The Experts below are selected from a list of 7485 Experts worldwide ranked by ideXlab platform
Raymond M. Welsh - One of the best experts on this subject based on the ideXlab platform.
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severity of acute infectious mononucleosis correlates with cross reactive influenza cd8 t cell receptor repertoires
Mbio, 2017Co-Authors: Nuray Aslan, Raymond M. Welsh, Anna Gil, Rabinarayan Mishra, Levi B. Watkin, Dario Ghersi, Fransenio G Clark, Katherine Luzuriaga, Liisa K. SelinAbstract:Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M158 (IAV-M1) and EBV BMLF1280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer+ frequencies directly correlated with AIM severity and were predictive of severe disease. Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity. There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. IAV-M1 tetramer+ cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology. Altogether, these data link Heterologous Immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection. In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter.IMPORTANCE The pathogenic impact of immune responses that by chance cross-react to unrelated viruses has not been established in human infections. Here, we demonstrate that the severity of acute infectious mononucleosis (AIM), an Epstein-Barr virus (EBV)-induced disease prevalent in young adults but not children, is associated with increased frequencies of T cells cross-reactive to EBV and the commonly acquired influenza A virus (IAV). The T-cell receptor (TCR) repertoire and functions of these cross-reactive T cells differed between mild- and severe-AIM patients, most likely because these two groups of patients had selected different memory TCR repertoires in response to IAV infections encountered earlier. This Heterologous Immunity may explain variability in disease outcome and why young adults with more-developed IAV-specific memory T-cell pools have more-severe disease than children, who have less-developed memory pools. This study provides a new framework for understanding the role of Heterologous Immunity in human health and disease and highlights an important developing field examining the role of T-cell repertoires in the mediation of immunopathology.
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Heterologous Immunity and persistent murine cytomegalovirus infection
Journal of Virology, 2017Co-Authors: Jenny Wunyue Che, Keith A Daniels, Liisa K. Selin, Raymond M. WelshAbstract:One's history of infections can affect the immune response to unrelated pathogens and influence disease outcome through the process of Heterologous Immunity. This can occur after acute viral infections, such as infections with lymphocytic choriomeningitis virus (LCMV) and vaccinia virus, where the pathogens are cleared, but it becomes a more complex issue in the context of persistent infections. In this study, murine cytomegalovirus (MCMV) was used as a persistent infection model to study Heterologous Immunity with LCMV. If mice were previously immune to LCMV and then infected with MCMV (LCMV+MCMV), they had more severe immunopathology, enhanced viral burden in multiple organs, and suppression of MCMV-specific T cell memory inflation. MCMV infection initially reduced the numbers of LCMV-specific memory T cells, but continued MCMV persistence did not further erode memory T cells specific to LCMV. When MCMV infection was given first (MCMV+LCMV), the magnitude of the acute T cell response to LCMV declined with age though this age-dependent decline was not dependent on MCMV. However, some of these MCMV persistently infected mice with acute LCMV infection (7 of 36) developed a robust immunodominant CD8 T cell response apparently cross-reactive between a newly defined putative MCMV epitope sequence, M57727–734, and the normally subdominant LCMV epitope L2062–2069, indicating a profound private specificity effect in Heterologous Immunity between these two viruses. These results further illustrate how a history of an acute or a persistent virus infection can substantially influence the immune responses and immune pathology associated with acute or persistent infections with an unrelated virus. IMPORTANCE This study extends our understanding of Heterologous Immunity in the context of persistent viral infection. The phenomenon has been studied mostly with viruses such as LCMV that are cleared, but the situation can be more complex with a persistent virus such as MCMV. We found that the history of LCMV infection intensifies MCMV immunopathology, enhances MCMV burden in multiple organs, and suppresses MCMV-specific T cell memory inflation. In the reverse infection sequence, we show that some of the long-term MCMV-immune mice mount a robust CD8 T cell cross-reactive response between a newly defined putative MCMV epitope sequence and a normally subdominant LCMV epitope. These results further illustrate how a history of infection can substantially influence the immune responses and immune pathology associated with infections with an unrelated virus.
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evaluation of non reciprocal Heterologous Immunity between unrelated viruses
Virology, 2015Co-Authors: Jenny Wunyue Che, Liisa K. Selin, Raymond M. WelshAbstract:Heterologous Immunity refers to the phenomenon whereby a history of an immune response against one pathogen can provide a level of Immunity to a second unrelated pathogen. Previous investigations have shown that Heterologous Immunity is not necessarily reciprocal, such as in the case of vaccinia virus (VACV). Replication of VACV is reduced in mice immune to a variety of pathogens, while VACV fails to induce Immunity to several of the same pathogens, including lymphocytic choriomeningitis virus (LCMV). Here we examine the lack of reciprocity of Heterologous Immunity between VACV and LCMV and find that they induce qualitatively different memory CD8 T cells. However, depending on the repertoire of an individual host, VACV can provide protection against LCMV simply by experimentally amplifying the quantity of T cells cross-reactive with the two viruses. Thus, one cause for lack of reciprocity is differences in the frequencies of cross-reactive T cells in immune hosts.
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disparate epitopes mediating protective Heterologous Immunity to unrelated viruses share peptide mhc structural features recognized by cross reactive t cells
Journal of Immunology, 2013Co-Authors: Zu T Shen, Raymond M. Welsh, Keith A Daniels, Tina T Nguyen, Lawrence J SternAbstract:Closely related peptide epitopes can be recognized by the same T cells and contribute to the immune response against pathogens encoding those epitopes, but sometimes cross-reactive epitopes share little homology. The degree of structural homology required for such disparate ligands to be recognized by cross-reactive TCRs remains unclear. In this study, we examined the mechanistic basis for cross-reactive T cell responses between epitopes from unrelated and pathogenic viruses, lymphocytic choriomeningitis virus (LCMV) and vaccinia virus. Our results show that the LCMV cross-reactive T cell response toward vaccinia virus is dominated by a shared asparagine residue, together with other shared structural elements conserved in the crystal structures of K(b)-VV-A11R and K(b)-LCMV-gp34. Based on analysis of the crystal structures and the specificity determinants for the cross-reactive T cell response, we were able to manipulate the degree of cross-reactivity of the T cell response, and to predict and generate a LCMV cross-reactive response toward a variant of a null OVA-derived peptide. These results indicate that protective Heterologous immune responses can occur for disparate epitopes from unrelated viruses.
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The Journal of Immunology Dynamics of Memory T Cell Proliferation Under Conditions of Heterologous Immunity and Bystander Stimulation 1
2013Co-Authors: Sung-kwon Kim, Raymond M. Welsh, Michael A. Brehm, Liisa K. SelinAbstract:By examining adoptively transferred CSFE-labeled lymphocytic choriomeningitis virus (LCMV)-immune donor T cells in Thy-1 congenic hosts inoculated with viruses or with the cytokine inducer poly(I:C), strikingly different responses of bona fide memory T cells were found in response to different stimuli. Poly(I:C) (cytokine) stimulation caused a limited synchronized division of memory CD8 T cells specific to each of five LCMV epitopes, with no increase and sometimes a loss in number, and no change in their epitope hierarchy. Homologous LCMV infection caused more than seven divisions of T cells specific for each epitope, with dramatic increases in number and minor changes in hierarchy. Infections with the Heterologous viruses Pichinde and vaccinia (VV) caused more than seven divisions and increases in number of T cells specific to some putatively cross-reactive but not other epitopes and resulted in substantial changes in the hierarchy of the LCMV-specific T cells. Hence, there can be memory T cell division without proliferation (i.e., increase in cell number) in the absence of Ag and division with proliferation in the presence of Ag from homologous or Heterologous viruses. Heterologous protective Immunity between viruses is not necessarily reciprocal, given that LCMV protects against VV but VV does not protect against LCMV. VV elicited proliferation of LCMV-induced CD8 and CD4 T cells, whereas LCMV did not elicit proliferation of VV-induced T cells. Thus, depending on the pathogen and the sequence of infection, a Heterologous agent may selectively stimulate the memory pool in patterns consistent with Heterologous Immunity. The Journal of Immunology, 2002, 169: 90–98. Memory CD8 T cells were once thought to be restin
Liisa K. Selin - One of the best experts on this subject based on the ideXlab platform.
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severity of acute infectious mononucleosis correlates with cross reactive influenza cd8 t cell receptor repertoires
Mbio, 2017Co-Authors: Nuray Aslan, Raymond M. Welsh, Anna Gil, Rabinarayan Mishra, Levi B. Watkin, Dario Ghersi, Fransenio G Clark, Katherine Luzuriaga, Liisa K. SelinAbstract:Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M158 (IAV-M1) and EBV BMLF1280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer+ frequencies directly correlated with AIM severity and were predictive of severe disease. Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity. There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. IAV-M1 tetramer+ cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology. Altogether, these data link Heterologous Immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection. In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter.IMPORTANCE The pathogenic impact of immune responses that by chance cross-react to unrelated viruses has not been established in human infections. Here, we demonstrate that the severity of acute infectious mononucleosis (AIM), an Epstein-Barr virus (EBV)-induced disease prevalent in young adults but not children, is associated with increased frequencies of T cells cross-reactive to EBV and the commonly acquired influenza A virus (IAV). The T-cell receptor (TCR) repertoire and functions of these cross-reactive T cells differed between mild- and severe-AIM patients, most likely because these two groups of patients had selected different memory TCR repertoires in response to IAV infections encountered earlier. This Heterologous Immunity may explain variability in disease outcome and why young adults with more-developed IAV-specific memory T-cell pools have more-severe disease than children, who have less-developed memory pools. This study provides a new framework for understanding the role of Heterologous Immunity in human health and disease and highlights an important developing field examining the role of T-cell repertoires in the mediation of immunopathology.
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Heterologous Immunity and persistent murine cytomegalovirus infection
Journal of Virology, 2017Co-Authors: Jenny Wunyue Che, Keith A Daniels, Liisa K. Selin, Raymond M. WelshAbstract:One's history of infections can affect the immune response to unrelated pathogens and influence disease outcome through the process of Heterologous Immunity. This can occur after acute viral infections, such as infections with lymphocytic choriomeningitis virus (LCMV) and vaccinia virus, where the pathogens are cleared, but it becomes a more complex issue in the context of persistent infections. In this study, murine cytomegalovirus (MCMV) was used as a persistent infection model to study Heterologous Immunity with LCMV. If mice were previously immune to LCMV and then infected with MCMV (LCMV+MCMV), they had more severe immunopathology, enhanced viral burden in multiple organs, and suppression of MCMV-specific T cell memory inflation. MCMV infection initially reduced the numbers of LCMV-specific memory T cells, but continued MCMV persistence did not further erode memory T cells specific to LCMV. When MCMV infection was given first (MCMV+LCMV), the magnitude of the acute T cell response to LCMV declined with age though this age-dependent decline was not dependent on MCMV. However, some of these MCMV persistently infected mice with acute LCMV infection (7 of 36) developed a robust immunodominant CD8 T cell response apparently cross-reactive between a newly defined putative MCMV epitope sequence, M57727–734, and the normally subdominant LCMV epitope L2062–2069, indicating a profound private specificity effect in Heterologous Immunity between these two viruses. These results further illustrate how a history of an acute or a persistent virus infection can substantially influence the immune responses and immune pathology associated with acute or persistent infections with an unrelated virus. IMPORTANCE This study extends our understanding of Heterologous Immunity in the context of persistent viral infection. The phenomenon has been studied mostly with viruses such as LCMV that are cleared, but the situation can be more complex with a persistent virus such as MCMV. We found that the history of LCMV infection intensifies MCMV immunopathology, enhances MCMV burden in multiple organs, and suppresses MCMV-specific T cell memory inflation. In the reverse infection sequence, we show that some of the long-term MCMV-immune mice mount a robust CD8 T cell cross-reactive response between a newly defined putative MCMV epitope sequence and a normally subdominant LCMV epitope. These results further illustrate how a history of infection can substantially influence the immune responses and immune pathology associated with infections with an unrelated virus.
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evaluation of non reciprocal Heterologous Immunity between unrelated viruses
Virology, 2015Co-Authors: Jenny Wunyue Che, Liisa K. Selin, Raymond M. WelshAbstract:Heterologous Immunity refers to the phenomenon whereby a history of an immune response against one pathogen can provide a level of Immunity to a second unrelated pathogen. Previous investigations have shown that Heterologous Immunity is not necessarily reciprocal, such as in the case of vaccinia virus (VACV). Replication of VACV is reduced in mice immune to a variety of pathogens, while VACV fails to induce Immunity to several of the same pathogens, including lymphocytic choriomeningitis virus (LCMV). Here we examine the lack of reciprocity of Heterologous Immunity between VACV and LCMV and find that they induce qualitatively different memory CD8 T cells. However, depending on the repertoire of an individual host, VACV can provide protection against LCMV simply by experimentally amplifying the quantity of T cells cross-reactive with the two viruses. Thus, one cause for lack of reciprocity is differences in the frequencies of cross-reactive T cells in immune hosts.
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Vaccination and Heterologous Immunity: educating the immune system.
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2015Co-Authors: Anna Gil, Laurie L Kenney, Rabinarayan Mishra, Levi B. Watkin, Nuray Aslan, Liisa K. SelinAbstract:This review discusses three inter-related topics: (1) the immaturity of the neonatal and infant immune response; (2) Heterologous Immunity, where prior infection history with unrelated pathogens alters disease outcome resulting in either enhanced protective Immunity or increased immunopathology to new infections, and (3) epidemiological human vaccine studies that demonstrate vaccines can have beneficial or detrimental effects on subsequent unrelated infections. The results from the epidemiological and Heterologous Immunity studies suggest that the immune system has tremendous plasticity and that each new infection or vaccine that an individual is exposed to during a lifetime will potentially alter the dynamics of their immune system. It also suggests that each new infection or vaccine that an infant receives is not only perturbing the immune system but is educating the immune system and laying down the foundation for all subsequent responses. This leads to the question, is there an optimum way to educate the immune system? Should this be taken into consideration in our vaccination protocols?
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The Journal of Immunology Dynamics of Memory T Cell Proliferation Under Conditions of Heterologous Immunity and Bystander Stimulation 1
2013Co-Authors: Sung-kwon Kim, Raymond M. Welsh, Michael A. Brehm, Liisa K. SelinAbstract:By examining adoptively transferred CSFE-labeled lymphocytic choriomeningitis virus (LCMV)-immune donor T cells in Thy-1 congenic hosts inoculated with viruses or with the cytokine inducer poly(I:C), strikingly different responses of bona fide memory T cells were found in response to different stimuli. Poly(I:C) (cytokine) stimulation caused a limited synchronized division of memory CD8 T cells specific to each of five LCMV epitopes, with no increase and sometimes a loss in number, and no change in their epitope hierarchy. Homologous LCMV infection caused more than seven divisions of T cells specific for each epitope, with dramatic increases in number and minor changes in hierarchy. Infections with the Heterologous viruses Pichinde and vaccinia (VV) caused more than seven divisions and increases in number of T cells specific to some putatively cross-reactive but not other epitopes and resulted in substantial changes in the hierarchy of the LCMV-specific T cells. Hence, there can be memory T cell division without proliferation (i.e., increase in cell number) in the absence of Ag and division with proliferation in the presence of Ag from homologous or Heterologous viruses. Heterologous protective Immunity between viruses is not necessarily reciprocal, given that LCMV protects against VV but VV does not protect against LCMV. VV elicited proliferation of LCMV-induced CD8 and CD4 T cells, whereas LCMV did not elicit proliferation of VV-induced T cells. Thus, depending on the pathogen and the sequence of infection, a Heterologous agent may selectively stimulate the memory pool in patterns consistent with Heterologous Immunity. The Journal of Immunology, 2002, 169: 90–98. Memory CD8 T cells were once thought to be restin
Jamie Rossjohn - One of the best experts on this subject based on the ideXlab platform.
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preferential hla b27 allorecognition displayed by multiple cross reactive antiviral cd8 t cell receptors
Frontiers in Immunology, 2020Co-Authors: Lloyd Dorsogna, Frans H J Claas, Louise C Rowntree, Thi H O Nguyen, Jamie Rossjohn, Heleen Van Den HeuvelAbstract:: T cells provide essential immunosurveillance to combat and eliminate infection from pathogens, yet these cells can also induce unwanted immune responses via T cell receptor (TCR) cross-reactivity, also known as Heterologous Immunity. Indeed, pathogen-induced TCR cross-reactivity has shown to be a common, robust, and functionally potent mechanism that can trigger a spectrum of human immunopathologies associated with either transplant rejection, drug allergy, and autoImmunity. Here, we report that several virus-specific CD8+ T cells directed against peptides derived from chronic viruses (EBV, CMV, and HIV-1) presented by high frequency HLA-A and -B allomorphs differentially cross-react toward HLA-B27 allotypes in a highly focused and hierarchical manner. Given the commonality of cross-reactive T cells and their potential contribution to adverse outcomes in allogeneic transplants, our study demonstrates that multiple antiviral T cells recognizing the same HLA allomorph could pose an extra layer of complexity for organ matching.
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inability to detect cross reactive memory t cells challenges the frequency of Heterologous Immunity among common viruses
Journal of Immunology, 2018Co-Authors: Louise C Rowntree, Thi H O Nguyen, Hanim Halim, Anthony W Purcell, Jamie Rossjohn, Stephanie GrasAbstract:Human memory T cells that cross-react with epitopes from unrelated viruses can potentially modulate immune responses to subsequent infections by a phenomenon termed Heterologous Immunity. However, it is unclear whether similarities in structure rather than sequence underpin Heterologous T cell cross-reactivity. In this study, we aimed to explore the mechanism of Heterologous Immunity involving immunodominant epitopes derived from common viruses restricted to high-frequency HLA allotypes (HLA-A*02:01, -B*07:02, and -B*08:01). We examined EBV-specific memory T cells for their ability to cross-react with CMV or influenza A virus–derived epitopes. Following T cell immunoassays to determine phenotype and function, complemented with biophysical and structural investigations of peptide/HLA complexes, we did not detect cross-reactivity of EBV-specific memory T cells toward either CMV or influenza A virus epitopes presented by any of the selected HLA allomorphs. Thus, despite the ubiquitous nature of these human viruses and the dominant immune response directed toward the selected epitopes, Heterologous virus-specific T cell cross-reactivity was not detected. This suggests that either Heterologous Immunity is not as common as previously reported, or that it requires a very specific biological context to develop and be clinically relevant.
Louise C Rowntree - One of the best experts on this subject based on the ideXlab platform.
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preferential hla b27 allorecognition displayed by multiple cross reactive antiviral cd8 t cell receptors
Frontiers in Immunology, 2020Co-Authors: Lloyd Dorsogna, Frans H J Claas, Louise C Rowntree, Thi H O Nguyen, Jamie Rossjohn, Heleen Van Den HeuvelAbstract:: T cells provide essential immunosurveillance to combat and eliminate infection from pathogens, yet these cells can also induce unwanted immune responses via T cell receptor (TCR) cross-reactivity, also known as Heterologous Immunity. Indeed, pathogen-induced TCR cross-reactivity has shown to be a common, robust, and functionally potent mechanism that can trigger a spectrum of human immunopathologies associated with either transplant rejection, drug allergy, and autoImmunity. Here, we report that several virus-specific CD8+ T cells directed against peptides derived from chronic viruses (EBV, CMV, and HIV-1) presented by high frequency HLA-A and -B allomorphs differentially cross-react toward HLA-B27 allotypes in a highly focused and hierarchical manner. Given the commonality of cross-reactive T cells and their potential contribution to adverse outcomes in allogeneic transplants, our study demonstrates that multiple antiviral T cells recognizing the same HLA allomorph could pose an extra layer of complexity for organ matching.
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inability to detect cross reactive memory t cells challenges the frequency of Heterologous Immunity among common viruses
Journal of Immunology, 2018Co-Authors: Louise C Rowntree, Thi H O Nguyen, Hanim Halim, Anthony W Purcell, Jamie Rossjohn, Stephanie GrasAbstract:Human memory T cells that cross-react with epitopes from unrelated viruses can potentially modulate immune responses to subsequent infections by a phenomenon termed Heterologous Immunity. However, it is unclear whether similarities in structure rather than sequence underpin Heterologous T cell cross-reactivity. In this study, we aimed to explore the mechanism of Heterologous Immunity involving immunodominant epitopes derived from common viruses restricted to high-frequency HLA allotypes (HLA-A*02:01, -B*07:02, and -B*08:01). We examined EBV-specific memory T cells for their ability to cross-react with CMV or influenza A virus–derived epitopes. Following T cell immunoassays to determine phenotype and function, complemented with biophysical and structural investigations of peptide/HLA complexes, we did not detect cross-reactivity of EBV-specific memory T cells toward either CMV or influenza A virus epitopes presented by any of the selected HLA allomorphs. Thus, despite the ubiquitous nature of these human viruses and the dominant immune response directed toward the selected epitopes, Heterologous virus-specific T cell cross-reactivity was not detected. This suggests that either Heterologous Immunity is not as common as previously reported, or that it requires a very specific biological context to develop and be clinically relevant.
Michael A. Brehm - One of the best experts on this subject based on the ideXlab platform.
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The Journal of Immunology Dynamics of Memory T Cell Proliferation Under Conditions of Heterologous Immunity and Bystander Stimulation 1
2013Co-Authors: Sung-kwon Kim, Raymond M. Welsh, Michael A. Brehm, Liisa K. SelinAbstract:By examining adoptively transferred CSFE-labeled lymphocytic choriomeningitis virus (LCMV)-immune donor T cells in Thy-1 congenic hosts inoculated with viruses or with the cytokine inducer poly(I:C), strikingly different responses of bona fide memory T cells were found in response to different stimuli. Poly(I:C) (cytokine) stimulation caused a limited synchronized division of memory CD8 T cells specific to each of five LCMV epitopes, with no increase and sometimes a loss in number, and no change in their epitope hierarchy. Homologous LCMV infection caused more than seven divisions of T cells specific for each epitope, with dramatic increases in number and minor changes in hierarchy. Infections with the Heterologous viruses Pichinde and vaccinia (VV) caused more than seven divisions and increases in number of T cells specific to some putatively cross-reactive but not other epitopes and resulted in substantial changes in the hierarchy of the LCMV-specific T cells. Hence, there can be memory T cell division without proliferation (i.e., increase in cell number) in the absence of Ag and division with proliferation in the presence of Ag from homologous or Heterologous viruses. Heterologous protective Immunity between viruses is not necessarily reciprocal, given that LCMV protects against VV but VV does not protect against LCMV. VV elicited proliferation of LCMV-induced CD8 and CD4 T cells, whereas LCMV did not elicit proliferation of VV-induced T cells. Thus, depending on the pathogen and the sequence of infection, a Heterologous agent may selectively stimulate the memory pool in patterns consistent with Heterologous Immunity. The Journal of Immunology, 2002, 169: 90–98. Memory CD8 T cells were once thought to be restin
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allografts stimulate cross reactive virus specific memory cd8 t cells with private specificity
American Journal of Transplantation, 2010Co-Authors: Michael A. Brehm, Keith A Daniels, Bhavana Priyadharshini, Thomas B Thornley, Dale L Greiner, Aldo A Rossini, Raymond M. WelshAbstract:Viral infections have been associated with the rejection of transplanted allografts in humans and mice, and the induction of tolerance to allogeneic tissues in mice is abrogated by an ongoing viral infection and inhibited in virus-immune mice. One proposed mechanism for this 'Heterologous Immunity' is the induction of alloreactive T cell responses that cross-react with virus-derived antigens. These cross-reactive CD8 T cells are generated during acute viral infection and survive into memory, but their ability to partake in the immune response to allografts in vivo is not known. We show here that cross-reactive, virus-specific memory CD8 T cells from mice infected with LCMV proliferated in response to allografts. CD8 T cells specific to several LCMV epitopes proliferated in response to alloantigens, with the magnitude and hierarchy of epitope-specific responses varying with the private specificities of the host memory T cell repertoire, as shown by adoptive transfer studies. Last, we show that purified LCMV-specific CD8 T cells rejected skin allografts in SCID mice. These findings therefore implicate a potential role for Heterologous Immunity in virus-induced allograft rejection.
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Heterologous Immunity between viruses
Immunological Reviews, 2010Co-Authors: Raymond M. Welsh, Michael A. Brehm, Jenny Wunyue Che, Liisa K. SelinAbstract:Immune memory responses to previously encountered pathogens can sometimes alter the immune response to and the course of infection of an unrelated pathogen by a process known as Heterologous Immunity. This response can lead to enhanced or diminished protective Immunity and altered immunopathology. Here, we discuss the nature of T-cell cross-reactivity and describe matrices of epitopes from different viruses eliciting cross-reactive CD8(+) T-cell responses. We examine the parameters of Heterologous Immunity mediated by these cross-reactive T cells during viral infections in mice and humans. We show that Heterologous Immunity can disrupt T-cell memory pools, alter the complexity of the T-cell repertoire, change patterns of T-cell immunodominance, lead to the selection of viral epitope-escape variants, alter the pathogenesis of viral infections, and, by virtue of the private specificity of T-cell repertoires within individuals, contribute to dramatic variations in viral disease. We propose that Heterologous Immunity is an important factor in resistance to and variations of human viral infections and that issues of Heterologous Immunity should be considered in the design of vaccines.
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frontiers in nephrology Heterologous Immunity t cell cross reactivity and alloreactivity
Journal of The American Society of Nephrology, 2007Co-Authors: Liisa K. Selin, Michael A. BrehmAbstract:Established memory T cell responses to a previously encountered pathogen can have a major impact on the course and outcome of a subsequent infection with an unrelated pathogen. This phenomenon, known as Heterologous Immunity, is dependent on the sequence of infections and can be either beneficial or detrimental to the host. Examples of Heterologous Immunity between unrelated viruses and alloantigens are mounting, and the role of cross-reactive T cells both in the pathogenesis of infections and in transplant rejection is now being explored. Memory T cells seem to be part of a continually evolving interactive network in which with each new infection, an alteration in the frequencies, distributions, and activities of memory cells is generated in response to previous infections and alloantigens.
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memory of mice and men cd8 t cell cross reactivity and Heterologous Immunity
Immunological Reviews, 2006Co-Authors: Liisa K. Selin, Sung-kwon Kim, Markus Cornberg, Michael A. Brehm, Yuri N Naumov, Shalyn Catherine Clute, Raymond M. WelshAbstract:Summary: The main functions of memory T cells are to provide protection upon re-exposure to a pathogen and to prevent the re-emergence of low-grade persistent pathogens. Memory T cells achieve these functions through their high frequency and elevated activation state, which lead to rapid responses upon antigenic challenge. The significance and characteristics of memory CD8+ T cells in viral infections have been studied extensively. In many of these studies of T-cell memory, experimental viral immunologists go to great lengths to assure that their animal colonies are free of endogenous pathogens in order to design reproducible experiments. These experimental results are then thought to provide the basis for our understanding of human immune responses to viruses. Although these findings can be enlightening, humans are not immunologically naive, and they often have memory T-cell populations that can cross-react with and respond to a new infectious agent or cross-react with allo-antigens and influence the success of tissue transplantation. These cross-reactive T cells can become activated and modulate the immune response and outcome of subsequent Heterologous infections, a phenomenon we have termed Heterologous Immunity. These large memory populations are also accommodated into a finite immune system, requiring that the host makes room for each new population of memory cell. It appears that memory cells are part of a continually evolving interactive network, where with each new infection there is an alteration in the frequencies, distributions, and activities of memory cells generated in response to previous infections and allo-antigens.