Thomas J. Braciale

Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10

Activated antigen-specific T cells produce a variety of effector molecules for clearing infection but also contribute to inflammation and tissue injury. Here we report an anti-inflammatory property of antiviral CD8+ and CD4+ effector T cells (Teff cells) in the infected periphery during acute virus infection. We find that, during acute influenza infection, interleukin-10 (IL-10) is produced in the infected lungs in large amounts—exclusively by infiltrating virus-specific Teff cells, with CD8+ Teff cells contributing a larger fraction of the IL-10 produced. These Teff cells in the periphery simultaneously produce IL-10 and proinflammatory cytokines and express lineage markers characteristic of conventional T helper type 1 or T cytotoxic type 1 cells. Notably, blocking the action of the Teff cell–derived IL-10 results in enhanced pulmonary inflammation and lethal injury. Our results show that antiviral Teff cells exert regulatory functions—that is, they fine-tune the extent of lung inflammation and injury associated with influenza infection by producing an anti-inflammatory cytokine. We discuss the potential implications of these findings for infection with highly pathogenic influenza viruses.

Accelerated Migration of Respiratory Dendritic Cells to the Regional Lymph Nodes Is Limited to the Early Phase of Pulmonary Infection

Respiratory dendritic cells (RDC) are believed to play a central role in the induction of adaptive immune responses to pulmonary infection. Herein we examine the basal migration of RDC from the lungs to secondary lymphoid tissues and their enhanced maturation/migration after pulmonary infection/inflammation. We demonstrate that the accelerated migration of RDC to the draining peribronchial lymph nodes occurs only during the first 24 hr after pulmonary virus infection. RDC are refractory to further migration thereafter in spite of ongoing virus replication and pulmonary inflammation. We further demonstrate that induction of this RDC refractory state suppresses additional RDC mobilization to subsequent pulmonary virus infection and results in concomitant suppression of an antiviral pulmonary CD8(+) T cell response.

Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation

Hepatitis C virus (HCV) is an important human pathogen that is remarkably efficient at establishing persistent infection. The HCV core protein is the first protein expressed during the early phase of HCV infection. Our previous work demonstrated that the HCV core protein suppresses host immune responses, including anti-viral cytotoxic T-lymphocyte responses in a murine model. To investigate the mechanism of HCV core-mediated immunosuppression, we searched for host proteins capable of associating with the core protein using a yeast two-hybrid system. Using the core protein as bait, we screened a human T cell-enriched expression library and identified a gene encoding the gC1q receptor (gC1qR). C1q is a ligand of gC1qR and is involved in the early host defense against infection. Like C1q, HCV core can inhibit T-cell proliferative responses in vitro. This core-induced anti-T-cell proliferation is reversed by addition of anti-gC1qR Ab in a T-cell proliferation assay. Furthermore, biochemical analysis of the interaction between core and gC1qR indicates that HCV core binds the region spanning amino acids 188 to 259 of gC1qR, a site distinct from the binding region of C1q. The inhibition of T-cell responsiveness by HCV core may have important implications for HCV persistence in humans.

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.

Respiratory syncytial virus infection suppresses lung CD8+ T-cell effector activity and peripheral CD8+ T-cell memory in the respiratory tract.

Respiratory syncytial virus (RSV) is a major cause of morbidity from respiratory infection in infants, young children and the elderly. No effective vaccine against RSV is currently available and studies of the natural history of RSV infection suggest repeated infections with antigenically related virus strains are common throughout an individuals lifetime. We have studied the CD8+ T-cell response during experimental murine RSV infection and found that RSV inhibits the expression of effector activity by activated RSV-specific CD8+ T cells infiltrating the lung parenchyma and the development of pulmonary CD8+ T-cell memory by interfering with TCR-mediated signaling. These data suggest a possible mechanism to explain the limited duration of protective immunity in RSV infection.

Activation, Differentiation, and Migration of Naive Virus-Specific CD8+ T Cells during Pulmonary Influenza Virus Infection

The low precursor frequency of individual virus-specific CD8+ T cells in a naive host makes the early events of CD8+ T cell activation, proliferation, and differentiation in response to viral infection a challenge to identify. We have therefore examined the response of naive CD8+ T cells to pulmonary influenza virus infection with a murine adoptive transfer model using hemagglutinin-specific TCR transgenic CD8+ T cells. Initial activation of CD8+ T cells occurs during the first 3 days postinfection exclusively within the draining lymph nodes. Acquisition of CTL effector functions, including effector cytokine and granule-associated protease expression, occurs in the draining lymph nodes and differentially correlates with cell division. Division of activated CD8+ T cells within the draining lymph nodes occurs in an asynchronous manner between days 3 and 4 postinfection. Despite the presence of Ag for several days within the draining lymph nodes, dividing T cells do not appear to maintain contact with residual Ag. After multiple cell divisions, CD8+ T cells exit the draining lymph nodes and migrate to the infected lung. Activated CD8+ T cells also disseminate throughout lymphoid tissue including the spleen and distal lymph nodes following their emigration from draining lymph nodes. These results demonstrate an important role for draining lymph nodes in orchestrating T cell responses during a local infection of a discrete organ to generate effector CD8+ T cells capable of responding to infection and seeding peripheral lymphoid tissues.

ANTIGEN PRESENTATION : STRUCTURAL THEMES AND FUNCTIONAL VARIATIONS

T cells recognize nonnative processed fragments of antigens presented in association with major histocompatibility complex (MHC) class I or class II molecules. Recently, an accumulating body of evidence has provided a functional linkage between antigen presentation events and the cell biology of MHC molecule assembly and transport. In this review Thomas and Vivian Braciale synthesize these developments into a cohesive model of MHC assembly and antigen presentation pathways.

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.

Immunopathology in RSV Infection Is Mediated by a Discrete Oligoclonal Subset of Antigen-Specific CD4+ T Cells

Vaccination with the respiratory syncytial virus (RSV) attachment (G) protein results in immune-mediated lung injury after natural RSV infection with pathogenic features characteristic of an exaggerated Th2 response. Here we demonstrate that approximately half of the CD4(+) T cells infiltrating the lungs of G-primed mice utilize a single V beta gene (V beta 14) with remarkably limited CDR3 diversity. Furthermore, elimination of these V beta 14-bearing CD4(+) T cells in vivo abolishes the type 2-like pulmonary injury. These results suggest that a novel subset of CD4(+) T cells may be crucial in the development of pathology during human RSV infection and that genetic or environmental factors prior to or at the time of G antigen exposure may affect the commitment of this discrete antigen-specific T cell subset to Th2 differentiation.

Frequency, Specificity, and Sites of Expansion of CD8 + T Cells during Primary Pulmonary Influenza Virus Infection

We have used intracellular cytokine staining and MHC class I tetramer binding in conjunction with granzyme B protease expression and in vivo BrdU uptake to characterize the primary murine CD8+ T cell response to pulmonary influenza virus infection. We have observed that the majority (>90%) of the CD8+ T cell response to the A/Japan/305/57 virus in the lung at the peak of the response (days 9–11) is directed to four epitopes (three dominant and one subdominant). Using induction of granzyme B as a surrogate to identify specific activated CD8+ T cells, we found that an unexpectedly large fraction (∼70%) of lung-infiltrating CD8+ T cells expressed granzyme B on day 6 of infection when estimates by MHC tetramer/intracellular cytokine staining yielded substantially lower frequencies (∼30%). In addition, by using intranasal administration of BrdU during infection, we obtained evidence for proliferative expansion of activated CD8+ T cells in the infected lung early (days 5–7) in the primary response. These results suggest that the frequency and number of specific CTL present in the lung early in infection may be underestimated by standard detection methods, and primary CD8+ T cell expansion may occur in both secondary lymphoid organs and the infected lung.