Salmonellae Alter Host Responses through Direct T Cell Contacts

ABSTRACT Friend virus (FV) and lactate dehydrogenase-elevating virus (LDV) are endemic mouse viruses that can cause long-term chronic infections in mice. We found that numerous mouse-passaged FV isolates also contained LDV and that coinfection with LDV delayed FV-specific CD8+ T-cell responses during acute infection. While LDV did not alter the type of acute pathology induced by FV, which was severe splenomegaly caused by erythroproliferation, the immunosuppression mediated by LDV increased both the severity and the duration of FV infection. Compared to mice infected with FV alone, those coinfected with both FV and LDV had delayed CD8+ T-cell responses, as measured by FV-specific tetramers. This delayed response accounted for the prolonged and exacerbated acute phase of FV infection. Suppression of FV-specific CD8+ T-cell responses occurred not only in mice infected concomitantly with LDV but also in mice chronically infected with LDV 8 weeks prior to infection with FV. The LDV-induced suppression was not mediated by T regulatory cells, and no inhibition of the CD4+ T-cell or antibody responses was observed. Considering that most human adults are carriers of chronically infectious viruses at the time of new virus insults and that coinfections with viruses such as human immunodeficiency virus and hepatitis C virus are currently epidemic, it is of great interest to determine how infection with one virus may impact host responses to a second infection. Coinfection of mice with LDV and FV provides a well-defined, natural host model for such studies.

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Increase of γδ T Lymphocytes in Murine Lungs Occurs during Recovery from Pulmonary Infection by Nocardia asteroides

Infection and Immunity ◽

10.1128/iai.69.10.6165-6171.2001 ◽

2001 ◽

Vol 69 (10) ◽

pp. 6165-6171 ◽

Cited By ~ 27

Author(s):

Stanley Tam ◽

Donald P. King ◽

Blaine L. Beaman

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Pulmonary Infection ◽

Γδ T Cells ◽

Host Responses ◽

Nocardia Asteroides ◽

Γδ T Cell ◽

Wild Type ◽

Murine Lung

ABSTRACT Previous studies have demonstrated that γδ T lymphocytes are important for host resistance to pulmonary infection of the murine lung by log-phase cells of Nocardia asteroides. To study the role of γδ T cells in nocardial interactions in the murine lung, C57BL/6J wild type and C57BL/6J-Tcrd (γδ T-cell knockout mice) were infected intranasally with log-phase cells of N. asteroidesGUH-2. At 3, 5, and 7 days after infection, the γδ T cells were quantified by multiparameter flow cytometry. At the same time, Gram and hematoxylin-eosin stains of paraffin sections were performed to monitor the host responses. The data showed that γδ T lymphocytes increased significantly within the lungs after intranasal infection, and the peak of this cellular increase occurred at 5 days. Furthermore, at this time, greater than 50% of the CD3 T-cell receptor (TCR)-positive (CD3+) cells were γδ TCR positive. Histological examination clearly showed divergent inflammatory responses in the lungs of wild-type mice compared to γδ T-cell knockout mice. The C57BL/6J-Tcrd mice were less capable of clearing the organism, and the polymorphonuclear leukocyte response lasted longer than in wild-type C57BL/6J mice. These results showed that γδ T cells were actively involved in modulating the innate host responses to murine pulmonary infection by N. asteroides.

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Robust T-cell signaling triggered on soft polydimethylsiloxane-supported lipid-bilayers

10.1101/2020.06.05.134684 ◽

2020 ◽

Author(s):

Anna H. Lippert ◽

Ivan B. Dimov ◽

Alexander Winkel ◽

James McColl ◽

Jane Humphrey ◽

...

Keyword(s):

T Cell ◽

Lipid Bilayers ◽

T Cell Activation ◽

Cell Activation ◽

Tyrosine Phosphatase ◽

Supported Lipid Bilayers ◽

Cell Contact ◽

Mechanical Resistance ◽

Cell Contacts ◽

Cell Cell

AbstractThe T-cell receptor (TCR) is thought to be triggered either by mechano-transduction or local tyrosine phosphatase exclusion at cell-cell contacts. However, the effects of the mechanical properties of activating surfaces have only been tested for late-stage T-cell activation, and phosphatase segregation has mostly been studied on glass-supported lipid bilayers that favor imaging but are orders-of-magnitude stiffer than typical cells. We developed a method for attaching lipid bilayers to polydimethylsiloxane polymer supports, producing ‘soft bilayers’ with physiological levels of mechanical resistance (Young’s modulus of 4 kPa). Comparisons of T-cell behavior on soft and glass-supported bilayers revealed that early calcium signaling is unaffected by substrate rigidity, implying that early steps in TCR triggering are not mechanosensitive. Robust phosphatase exclusion was observed on the soft bilayers, however, suggesting it likely occurs at cell-cell contacts. This work sets the stage for an imaging-based exploration of receptor signaling under conditions closely mimicking physiological cell-cell contact.

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A Novel Adaptor Protein Orchestrates Receptor Patterning and Cytoskeletal Polarity in T-Cell Contacts

Cell ◽

10.1016/s0092-8674(00)81608-6 ◽

1998 ◽

Vol 94 (5) ◽

pp. 667-677 ◽

Cited By ~ 511

Author(s):

Michael L Dustin ◽

Michael W Olszowy ◽

Amy D Holdorf ◽

Jun Li ◽

Shannon Bromley ◽

...

Keyword(s):

T Cell ◽

Adaptor Protein ◽

Cell Contacts

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CD43 Interacts With Moesin and Ezrin and Regulates Its Redistribution to the Uropods of T Lymphocytes at the Cell-Cell Contacts

Blood ◽

10.1182/blood.v91.12.4632 ◽

1998 ◽

Vol 91 (12) ◽

pp. 4632-4644 ◽

Cited By ~ 126

Author(s):

Juan M. Serrador ◽

Marta Nieto ◽

José L. Alonso-Lebrero ◽

Miguel A. del Pozo ◽

Javier Calvo ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Binding Proteins ◽

Cell Aggregation ◽

Actin Binding ◽

Cell Aggregates ◽

Actin Binding Proteins ◽

Cell Contacts ◽

T Lymphoblasts ◽

Cell Cell

Abstract Chemokines as well as the signaling through the adhesion molecules intercellular adhesion molecule (ICAM)-3 and CD43 are able to induce in T lymphocytes their switching from a spherical to a polarized motile morphology, with the formation of a uropod at the rear of the cell. We investigated here the role of CD43 in the regulation of T-cell polarity, CD43-cytoskeletal interactions, and lymphocyte aggregation. Pro-activatory anti-CD43 monoclonal antibody (MoAb) induced polarization of T lymphocytes with redistribution of CD43 to the uropod and the CCR2 chemokine receptor to the leading edge of the cell. Immunofluorescence analysis showed that all three ezrin-radixin-moesin (ERM) actin-binding proteins localized in the uropod of both human T lymphoblasts stimulated with anti-CD43 MoAb and tumor-infiltrating T lymphocytes. Radixin localized at the uropod neck, whereas ezrin and moesin colocalized with CD43 in the uropod. Biochemical analyses showed that ezrin and moesin coimmunoprecipitated with CD43 in T lymphoblasts. Furthermore, in these cells, the CD43-associated moesin increased after stimulation through CD43. The interaction of moesin and ezrin with CD43 was specifically mediated by the cytoplasmic domain of CD43, as shown by precipitation of both ERM proteins with a GST-fusion protein containing the CD43 cytoplasmic tail. Videomicroscopy analysis of homotypic cell aggregation induced through CD43 showed that cellular uropods mediate cell-cell contacts and lymphocyte recruitment. Immunofluorescence microscopy performed in parallel showed that uropods enriched in CD43 and moesin localized at the cell-cell contact areas of cell aggregates. The polarization and homotypic cell aggregation induced through CD43 was prevented by butanedione monoxime, indicating the involvement of myosin cytoskeleton in these phenomena. Altogether, these data indicate that CD43 plays an important regulatory role in remodeling T-cell morphology, likely through its interaction with actin-binding proteins ezrin and moesin. In addition, the redistribution of CD43 to the uropod region of migrating lymphocytes and during the formation of cell aggregates together with the enhancing effect of anti-CD43 antibodies on lymphocyte cell recruitment suggest that CD43 plays a key role in the regulation of cell-cell interactions during lymphocyte traffic.

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Recombinant interleukin 12 cures mice infected with Leishmania major.

Journal of Experimental Medicine ◽

10.1084/jem.177.5.1505 ◽

1993 ◽

Vol 177 (5) ◽

pp. 1505-1509 ◽

Cited By ~ 449

Author(s):

F P Heinzel ◽

D S Schoenhaut ◽

R M Rerko ◽

L E Rosser ◽

M K Gately

Keyword(s):

T Cell ◽

Leishmania Major ◽

Durable Resistance ◽

Cell Subset ◽

Host Responses ◽

Interleukin 12 ◽

Self Healing ◽

T Lymphocyte Subsets ◽

Ifn Gamma

Resistant C57BL/6 mice infected with Leishmania major are self-healing, whereas susceptible BALB/c mice fail to contain cutaneous infection and subsequently undergo fatal visceral dissemination. These disparate outcomes are mediated by dissimilar expansions of T helper type 1 (Th1) and Th2 CD4+ T lymphocyte subsets in vivo during cure and progression of disease. Because interleukin 12 (IL-12) has potent T cell growth and interferon gamma (IFN-gamma) stimulatory effects, we studied its effect on CD4+ T cell differentiation during murine leishmaniasis. Treatment with recombinant murine (rMu)IL-12 during the first week of infection cured 89% of normally susceptible BALB/c mice, as defined by decreased size of infected footpads and 1,000-10,000-fold reduced parasite burdens, and provided durable resistance against reinfection. Cure was associated with markedly depressed production of IL-4 by lymph node cells cultured with antigen or mitogen, but preserved or increased production of IFN-gamma relative to untreated mice. IL-4 and IFN-gamma mRNA associated with CD4+ T lymphocytes isolated from infected lymph nodes showed similar reciprocal changes in response to rMuIL-12 therapy. A single injection of anti-IFN-gamma monoclonal antibody abrogated the protective effect of rMuIL-12 therapy and restored Th2 cytokine responses. We conclude that rMuIL-12 prevents deleterious Th2 T cell responses and promotes curative Th1 responses in an IFN-gamma-dependent fashion during murine leishmaniasis. Since BALB/c leishmaniasis cannot be cured with rMuIFN-gamma alone, additional direct effects of IL-12 during T cell subset selection are suggested. Because rMuIL-12 is uniquely protective in this well-characterized model of chronic parasitism, differences in IL-12 production may underlie heterogenous host responses to L. major and other intracellular pathogens.

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Divergent Host Responses during Primary Simian Immunodeficiency Virus SIVsm Infection of Natural Sooty Mangabey and Nonnatural Rhesus Macaque Hosts

Journal of Virology ◽

10.1128/jvi.79.7.4043-4054.2005 ◽

2005 ◽

Vol 79 (7) ◽

pp. 4043-4054 ◽

Cited By ~ 144

Author(s):

Guido Silvestri ◽

Andrew Fedanov ◽

Stephanie Germon ◽

Natalia Kozyr ◽

William J. Kaiser ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Rhesus Macaque ◽

Simian Immunodeficiency Virus ◽

Chronic Phase ◽

Host Responses ◽

T Cell Proliferation ◽

Sooty Mangabey ◽

Immunodeficiency Virus ◽

Species Specific

ABSTRACT To understand how natural sooty mangabey hosts avoid AIDS despite high levels of simian immunodeficiency virus (SIV) SIVsm replication, we inoculated mangabeys and nonnatural rhesus macaque hosts with an identical inoculum of uncloned SIVsm. The unpassaged virus established infection with high-level viral replication in both macaques and mangabeys. A species-specific, divergent immune response to SIV was evident from the first days of infection and maintained in the chronic phase, with macaques showing immediate and persistent T-cell proliferation, whereas mangabeys displayed little T-cell proliferation, suggesting subdued cellular immune responses to SIV. Importantly, only macaques developed CD4+-T-cell depletion and AIDS, thus indicating that in mangabeys limited immune activation is a key mechanism to avoid immunodeficiency despite high levels of SIVsm replication. These studies demonstrate that it is the host response to infection, rather than properties inherent to the virus itself, that causes immunodeficiency in SIV-infected nonhuman primates.

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