic epitopes, BMLF1280 (17/29) and BRLF1109 (19/20). Disease severity of IM directly correlated with significantly increased frequencies of crossreactive IAV-M1/EBV-BMLF1, IAV-M1, and EBV-BMLF1 specific CD8 cells, and with mean viral load over the first 5 weeks of infection. Disease severity did not correlate with BRLF1 or M1/BRLF1 crossreactive responses. When severity of IM was scored and patients were assigned to either mild or severe groups, disease severity correlated with specific TCR Vb usage in IAV-M1 population suggesting that TcR selection is driving disease outcome. Consistent with crossreactive responses driving increased immunopathology was the observation that tetramer-sorted crossreactive responses had co...

The Journal of Immunology

Generally, it has been assumed that memory T cells are dormant and inactive cells in the absence ... more Generally, it has been assumed that memory T cells are dormant and inactive cells in the absence of their specific Ag. Recent work has challenged this assumption by showing that a portion of the CD8+ memory T cell pool is in cycle. In this study, we demonstrate that a significant number of blast-size memory CD8+ T cells in mice, long after lymphocytic choriomeningitis virus (LCMV) infection, mediate cytolysis against highly sensitive targets without any in vivo or in vitro restimulation and expansion with Ag. Peptide-coated RMA-S targets were sufficiently sensitive to detect low but significant cytolytic activity in bulk 51Cr release assays in nonstimulated LCMV-specific splenic memory CTL populations. Most of the directly cytotoxic activity was against the GP33 epitope, and this persisted throughout the lifetime of the mouse following infection. The cytotoxic activity was not inhibited by cyclosporin A, indicating that these cells were already in an active state and not dependent o...

The Journal of Immunology

The gamma-herpes Epstein-Barr virus (EBV) infects ~90% of individuals globally, establishing a li... more The gamma-herpes Epstein-Barr virus (EBV) infects ~90% of individuals globally, establishing a life-long infection. The clinical presentation of EBV infection can range from asymptomatic to severe, occasionally fatal, acute infectious mononucleosis (IM). There is also a strong causal relationship between EBV infection and common malignancies, including carcinoma’s, and Burkitt’s lymphoma. However it is unknown why 5-10% of adults remain EBV-sero-negative (EBV-SN), despite the fact the virus infects the vast majority of the population and is actively shed at high titers even during chronic infection. Here, we show that EBV-SN HLA-A2+ adults possess cross-reactive IAV-GIL/EBV-GLC memory CD8 T-cells that show highly unique properties. These IAV-GIL crossreactive cells preferentially expand, and produce cytokines to, EBV antigens with high avidity. Additionally they are capable of lysing EBV-infected targets and show the potential to enter the mucosal epithelial tissue where infection i...

The Journal of Immunology

Heterologous immunity may help explain why any respiratory infection can cause a wide range of di... more Heterologous immunity may help explain why any respiratory infection can cause a wide range of disease from asymptomatic to extremely severe, even resulting in death. Prior immunity to influenza A led to significantly increased viral load and lung pathology upon LCMV infection, the severity of which varied between genetically identical mice, but did not correlate with viral load. Flu-specific memory CD8 T cells mediated this increased pathology as evidenced by CD8 depletion studies and the observation that disease severity directly correlated with the expansion of two cross-reactive Flu-epitope specific memory CD8 T cell responses during LCMV infection. H2-Kb-restricted IAV-PB1703 and H2-Db-restricted IAV-PA224 responses cross-reacted with LCMV-GP34, and -GP276, respectively. Functionally inactivating these memory populations by peptide tolerization or blocking IFNγ activity greatly decreased lung pathology demonstrating novel therapeutic interventions. Flu-specific memory CD4 T cel...

Viruses

Immunological memory to a previously encountered pathogen can influence the outcome of a sequenti... more Immunological memory to a previously encountered pathogen can influence the outcome of a sequential infection, which is called heterologous immunity. Lymphocytic choriomeningitis virus (LCMV) immune mice develop a NP205-specific T cell response that is cross-reactive to Pichinde virus infection (PICV). So far, limited data are available if cross-reactive T cell responses appear also during chronic infections with exhausted T cell responses. Exhaustion in chronic viral infections can be treated with checkpoint inhibitors, which might affect heterologous outcomes unexpectedly. The aim of this study was to investigate the cross-reactive immune response in chronic LCMV clone 13 (LCMVcl13) infection during primary PICV infection at phenotypic, functional, and T cell receptor (TCR) level. Moreover, the influence of checkpoint inhibitor therapy with αPD-L1 was investigated. Cross-reactive NP205-specific responses were present and functional in the chronic environment. Additionally, chronic...

The T cell receptor (TCR) repertoire is an essential component of the CD8 T-cell immune response.... more The T cell receptor (TCR) repertoire is an essential component of the CD8 T-cell immune response. Here, we seek to investigate factors that drive selection of TCR repertoires specific to the HLA-A2-restricted immunodominant epitope BRLF1109-117 (YVLDHLIVV) over the course of primary Epstein Barr virus (EBV) infection. Using single-cell paired TCRalphabeta sequencing of tetramer sorted CD8 T cells ex vivo, we show at the clonal level that recognition of the HLA-A2-restricted BRLF1 (YVL-BR, BRLF-1109) epitope is mainly driven by the TCRalpha chain. For the first time, we identify a CDR3alpha (complementarity determining region 3 alpha) motif, KDTDKL, resulting from an obligate AV8.1-AJ34 pairing that was shared by all four individuals studied. This observation coupled with the fact that this public AV8.1-KDTDKL-AJ34 TCR pairs with multiple different TCRbeta chains within the same donor (median 4; range: 1-9), suggests that there are some unique structural features of the interaction b...

Journal of Immunology, May 1, 2014

This article was submitted to

doi: 10.3389/fimmu.2013.00229 Immune parameters to consider when choosingT-cell receptors for the... more doi: 10.3389/fimmu.2013.00229 Immune parameters to consider when choosingT-cell receptors for therapy

Journal of Immunology, 2014

During EBV-associated IM IAV-specific crossreactive memory T cells are activated and play a role ... more During EBV-associated IM IAV-specific crossreactive memory T cells are activated and play a role in disease severity. In HLA-A2+ IM patients, influenza M1-58 (IAV-M1)-specific CD8 memory T cell responses crossreacted with two different EBV lytic epitopes, BMLF1-280 (17/29) and BRLF1-109 (19/20). Furthermore, 11/22 IM patients demonstrated some intra-viral crossreactivity between EBV-BRLF1 and -BMLF1 responses. Disease severity of IM directly correlated with significantly increased frequencies of crossreactive IAV-M1/EBV-BMLF1, IAV-M1, and EBV-BMLF1 specific CD8 cells, and with mean viral load over the first 5 weeks of infection. Disease severity did not correlate with BRLF1 or M1/BRLF1 crossreactive responses. When severity of IM was scored and patients were assigned to either mild or severe groups, disease severity correlated with specific TCR Vb usage in IAV-M1 population suggesting that TcR selection is driving disease outcome. Consistent with IAV-M1 and EBV-BMLF1 responses drivi...