Taeg S. Kim

Respiratory Dendritic Cell Subsets Differ in Their Capacity to Support the Induction of Virus-Specific Cytotoxic CD8+ T Cell Responses

Dendritic cells located at the body surfaces, e.g. skin, respiratory and gastrointestinal tract, play an essential role in the induction of adaptive immune responses to pathogens and inert antigens present at these surfaces. In the respiratory tract, multiple subsets of dendritic cells (RDC) have been identified in both the normal and inflamed lungs. While the importance of RDC in antigen transport from the inflamed or infected respiratory tract to the lymph nodes draining this site is well recognized, the contribution of individual RDC subsets to this process and the precise role of migrant RDC within the lymph nodes in antigen presentation to T cells is not clear. In this report, we demonstrate that two distinct subsets of migrant RDC - exhibiting the CD103+ and CD11bhi phenotype, respectively - are the primary DC presenting antigen to naïve CD4+ and CD8+ T lymphocytes in the draining nodes in response to respiratory influenza virus infection. Furthermore, the migrant CD103+ RDC subset preferentially drives efficient proliferation and differentiation of naive CD8+ T cells responding to infection into effector cells, and only the CD103+ RDC subset can present to naïve CD8+ T cells non-infectious viral vaccine introduced into the respiratory tract. These results identify CD103+ and CD11bhi RDC as critical regulators of the adaptive immune response to respiratory tract infection and potential targets in the design of mucosal vaccines.

Regulating the adaptive immune response to respiratory virus infection

Recent years have seen several advances in our understanding of immunity to virus infection of the lower respiratory tract, including to influenza virus infection. Here, we review the cellular targets of viruses and the features of the host immune response that are unique to the lungs. We describe the interplay between innate and adaptive immune cells in the induction, expression and control of antiviral immunity, and discuss the impact of the infected lung milieu on moulding the response of antiviral effector T cells. Recent findings on the mechanisms that underlie the increased frequency of severe pulmonary bacterial infections following respiratory virus infection are also discussed.

Antiviral CD8+ T cell effector activities in situ are regulated by target cell type

In the lungs of mice infected with influenza, the activity of cytotoxic T lymphocytes is modulated by the type of target cell encountered.

Differential Response of Respiratory Dendritic Cell Subsets to Influenza Virus Infection

ABSTRACT Dendritic cells (DC) are believed to play an important role in the initiation of innate and adaptive immune responses to infection, including respiratory tract infections, where respiratory DC (RDC) perform this role. In this report, we examined the susceptibilities of isolated murine RDC to influenza virus infection in vitro and the effect of the multiplicity of infection (MOI) on costimulatory ligand upregulation and inflammatory cytokine/chemokine production after infection. We found that the efficiency of influenza virus infection of RDC increased with increasing MOIs. Furthermore, distinct subpopulations of RDC differed in their susceptibilities to influenza virus infection and in the magnitude/tempo of costimulatory ligand expression. Additional characterization of the CD11c-positive (CD11c+) RDC revealed that the identifiable subsets of RDC differed in susceptibility to infection, with CD11c+ CD103+ DC exhibiting the greatest susceptibility, CD11c+ CD11bhi DC exhibiting intermediate susceptibility, and CD11c+ B220+ plasmacytoid DC (pDC) exhibiting the least susceptibility to infection. A companion analysis of the in vivo susceptibilities of these RDC subsets to influenza virus revealed a corresponding infection pattern. The three RDC subsets displayed different patterns of cytokine/chemokine production in response to influenza virus infection in vitro: pDC were the predominant producers of most cytokines examined, while CD103+ DC and CD11bhi DC produced elevated levels of the murine chemokine CXCL1 (KC), interleukin 12p40, and RANTES in response to influenza virus infection. Our results indicate that RDC are targets of influenza virus infection and that distinct RDC subsets differ in their susceptibilities and responses to infection.

Antigen persistence and the control of local T cell memory by migrant respiratory dendritic cells after acute virus infection

Acute viral infections induce robust adaptive immune responses resulting in virus clearance. Recent evidence suggests that there may be depots of viral antigen that persist in draining lymph nodes (DLNs) after virus clearance and could, therefore, affect the adaptive immune response and memory T cell formation. The nature of these residual antigen depots, the mechanism of antigen persistence, and the impact of the persistent antigen on memory T cells remain ill defined. Using a mouse model of influenza virus infection of the respiratory tract, we identified respiratory dendritic cells (RDCs) as essential for both sampling and presenting residual viral antigen. RDCs in the previously infected lung capture residual viral antigen deposited in an irradiation-resistant cell type. RDCs then transport the viral antigen to the LNs draining the site of infection, where they present the antigen to T cells. Lastly, we document preferential localization of memory T cells to the DLNs after virus clearance as a consequence of presentation of residual viral antigen by the migrant RDC.

Distinct Dendritic Cell Subsets Dictate the Fate Decision between Effector and Memory CD8+ T Cell Differentiation by a CD24-Dependent Mechanism

The contribution of different DC subsets to effector and memory CD8(+) T cell generation during infection and the mechanism by which DCs controls these fate decisions is unclear. Here we demonstrated that the CD103(+) and CD11b(hi) migratory respiratory DC (RDC) subsets after influenza virus infection activated naive virus-specific CD8(+) T cells differentially. CD103(+) RDCs supported the generation of CD8(+) T effector (Teff) cells, which migrate from lymph nodes to the infected lungs. In contrast, migrant CD11b(hi) RDCs activated CD8(+) T cells characteristic of central memory CD8(+) T (CD8(+) Tcm) cells including retention within the draining lymph nodes. CD103(+) RDCs expressed CD24 at an elevated level, contributing to the propensity of this DC subpopulation to support CD8(+) Teff cell differentiation. Mechanistically, CD24 was shown to regulate CD8(+) T cell activation through HMGB1-mediated engagement of T cell RAGE. Thus, there is distribution of labor among DC subsets in regulating CD8(+) T cell differentiation.

Enhanced Virulence Mediated by the Murine Coronavirus, Mouse Hepatitis Virus Strain JHM, Is Associated with a Glycine at Residue 310 of the Spike Glycoprotein

ABSTRACT The coronavirus, mouse hepatitis virus strain JHM, causes acute and chronic neurological diseases in rodents. Here we demonstrate that two closely related virus variants, both of which cause acute encephalitis in susceptible strains of mice, cause markedly different diseases if mice are protected with a suboptimal amount of an anti-JHM neutralizing antibody. One strain, JHM.SD, caused acute encephalitis, while infection with JHM.IA resulted in no acute disease. Using recombinant virus technology, we found that the differences between the two viruses mapped to the spike (S) glycoprotein and that the two S proteins differed at four amino acids. By engineering viruses that differed by only one amino acid, we identified a serine-to-glycine change at position 310 of the S protein (S310G) that recapitulated the more neurovirulent phenotype. The increased neurovirulence mediated by the virus encoding glycine at position S310 was not associated with a different tropism within the central nervous system (CNS) but was associated with increased lateral spread in the CNS, leading to significantly higher brain viral titers. In vitro studies revealed that S310G was associated with decreased S1-S2 stability and with enhanced ability to mediate infection of cells lacking the primary receptor for JHM (“receptor-independent spread”). These enhanced fusogenic properties of viruses encoding a glycine at position 310 of the S protein may contribute to spread within the CNS, a tissue in which expression of conventional JHM receptors is low.

T cell responses during influenza infection: getting and keeping control

The 2009 influenza pandemic highlighted the threat that type A influenza poses to human health. Thus, there is an urgency to understand the pathobiology of influenza infection and the contribution of the host immune response to virus elimination and the development of lung injury. This review focuses on the T cell arm of the adaptive host immune response to influenza. We assess recent developments in the understanding of how primary influenza virus-specific T cell responses are induced by antigen-presenting cells, the interaction of activated effector T cells with antigen-bearing cells in the infected lungs. Also examined is the contribution of influenza-specific effector T cells to the development and control of lung injury and inflammation during infection.

The Cell Cycle Time of CD8+ T Cells Responding In Vivo Is Controlled by the Type of Antigenic Stimulus

A hallmark of cells comprising the mammalian adaptive immune system is the requirement for these rare naïve T (and B) lymphocytes directed to a specific microorganism to undergo proliferative expansion upon first encounter with this antigen. In the case of naïve CD8+ T cells the ability of these rare quiescent lymphocytes to rapidly activate and expand into effector T cells in numbers sufficient to control viral and certain bacterial infections can be essential for survival. In this report we examined the activation, cell cycle time and initial proliferative response of naïve murine CD8+ T cells responding in vivo to Influenza and Vaccinia virus infection or vaccination with viral antigens. Remarkably, we observed that CD8+ T cells could divide and proliferate with an initial cell division time of as short as 2 hours. The initial cell cycle time of responding CD8+ T cells is not fixed but is controlled by the antigenic stimulus provided by the APC in vivo. Initial cell cycle time influences the rate of T cell expansion and the numbers of effector T cells subsequently accumulating at the site of infection. The T cell cycle time varies with duration of the G1 phase of the cell cycle. The duration of G1 is inversely correlated with the phosphorylation state of the retinoblastoma (Rb) protein in the responding T cells. The implication of these findings for the development of adaptive immune responses and the regulation of cell cycle in higher eukaryotic cells is discussed.

Maturation and localization of macrophages and microglia during infection with a neurotropic murine coronavirus.

Macrophages and microglia are critical in the acute inflammatory response and act as final effector cells of demyelination during chronic infection with the neutrotropic MHV‐JHM strain of mouse hepatitis virus (MHV‐JHM). Herein, we show that “immature” F4/80+Ly‐6Chi monocytes are the first cells, along with neutrophils, to enter the MHV‐JHM‐infected central nervous system (CNS). As the infection progresses, macrophages in the CNS down‐regulate expression of Ly‐6C and CD62L, consistent with maturation, and a higher frequency express CD11c, a marker for dendritic cells (DCs). Microglia also express CD11c during this phase of the infection. CD11c+ macrophages in the infected CNS exhibit variable properties of immature antigen‐presenting cells (APCs), with modestly increased CD40 and MHC expression, and equivalent potent antigen uptake when compared with CD11c‐ macrophages. Furthermore, CDllc+ and F4/80+ macrophages and microglia are localized to areas of demyelination, in some instances directly associated with damaged axons. These results suggest that chronic CNS infection results in the appearance of CD11c‐expressing macrophages from the blood that exhibit properties of immature APCs, are closely associated with areas of demyelination, and may act as final effectors of myelin destruction.