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Marcia A Blackman

Publications and source records attributed to Marcia A Blackman.

At least 19 recordsLinked to original sources
PubMed2007

Aging and CD8+ T cell immunity to respiratory virus infections.

The capacity of the immune system to mediate effective immune responses to pathogens declines with age. In the case of immune responses to newly encountered antigens, several studies have demonstrated that this decline reflects both a loss of naïve T cells and changes in the repertoire and function of these cells over time. However, comparatively little is known about the impact of age on established memory T cells pools. Here we discuss age-related changes in memory CD8(+) T cell pools elicited by influenza and parainfluenza viruses and the impact of these changes on immunity in general.

Aging↗
PubMed2006

Immunity and age: living in the past?

Increasing age is associated with a decreasing ability to mediate effective immune responses to newly encountered antigens. It is generally believed that this reflects the age-associated decline in the number, repertoire and function of available naive T cells. Here, we propose that naive T cells become increasingly irrelevant to the immune system, and that responses to newly encountered antigens are progressively dominated by cross-reactive memory T cells as the individual ages. In addition, we propose that the majority, if not all, of the response to newly encountered antigens in the elderly is mediated by cross-reactive memory T cells. This predicts highly stochastic responses to new infections that should vary between individuals, and has important implications for vaccination strategies in the elderly.

Aged↗
PubMed2006

T-cell memory and recall responses to respiratory virus infections.

The respiratory tract is characterized by its large surface area and the close association of an extensive vasculature with the external environment. As such, the respiratory tract is a major portal of entry for many pathogens. The immune system is able to effectively control most pulmonary pathogens and establish immunological memory that is capable of mediating an accelerated and enhanced recall response to secondary pathogen challenge. A key component of the recall response in the lung involves the rapid response of antigen-specific memory CD8+ T cells. Recent studies have shown that memory CD8+ T cells are extremely heterogeneous in terms of phenotype, function, anatomical distribution, and longevity. However, we have little understanding of how the different subsets of memory cells actually contribute to the recall response, especially with respect to peripheral or mucosal sites, such as the lung. Since immunological memory is the cornerstone of vaccination, it is essential that we understand how different memory CD8+ T-cell subsets are initially generated, maintained over time, and contribute to recall responses. This review focuses on memory T cells that mediate recall responses to influenza and parainfluenza virus infections in the lung.

Animals↗
PubMed2005

Infection of dendritic cells by a gamma2-herpesvirus induces functional modulation.

The murine gamma-herpesvirus-68 (gammaHV68) establishes viral latency in dendritic cells (DCs). In the present study, we examined the specific consequences of DC infection by gammaHV68, both in vivo and in vitro. Ex vivo analysis of infected mice showed that the virus colonizes respiratory DCs very early after infection and that all subsets of splenic DCs analyzed are viral targets. We have developed and characterized an in vitro model of gammaHV68 infection of DCs. Using this model, we demonstrated that viral infection neither induces full DC maturation nor interferes with exogenous activation, which is assessed by cell surface phenotypic changes. However, whereas gammaHV68 infection alone failed to elicit cytokine secretion, IL-10 secretion of exogenously activated DCs was enhanced. Furthermore, gammaHV68-infected DCs efficiently stimulated virus-specific T cell hybridomas but failed to induce alloreactive stimulation of normal T cells. These data indicate that viral infection doesn't interfere with Ag processing and presentation but does interfere with the ability of DCs to activate T cells. The inhibition of T cell activation was partially reversed by blocking IL-10. Analysis of infected mice shows elevated levels of IL-10 expression in DCs and that lack of endogenous IL-10 is associated with decreased gammaHV68 long-term latency. Taken together, these observations indicate that gamma2-herpesvirus infection of DCs is a mechanism of viral immune evasion, partially mediated by IL-10.

Animals↗
PubMed2005

Early establishment of gamma-herpesvirus latency: implications for immune control.

The human gamma-herpesviruses, EBV and Kaposi's sarcoma-associated herpesvirus, infect >90% of the population worldwide, and latent infection is associated with numerous malignancies. Rational vaccination and therapeutic strategies require an understanding of virus-host interactions during the initial asymptomatic infection. Primary EBV infection is associated with virus replication at epithelial sites and entry into the circulating B lymphocyte pool. The virus exploits the life cycle of the B cell and latency is maintained long term in resting memory B cells. In this study, using a murine gamma-herpesvirus model, we demonstrate an early dominance of latent virus at the site of infection, with lung B cells harboring virus almost immediately after infection. These data reinforce the central role of the B cell not only in the later phase of infection, but early in the initial infection. Early inhibition of lytic replication does not impact the progression of the latent infection, and latency is established in lymphoid tissues following infection with a replication-deficient mutant virus. These data demonstrate that lytic viral replication is not a requirement for gamma-herpesvirus latency in vivo and suggest that viral latency can be disseminated by cellular proliferation. These observations emphasize that prophylactic vaccination strategies must target latent gamma-herpesvirus at the site of infection.

Animals↗
PubMed2005

Immunity: it's in our bones.

Accumulating data suggest that the bone marrow is a reservoir for memory CD8+ T cells. In this issue of Immunity, show that bone marrow CD8+ T cells are predominantly CCR7+/CD62L+ "central memory" cells and describe specific signals that mediate their constitutive recruitment from the blood.

Animals↗
PubMed2004

Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo.

Lymphocyte activation gene-3 (LAG-3) is a CD4-related, activation-induced cell surface molecule that binds to MHC class II with high affinity. In this study, we used four experimental systems to reevaluate previous suggestions that LAG-3(-/-) mice had no T cell defect. First, LAG-3(-/-) T cells exhibited a delay in cell cycle arrest following in vivo stimulation with the superantigen staphylococcal enterotoxin B resulting in increased T cell expansion and splenomegaly. Second, increased T cell expansion was also observed in adoptive recipients of LAG-3(-/-) OT-II TCR transgenic T cells following in vivo Ag stimulation. Third, infection of LAG-3(-/-) mice with Sendai virus resulted in increased numbers of memory CD4(+) and CD8(+) T cells. Fourth, CD4(+) T cells exhibited a delayed expansion in LAG-3(-/-) mice infected with murine gammaherpesvirus. In summary, these data suggest that LAG-3 negatively regulates T cell expansion and controls the size of the memory T cell pool.

Adoptive Transfer↗
PubMed2004

T cell reactivity during infectious mononucleosis and persistent gammaherpesvirus infection in mice.

Intranasal infection of mice with murine gammaherpesvirus 68 causes a dramatic increase in numbers of activated CD8(+) T cells in the blood, analogous in many respects to EBV-induced infectious mononucleosis in humans. In the mouse model, this lymphocytosis has two distinct components: an early, conventional virus-specific CD8(+) T cell response, and a later response characterized by a dramatic increase among CD8(+) T cells that bear Vbeta4(+) TCRs. We previously demonstrated that Vbeta4(+)CD8(+) T cells recognize an uncharacterized ligand expressed on latently infected B cells in an MHC-independent manner. The frequency of Vbeta4(+)CD8(+) T cells increases dramatically following the peak of viral latency in the spleen. In the current studies, we show that elevated Vbeta4(+)CD8(+) T cell levels are sustained long-term in persistently infected mice, apparently a consequence of continued ligand expression. In addition, we show that Vbeta4(+)CD8(+) T cells can acquire effector functions, including cytotoxicity and the capacity to secrete IFN-gamma, although they have an atypical activation profile compared with well-characterized CD8(+) T cells specific for conventional viral epitopes. The characteristics of Vbeta4(+)CD8(+) T cells (potential effector function, stimulation by latently infected B cells, and kinetics of expansion) suggested that this dominant T cell response plays a key role in the immune control of latent virus. However, Ab depletion and adoptive transfer studies show that Vbeta4(+)CD8(+) T cells are not essential for this function. This murine model of infection may provide insight into the role of unusual populations of activated T cells associated with persistent viral infections.

Animals↗
PubMed2004

Intact type 1 immunity and immune-associated coagulative responses in mice lacking IFN gamma-inducible fibrinogen-like protein 2.

Fibrinogen-like protein 2 (Fgl2, fibroleukin) is a leukocyte product that exhibits significant homology to secreted proteins of diverse function, including growth factors, lectins, and components of extracellular matrix. Prior studies found that Fgl2 is IFN gamma-inducible, possesses direct coagulant activity, and inhibits T cell proliferation and dendritic cell maturation in vitro. Here, we demonstrate that Fgl2 expression is up-regulated during type 1 immunity in vivo and establish that such up-regulation is IFN gamma-, signal transducer and activation of transcription protein 1-, and IFN response factor 1-dependent. To investigate functional roles for Fgl2 during type 1 immunity, we generated Fgl2-deficient mice. Those animals are born at predicted Mendelian frequencies, appear overtly healthy, and contain normal numbers and frequencies of lymphoid cells. Although Fgl2 is IFN gamma-inducible and putatively regulates T cell activation/proliferation, we demonstrate that Fgl2-deficient and control mice exhibit similar degrees of T cell expansion, immunopathology, and/or pathogen burdens during protozoan (Toxoplasma gondii), bacterial (Yersinia enterocolitica, Listeria monocytogenes, and Mycobacterium tuberculosis), and viral (murine gamma-herpesvirus-68 and Sendai) infections. Fgl2-deficient mice also reject allografts with similar kinetics as control mice. Moreover, despite prior reports that Fgl2 functions as a procoagulant enzyme, we demonstrate that Fgl2-deficient and control mice produce similar levels of fibrin, a product of the coagulation cascade, during T. gondii infection and allograft rejection. Together, our findings suggest that Fgl2, although highly conserved and IFN gamma-inducible, is not a critical mediator of either type 1 immunity or immune-associated coagulant activity.

Animals↗
PubMed2003

Maintenance of long term gamma-herpesvirus B cell latency is dependent on CD40-mediated development of memory B cells.

It has been proposed that the gamma-herpesviruses maintain lifelong latency in B cells by gaining entry into the memory B cell pool and taking advantage of host mechanisms for maintaining these cells. We directly tested this hypothesis by kinetically monitoring viral latency in CD40(+) and CD40(-) B cells from CD40(+)CD40(-) mixed bone marrow chimera mice after infection with a murine gamma-herpesvirus, MHV-68. CD40(+) B cells selectively entered germinal centers and differentiated into memory B cells. Importantly, latency was progressively lost in the CD40(-) B cells and preferentially maintained in the long-lived, isotype-switched CD40(+) B cells. These data directly demonstrate viral exploitation of the normal B cell differentiation pathway to maintain latency.

3T3 Cells↗
PubMed2003

Differential gamma-herpesvirus distribution in distinct anatomical locations and cell subsets during persistent infection in mice.

Murine gamma-herpesvirus 68 (MHV-68) provides an important experimental model for analyzing gamma-herpesvirus latent infection. After intranasal infection with MHV-68, we analyzed the distribution of the virus in different anatomical locations and purified populations of cells. Our data show that long-term latency is maintained in a variety of anatomical locations and cell populations with different frequencies. Importantly, we demonstrate that although latency in the lung is established in a variety of cell subsets, long-term latency in the lung is only maintained in B cells. In contrast, splenic latency is maintained in macrophages and dendritic cells, as well as in B cells. In blood, isotype-switched B cells constitute the major viral reservoir. These results show that the cell subsets in which latency is established vary within different anatomical sites. Finally, we demonstrate that long-term latency is accompanied by a low level of infectious virus in lung and spleen. These data have important implications for understanding the establishment and maintenance of latency by gamma(2)-herpesviruses.

Animals↗
PubMed2003

Persistence and turnover of antigen-specific CD4 T cells during chronic tuberculosis infection in the mouse.

CD4 T cells are critical for resistance to Mycobacterium tuberculosis infection, but how effective T cell responses are maintained during chronic infection is not well understood. To address this question we examined the CD4 T cell response to a peptide from ESAT-6 during tuberculosis infection in the mouse. The ESAT-6(1-20)/IA(b)-specific CD4 T cell response in the lungs, mediastinal lymph nodes, and spleen reached maxima 3-4 wk postinfection, when the bacteria came under the control of the immune response. Once chronic infection was established, the relative frequencies of Ag-specific CD4 T cells were maintained at nearly constant levels for at least 160 days. ESAT-6(1-20)/IA(b)-specific CD4 T cells that responded in vitro expressed activation markers characteristic of chronically activated effector cells and used a limited Vbeta repertoire that was clonally stable in vivo for at least 12 wk. 5-Bromo-2-deoxyuridine incorporation studies indicated a relatively high rate of cell division among both total CD4 and ESAT-6(1-20)/IA(b)-specific CD4 T cells during acute infection, but the degree of 5-bromo-2-deoxyuridine incorporation by both the CD4 T cells and the Ag-specific cells declined at least 3-fold during chronic infection. The data indicate that the peripheral ESAT-6(1-20)/IA(b)-specific CD4 T cell response to M. tuberculosis is characterized during the acute phase of infection by a period of extensive proliferation, but once bacterial control is achieved, this is followed during chronic infection by an extended containment phase that is associated with a persistent response of activated, yet more slowly proliferating, T cells.

Animals↗
PubMed2003

Murid herpesvirus 4 strain 68 M2 protein is a B-cell-associated antigen important for latency but not lymphocytosis.

This work describes analyses of the function of the murid herpesvirus 4 strain 68 (MHV-68) M2 gene. A frameshift mutation was made in the M2 open reading frame that caused premature termination of translation of M2 after amino acid residue 90. The M2 mutant showed no defect in productive replication in vitro or in lungs after infection of mice. Likewise, the characteristic transient increase in spleen cell number, Vbeta4 T-cell-receptor-positive CD8(+) T-cell mononucleosis, and establishment of latency were unaffected. However, the M2 mutant virus was defective in its ability to cause the transient sharp rise in latently infected cells normally seen in the spleen after infection of mice. We also demonstrate that expression of M2 is restricted to B cells in the spleen and that M2 encodes a 30-kDa protein localizing predominantly in the cytoplasm and plasma membrane of B cells.

Amino Acid Sequence↗
PubMed2002

Gamma-herpesvirus latency is preferentially maintained in splenic germinal center and memory B cells.

The gamma-herpesviruses are oncogenic B cell lymphotrophic viruses that establish life-long latency in the host. Murine gamma-herpesvirus 68 (MHV-68) infection of mice represents a unique system for analyzing gamma-herpesvirus latency in splenic B cells at different stages of infection. After intranasal infection with MHV-68 we analyzed the establishment of latency 14 days after infection, and the maintenance of latency 3 months after infection in different purified subpopulations of B cells in the spleen. The data show that MHV-68 latency is mainly established in germinal center B cells and that long-term latency is preferentially maintained in two different subsets of isotype-switched B cells, germinal center and memory B cells. Cell cycle analysis indicates that MHV-68 is located in both cycling and resting isotype-switched B cells. Analysis of viral gene expression showed that both lytic and latent viral transcripts were differentially expressed in germinal center and memory B cells during long-term latency. Together, these observations suggested that gamma-herpesviruses exploit the B cell life cycle in the spleen.

Animals↗
PubMed2002

Antibody-mediated control of persistent gamma-herpesvirus infection.

The human gamma-herpesviruses, EBV and Kaposi's sarcoma-associated herpesvirus, establish life-long latency and can reactivate in immunocompromised individuals. T cells play an important role in controlling persistent EBV infection, whereas a role for humoral immunity is less clear. The murine gamma-herpesvirus-68 has biological and structural similarities to the human gamma-herpesviruses, and provides an important in vivo experimental model for dissecting mechanisms of immune control. In the current studies, CD28(-/-) mice were used to address the role of Abs in control of persistent murine gamma-herpesvirus-68 infection. Lytic infection was controlled in the lungs of CD28(-/-) mice, and latency was maintained in B cells at normal frequencies. Although class-switched virus-specific Abs were initially generated in the absence of germinal centers, titers and viral neutralizing activity rapidly waned. T cell depletion in CD28(-/-) mice with compromised Ab responses, but not in control mice with intact Ab responses, resulted in significant recrudescence from latency, both in the spleen and the lung. Recrudescence could be prevented by passive transfer of immune serum. These data directly demonstrate an important contribution of humoral immunity to control of gamma-herpesvirus latency, and have significant implications for clinical intervention.

Animals↗