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Biomedical subjects

Susan L Swain

Publications and source records attributed to Susan L Swain.

At least 19 recordsLinked to original sources
PubMed2007

Priming with cold-adapted influenza A does not prevent infection but elicits long-lived protection against supralethal challenge with heterosubtypic virus.

We show in this study several novel features of T cell-based heterosubtypic immunity against the influenza A virus in mice. First, T cell-mediated heterosubtypic protection against lethal challenge can be generated by a very low priming dose. Second, it becomes effective within 5-6 days. Third, it provides protection against a very high dose challenge for >70 days. Also novel is the finding that strong, long-lasting, heterosubtypic protection can be elicited by priming with attenuated cold-adapted strains. We demonstrate that priming does not prevent infection of the lungs following challenge, but leads to earlier clearance of the virus and 100% survival after otherwise lethal challenge. Protection is dependent on CD8 T cells, and we show that CD4 and CD8 T cells reactive to conserved epitopes of the core proteins of the challenge virus are present after priming. Our results suggest that intranasal vaccination with cold-adapted, attenuated live virus has the potential to provide effective emergency protection against emerging influenza strains for several months.

Adaptation, Biological↗
PubMed2006

Unique ability of activated CD4+ T cells but not rested effectors to migrate to non-lymphoid sites in the absence of inflammation.

Recent studies suggest that effector T cells generated by immune responses migrate to multiple non-lymphoid sites, even those without apparent expression of antigen or inflammation. To investigate the ability of distinct CD4(+) T lymphocyte subsets to enter and persist in non-lymphoid, noninflamed compartments, we examined the migration and persistence of naïve, effector, and rested effector CD4(+) T cells generated in vitro following transfer to nonimmunized adoptive hosts. Th1 and Th2 effectors migrated to both lymphoid and non-lymphoid organs (peritoneum, fat pads, and lung). In contrast, rested effectors and naïve cells migrated only to lymphoid areas. Adhesion molecule expression, but not chemokine receptor expression, correlated with the ability to enter non-lymphoid sites. Donor cells persisted longer in lymphoid than in non-lymphoid sites. When hosts with naïve and memory donor cells were challenged with antigen, effectors developed in situ, which also migrated to non-lymphoid sites. Memory cells showed an accelerated shift to non-lymphoid migration, in keeping with memory effector formation. These results suggest that only recently activated effector T cells can disperse to non-lymphoid sites in the absence of antigen and inflammation, and as effectors return to rest, they lose this ability. These data also argue that memory cells in lymphoid sites are longer lived and not in equilibrium with those in non-lymphoid sites.

Adipose Tissue↗
PubMed2006

SAP is required for Th cell function and for immunity to influenza.

Ab is a crucial component of protective immunity to infection, but Ab responses do not proceed normally when defects occur in a protein called signaling lymphocytic activation molecule-associated protein (SAP). To explain this Ab defect, we analyzed B cell and plasma cell responses under conditions of SAP deficiency. Our results demonstrate that SAP-deficient (SAP knockout (KO)) mice have a profound CD4 T cell-intrinsic defect in generating Ag-specific plasma cells following challenge with model Ags or influenza virus, resulting in low Ag-specific Ab titers. We also show that SAP is required in CD4 T cells for normal division and expansion of B cells. These B cell and plasma cell defects were observed during the expansion phase of the primary immune response, indicating early defects in Th cell activity. In fact, additional experiments revealed a nearly complete lack of T cell help for B cells in SAP KO mice. Our work suggests that the ability of SAP to promote T-dependent humoral immune responses is important for antiviral immunity because mice lacking SAP are unable to prevent high dose secondary influenza infection, and because passive transfer of IgG in immune serum from wild-type, but not SAP KO mice can protect mice from an otherwise lethal influenza infection. Overall, our results demonstrate that SAP is required in CD4 T cells for their ability to help B cell responses and promote influenza-specific immunity.

Animals↗
PubMed2006

CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch.

The mechanisms whereby CD4 T cells contribute to the protective response against lethal influenza infection remain poorly characterized. To define the role of CD4 cells in protection against a highly pathogenic strain of influenza, virus-specific TCR transgenic CD4 effectors were generated in vitro and transferred into mice given lethal influenza infection. Primed CD4 effectors conferred protection against lethal infection over a broad range of viral dose. The protection mediated by CD4 effectors did not require IFN-gamma or host T cells, but did result in increased anti-influenza Ab titers compared with untreated controls. Further studies indicated that CD4-mediated protection at high doses of influenza required B cells, and that passive transfer of anti-influenza immune serum was therapeutic in B cell-deficient mice, but only when CD4 effectors were present. Primed CD4 cells also acquired perforin (Pfn)-mediated cytolytic activity during effector generation, suggesting a second mechanism used by CD4 cells to confer protection. Pfn-deficient CD4 effectors were less able to promote survival in intact BALB/c mice and were unable to provide protection in B cell-deficient mice, indicating that Ab-independent protection by CD4 effectors requires Pfn. Therefore, CD4 effectors mediate protection to lethal influenza through at least two mechanisms: Pfn-mediated cytotoxicity early in the response promoted survival independently of Ab production, whereas CD4-driven B cell responses resulted in high titer Abs that neutralized remaining virus.

Animals↗
PubMed2006

Why aging T cells fail: implications for vaccination.

The decline in CD4+ T cell function with aging contributes to reduced vaccine efficacy. In this commentary, we discuss the factors leading to age-related changes in T cell function and propose how they may be overcome to enhance vaccine efficacy for the elderly.

Adjuvants, Immunologic↗
PubMed2006

SAP deficiency results in a striking alteration of the protein profile in activated CD4 T cells.

Deficiency in a protein called signaling lymphocytic activation molecule-associated protein (SAP) causes X-linked lymphoproliferative disease (XLP) and helper T cell-dependent antibody defects. To identify proteins regulated by SAP, we performed proteomic analyses of SAP deficient vs wild type T cells. Our results reveal protein species whose abundances are profoundly altered by SAP. Our work therefore identifies candidate cellular mediators of SAP-dependent T cell help.

Animals↗
PubMed2006

CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza.

We have outlined the carefully orchestrated process of CD4+ T-cell differentiation from naïve to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T-cell interaction with antigen-presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4+ T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multifaceted roles of CD4+ effector and memory T cells in protective responses to influenza infection and support the concept that efficient priming of CD4+ T cells that react to shared influenza proteins could contribute greatly to vaccine strategies for influenza.

Animals↗
PubMed2005

Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation.

The kinetics of presentation of influenza virus-derived antigens (Ags), resulting in CD4 T cell effector and memory generation, remains undefined. Naive influenza-specific CD4 T cells were transferred into mice at various times after influenza infection to determine the duration and impact of virus-derived Ag presentation. Ag-specific T cell responses were generated even when the donor T cells were transferred 3-4 wk after viral clearance. Transfer of naive CD4 T cells during early phases of infection resulted in a robust expansion of highly differentiated effectors, which then contracted to a small number of memory T cells. Importantly, T cell transfer during later phases of infection resulted in a modest expansion of effectors with intermediate phenotypes, which were capable of persisting as memory with high efficiency. Thus, distinct stages of pathogen-derived Ag presentation may provide a mechanism by which T cell heterogeneity is generated and diverse memory subsets are maintained.

Animals↗
PubMed2005

Uneven distribution of MHC class II epitopes within the influenza virus.

The identification of T cell epitopes is crucial for the understanding of the host immune response during infection. While much is known about the MHC class I-restricted response following influenza virus infection of C57BL/6 mice, with over 16 CD8 epitopes identified to date, less is known about the MHC class II-restricted response. Currently, only a few I-A(b)-restricted T helper epitopes have been identified. Therefore, several important questions remain about how many class II epitopes exist in this system and whether these epitopes are evenly distributed within the most abundant viral proteins. In order to address these questions, we analyzed the repertoire of epitopes that drive the CD4+ approximately 20-30 epitopes drive the CD4 T cell response and that the majority of these peptides are derived from the NP and HA proteins. We were also able to demonstrate that vaccination with one of the newly identified epitopes, HA(211-225)/A(b), resulted in increased epitope-specific T cell numbers and a significant reduction in viral titers following influenza virus challenge.

Animals↗
PubMed2005

Effector CD4+ T cells generate intermediate caspase activity and cleavage of caspase-8 substrates.

Caspase-8 activation promotes cell apoptosis but is also essential for T cell activation. The extent of caspase activation and substrate cleavage in these divergent processes remains unclear. We show that murine effector CD4(+) T cells generated levels of caspase activity intermediate between unstimulated T cells and apoptotic populations. Both caspase-8 and caspase-3 were partially activated in effector T cells, which was reflected in cleavage of the caspase-8 substrates, c-FLIP(L), receptor interacting protein 1, and to a lesser extent Bid, but not the caspase-3 substrate inhibitor of caspase-activated DNase. Th2 effector CD4(+) T cells manifested more caspase activity than did Th1 effectors, and caspase blockade greatly decreased initiation of cell cycling. The current findings define the level of caspase activity and substrates during initiation of T cell cycling.

Animals↗
PubMed2005

Repeated stimulation of CD4 effector T cells can limit their protective function.

Chronic infections often result in CD8 T-cell deletion or functional nonresponsiveness. However, to date no definitive studies have attempted to determine the impact of repeated T cell receptor stimulation on CD4 effector T cell generation. We have determined that when antigen presentation is limited to 2 d, optimum in vitro CD4 effector generation is achieved. Alternatively, repeated stimulation results in decreased CD4 effector expansion, decreased cytokine production, and altered migration. Similarly, functionally impaired effectors develop in vivo when antigen-pulsed antigen-presenting cells are replenished every 24 h during a primary immune response. CD4 effectors that are generated with repeated stimulation provide no protection during influenza infection, and have an impaired ability to provide cognate help to B cells. These results suggest that duration of antigen presentation dictates CD4 effector function, and repeated T cell receptor stimulation in vitro and in vivo that exceeds an optimal threshold results in effectors with impaired function.

Animals↗
PubMed2005

Newly generated CD4 T cells in aged animals do not exhibit age-related defects in response to antigen.

Using a T cell receptor transgenic (TCR Tg) mouse model, we have shown that TCR Tg CD4 cells from aged mice retain a naive phenotype, but exhibit reduced proliferation and IL-2 production in response to the antigen compared with cells from young mice. We hypothesize that age-related decreases in T cell function may be partly related to the age of the T cells. Because thymic output is decreased with age, peripheral T cells in older individuals are likely to be older than those in younger individuals. To investigate this possibility, we have manipulated the age of CD4 T cells in the periphery of young and aged mice. The production of new T cells was induced by depleting peripheral CD4 T cells or by creating bone marrow chimeras. In both young and aged individuals where we induced the production of new T cells, these newly generated cells exhibited robust responses to antigen ex vivo and in vivo, exhibiting good expansion, IL-2 production, and cognate helper function. Our results suggest that age-related defects in response to antigenic stimulation, in part, are caused by the age of the CD4 T cells.

Aging↗
PubMed2005

IL-7: maintaining T-cell memory and achieving homeostasis.

During an immune response, peripheral T-cell populations expand and then contract as the response subsides, thus maintaining a fairly constant number of CD4 and CD8 T cells throughout the life of the individual. The important factors that control this homeostasis are now beginning to be understood. Interleukin-7 (IL-7) has emerged as a central regulator of the survival and homeostasis of CD4 and CD8 T cells. Both naive and memory T-cell populations are highly dependent on the presence of IL-7 for their persistence and survival. In this Review, we discuss the role of IL-7 in the survival and homeostasis of naive and memory T cells and how that role is regulated by other factors.

CD4-Positive T-Lymphocytes↗
PubMed2004

Inflammatory cytokines overcome age-related defects in CD4 T cell responses in vivo.

Age-related decreases in immune function are thought to contribute to the reduced efficacy of vaccinations seen in elderly populations. Our previous in vitro studies demonstrated that naive CD4 T cells from aged TCR-transgenic mice proliferate less than young cells and generate poorly functioning effectors due to decreased IL-2 production. In this current study, we show that this age-related defect in CD4 T cell response also occurs in vivo and that it is correlated with reduced NF-kappa B activation. After transfer to young hosts, CD4 T cells from aged transgenic mice proliferate less and produce reduced levels of IL-2 upon immunization with Ag and alum. Introducing a combination of the inflammatory cytokines TNF-alpha, IL-1, and IL-6, or the use of an adjuvant such as CFA that induces these cytokines, markedly enhanced responses of these aged CD4 T cells, so that they proliferated and produced IL-2 similar to young cells. This enhancement is correlated with the enhanced activation of the transcription factor NF-kappa B in aged cells. We suggest that induction of inflammatory cytokines via adjuvants may enhance the efficacy of vaccinations in elderly populations.

Adoptive Transfer↗
PubMed2004

CD8+ T cells responding to influenza infection reach and persist at higher numbers than CD4+ T cells independently of precursor frequency.

The activation, localization, phenotypic changes, and function of CFSE-labeled naive influenza-specific CD8(+) and CD4(+) T cells following influenza infection were examined. Response of adoptively transferred CD8(+) T cells was seen earliest in draining lymph node. Highly activated cells were found later in the lung, airways, and spleen, were cytolytic, and expressed IFN-gamma upon restimulation. Similar amounts of division at early time points, but higher numbers of CD8(+) T cells, were detected at 9 and 30 days postinfection after cotransfer of CD4(+) and CD8(+) T cells followed by infection. Transfer of much smaller numbers of CD4(+) and CD8(+) T cells led to more extensive expansion but the same difference in final number between the two cell types. These studies demonstrate how CD8(+) and CD4(+) T cells respond to influenza at early time points postinfection and the differential kinetics of antigen-specific CD4(+) and CD8(+) T cells.

Animals↗
PubMed2004

CD4 T cell responses to influenza infection.

Immune responses to viral infections involve a complex orchestration between innate signals and adaptive responses of specific T and B cells. Anti-viral CD4 cells can direct CD8 responses by secreting a Type 1 panel of cytokines including IFN-gamma, IL-2 and TNF-alpha and can drive B cell production of IgG2a to neutralize infective viral particles. This review will focus specifically on the role of CD4 cells in the immune response to influenza, an acute, localized respiratory viral infection. We suggest that CD4 cells act as direct effectors in protection against influenza, may contribute to immunopathology and generate functionally distinct memory subsets.

Animals↗
PubMed2004

T cell responses to influenza virus infection: effector and memory cells.

New approaches to visualizing antigen-specific primary responses to influenza and the development of memory subsets in distinct sites suggest that both CD4 and CD8 T cells play complex roles in primary viral clearance and have the potential to contribute to protection from secondary infection.

Animals↗