Tumor necrosis factor receptor superfamily member 25 (TNFRSF25) agonists in islet transplantation: Endogenous in vivo regulatory T cell expansion promotes prolonged allograft survival.

Regulatory T cells (Tregs) modulate alloimmune responses and may facilitate minimization or withdrawal of immunosuppression posttransplant. Current approaches, however, rely on complex ex vivo Treg expansion protocols. Herein, we explore endogenous in vivo Treg expansion through antibody-mediated agonistic stimulation of the tumor necrosis factor receptor superfamily member 25 (TNFRSF25) pathway and its potential to prolong graft survival in a mouse model of islet allotransplantation.

Lack of B Lymphocytes Enhances CD8 T Cell-Mediated Resistance against Respiratory Viral Infection but Compromises Memory Cell Formation.

Following a respiratory virus infection, CXCR3 CX3CR1 and CXCR3 CX3CR1 CD8 T cells localize to different compartments within the lung and play an important role in host resistance, but mechanisms governing their optimal generation are poorly defined. We serendipitously found that B cell-deficient (μMT) mice were highly resistant to lethal infection with a virulent poxvirus strain and that depletion of CD8 T cells rendered these mice susceptible to infection. B cells were not required for the expansion of virus-specific CD8 T cells, but a greater proportion of activated CD8 T cells acquired an effector-like CXCR3 CX3CR1 phenotype in the absence of B cells.

Batf3-Dependent Dendritic Cells Promote Optimal CD8 T Cell Responses against Respiratory Poxvirus Infection.

Respiratory infection with vaccinia virus (VacV) elicits robust CD8 T cell responses that play an important role in host resistance. In the lung, VacV encounters multiple tissue-resident antigen-presenting cell (APC) populations, but which cell plays a dominant role in priming of virus-specific CD8 effector T cell responses remains poorly defined. We used Batf3 mice to investigate the impact of CD103 and CD8α dendritic cell (DC) deficiency on anti-VacV CD8 T cell responses.

The TNF Superfamily Molecule LIGHT Promotes the Generation of Circulating and Lung-Resident Memory CD8 T Cells following an Acute Respiratory Virus Infection.

The transition of effector T cells or memory precursors into distinct long-lived memory T cell subsets is not well understood. Although many molecules made by APCs can contribute to clonal expansion and effector cell differentiation, it is not clear if clonal contraction and memory development is passive or active. Using respiratory virus infection, we found that CD8 T cells that cannot express the TNF family molecule lymphotoxin-like, exhibits nducible expression, competes with HSV lycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes (LIGHT) are unimpaired in their initial response and clonally expand to form effector cell pools.

Inflammatory monocytes contribute to the persistence of CXCR3 CX3CR1 circulating and lung-resident memory CD8 T cells following respiratory virus infection.

Phenotypically diverse memory CD8 T cells are present in the lungs that either re-circulate or reside within the tissue. Understanding the key cellular interactions that regulate the generation and then persistence of these different subsets is of great interest. Recently, DNGR-1 dendritic cell (DC) mediated priming was reported to control the generation of lung-resident but not circulating memory cells following respiratory viral infection.

OX40 Cooperates with ICOS To Amplify Follicular Th Cell Development and Germinal Center Reactions during Infection.

Cognate interactions between T follicular helper (Tfh) cells and B cells are essential for promoting protective Ab responses. Whereas costimulatory receptors such as ICOS are accepted as being important for the induction of Tfh cell fate decision, other molecules may play key roles in amplifying or maintaining the Tfh phenotype. In this study, with vaccinia virus infection in mice, we show that OX40 was expressed on Tfh cells that accumulated at the T/B borders in the white pulp of the spleen and that OX40-dependent signals directly shaped the magnitude and quality of the their response to viral Ags.

Tissue-specific programming of memory CD8 T cell subsets impacts protection against lethal respiratory virus infection.

How tissue-specific anatomical distribution and phenotypic specialization are linked to protective efficacy of memory T cells against reinfection is unclear. Here, we show that lung environmental cues program recently recruited central-like memory cells with migratory potentials for their tissue-specific functions during lethal respiratory virus infection. After entering the lung, some central-like cells retain their original CD27CXCR3 phenotype, enabling them to localize near the infected bronchiolar epithelium and airway lumen to function as the first line of defense against pathogen encounter.

Transcription Factor Bcl11b Controls Effector and Memory CD8 T cell Fate Decision and Function during Poxvirus Infection.

CD8 T cells play an important role in host resistance to many viral infections, but the underlying transcriptional mechanisms governing their differentiation and functionality remain poorly defined. By using a highly virulent systemic and respiratory poxvirus infection in mice, we show that the transcription factor Bcl11b provides a dual trigger that sustains the clonal expansion of virus-specific effector CD8 T cells, while simultaneously suppressing the expression of surface markers associated with short-lived effector cell (SLEC) differentiation. Additionally, we demonstrate that Bcl11b supports the acquisition of memory precursor effector cell (MPEC) phenotype and, thus, its absence causes near complete loss of lymphoid and lung-resident memory cells.

Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection.

Unlabelled: In establishing a respiratory infection, vaccinia virus (VACV) initially replicates in airway epithelial cells before spreading to secondary sites of infection, mainly the draining lymph nodes, spleen, gastrointestinal tract, and reproductive organs. We recently reported that interferon gamma (IFN-γ) produced by CD8 T cells ultimately controls this disseminated infection, but the relative contribution of IFN-γ early in infection is unknown. Investigating the role of innate immune cells, we found that the frequency of natural killer (NK) cells in the lung increased dramatically between days 1 and 4 postinfection with VACV.

Vaccine-induced protection against orthopoxvirus infection is mediated through the combined functions of CD4 T cell-dependent antibody and CD8 T cell responses.

Unlabelled: Antibody production by B cells in the absence of CD4 T cell help has been shown to be necessary and sufficient for protection against secondary orthopoxvirus (OPV) infections. This conclusion is based on short-term depletion of leukocyte subsets in vaccinated animals, in addition to passive transfer of immune serum to naive hosts that are subsequently protected from lethal orthopoxvirus infection. Here, we show that CD4 T cell help is necessary for neutralizing antibody production and virus control during a secondary ectromelia virus (ECTV) infection.

CD8 T cells use IFN-γ to protect against the lethal effects of a respiratory poxvirus infection.

CD8 T cells are a key component of immunity to many viral infections. They achieve this through using an array of effector mechanisms, but precisely which component/s are required for protection against a respiratory orthopox virus infection remains unclear. Using a model of respiratory vaccinia virus infection in mice, we could specifically determine the relative contribution of perforin, TRAIL, and IFN-γ-mediated pathways in protection against virus induced morbidity and mortality.

The orchestrated functions of innate leukocytes and T cell subsets contribute to humoral immunity, virus control, and recovery from secondary poxvirus challenge.

A pivotal role for antigen-specific recall responses to secondary virus infection is well established, but the contribution of innate immune cells to this process is unknown. Recovery of mice from a primary orthopoxvirus (ectromelia virus [ECTV]) infection requires the function of natural killer (NK) cells, granulocytes, plasmacytoid dendritic cells (pDC), T cells, and B cells. However, during a secondary challenge, resolution of infection is thought to be dependent on antibody but not T cell function.

Targeting 4-1BB (CD137) to enhance CD8 T cell responses with poxviruses and viral antigens.

Attenuated vaccinia virus (VACV) vectors are considered prime vaccine candidates for use in immunotherapy of infectious disease. In spite of this, recent data show that the level of attenuation may hamper the efficient generation of protective CD8 T cells. This suggests that additional adjuvant-like activities may need to be combined with attenuated VACV for optimal vaccination.

CD8 T cells are essential for recovery from a respiratory vaccinia virus infection.

The precise immune components required for protection against a respiratory Orthopoxvirus infection, such as human smallpox or monkeypox, remain to be fully identified. In this study, we used the virulent Western Reserve strain of vaccinia virus (VACV-WR) to model a primary respiratory Orthopoxvirus infection. Naive mice infected with VACV-WR mounted an early CD8 T cell response directed against dominant and subdominant VACV-WR Ags, followed by a CD4 T cell and Ig response.

OX40:OX40L axis: emerging targets for improving poxvirus-based CD8(+) T-cell vaccines against respiratory viruses.

The human respiratory tract is an entry point for over 200 known viruses that collectively contribute to millions of annual deaths worldwide. Consequently, the World Health Organization has designated respiratory viral infections as a priority for vaccine development. Despite enormous advances in understanding the attributes of a protective mucosal antiviral immune response, current vaccines continue to fail in effectively generating long-lived protective CD8(+) T-cell immunity.

Topology and identification of critical residues of the O-acetyltransferase of serotype-converting bacteriophage, SF6, of Shigella flexneri.

The modification of the LPS O-antigen, seen in the diverse serotypes of Shigella flexneri is brought about by the glucosyltransferases (Gtr) and the O-acetyltransferase (Oac). In this study, we establish the membrane topology of Oac using the dual reporter PhoA-LacZalpha. We have determined that Oac is an integral membrane protein with 10 transmembrane regions.