PubMed Health⌕ Search

Biomedical subjects

Laura Haynes

Publications and source records attributed to Laura Haynes.

At least 19 recordsLinked to original sources
PubMed2006

How vaccines work on the background of the aging immune system.

The elderly exhibit reduced responses to vaccinations, leaving them more susceptible to preventable infectious diseases such as influenza and pneumonia. It has been unclear as to the specific changes in the aging immune system that contribute to this decline, thus we have developed a mouse model to examine this phenomenon and determine why it occurs and how it can be overcome. Our ultimate goal is to determine how to enhance vaccine efficacy for elderly populations.

Aging↗
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

Murine [corrected] myeloid dendritic cell-dependent toll-like receptor immunity is preserved with aging.

The immune response is the result of the interplay between innate and adaptive immunity, yet the impact of aging on this interaction is unclear. Addressing this fundamental question will be critical for the development of effective vaccines for the rapidly rising older subpopulation that manifests increased prevalence of malignancies and infections. Therefore, we undertook the current study to investigate whether aging impairs toll-like receptor (TLR) function in myeloid dendritic cells and whether this leads to reduced T-cell priming. Our results demonstrate that innate TLR immune priming function of myeloid bone marrow derived and splenic dendritic cells (DC) is preserved with aging using both allogeneic and infectious murine experimental systems. In contrast, aging impairs in vitro and in vivo intrinsic T-cell function. Therefore, our results demonstrate that myeloid DCs manifest preserved TLR-mediated immune responses with aging. However, aging critically impairs intrinsic adaptive T-cell function.

Adaptation, Physiological↗
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

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

The effect of aging on cognate function and development of immune memory.

Immunological memory is one of the central features of the immune system and can be described as the ability of the immune system to respond more efficiently to a second encounter with the same pathogen. The immune system is dramatically affected by age-related changes and it is becoming apparent that immune memory exhibits significant defects as a result of aging. Although immune memory generated during youth functions well into old age, that generated later in life functions poorly. Importantly, age-related defects in the cognate helper function of CD4(+) T cells can potentially influence the development of both humoral and cell-mediated immune memory. These defects ultimately result in aged individuals who exhibit reduced responses to both infections and vaccinations.

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↗
PubMed2005

Homeostasis and the age-associated defect of CD4 T cells.

Survival and homeostatic division of naive CD4 T cells is regulated by the cellular and non-cellular milieu and together these processes ensure that a population of naive CD4 T cells persists into old age. However, the naive CD4 T cells from aged animals show reduced IL-2 production, proliferation, helper function and effector generation and memory function. We explore here whether the age-related defects in naive CD4 T cells are due to the aged environment from which they come or to intrinsic defects that are caused by homeostasis and their long lifespan.

Aging↗
PubMed2005

The effect of age on the cognate function of CD4+ T cells.

With increasing age, the ability to produce protective antibodies in response to immunization declines, resulting in reduced efficacy of vaccination. We have examined how reductions in CD4(+) T-cell function contribute to reduced humoral responses, using a model that allows us to compare identical numbers of antigen-specific naive T cells from young and aged T-cell receptor transgenic mice. Naive cells from aged mice exhibit reduced responses, both in vitro and in vivo. In vitro, responses of aged T cells can be enhanced by addition of interleukin (IL)-2. In vivo, using an adoptive transfer model with young hosts, naive cells from aged mice exhibit significant reductions in cognate helper function, leading to reduced B-cell expansion and differentiation. These age-related defects could be overcome by prior in vitro T helper 2 effector generation with aged T cells. This improvement in cognate function of the aged effectors may be related to the enhancement of CD154 expression, which occurs on aged T cells in the presence of exogenous IL-2. We also found no difference in B-cell expansion and differentiation when young cells were transferred to young or aged hosts. Our results indicate that age-related reductions in humoral responses are mainly due to defects in the cognate helper function of naive CD4(+) T cells from aged individuals.

Aging↗
PubMed2005

Gamma interferon-induced T-cell loss in virulent Mycobacterium avium infection.

Infection by virulent Mycobacterium avium caused progressive severe lymphopenia in C57BL/6 mice due to increased apoptosis rates. T-cell depletion did not occur in gamma interferon (IFN-gamma)-deficient mice which showed increased T-cell numbers and proliferation; in contrast, deficiency in nitric oxide synthase 2 did not prevent T-cell loss. Although T-cell loss was IFN-gamma dependent, expression of the IFN-gamma receptor on T cells was not required for depletion. Similarly, while T-cell loss was optimal if the T cells expressed IFN-gamma, CD8(+) T-cell depletion could occur in the absence of T-cell-derived IFN-gamma. Depletion did not require that the T cells be specific for mycobacterial antigen and was not affected by deficiencies in the tumor necrosis factor receptors p55 or p75, the Fas receptor (CD95), or the respiratory burst enzymes or by forced expression of bcl-2 in hematopoietic cells.

Animals↗
PubMed2004

Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses.

With increasing age, the ability to produce protective antibodies in response to immunization declines, leading to a reduced efficacy of vaccination in the elderly. To examine the effect of age on the cognate function of CD4 T cells, we have used a novel adoptive transfer model that allows us to compare identical numbers of antigen-specific naive T cells from young and aged TCR transgenic (Tg) donors. Upon transfer of aged donor CD4 T cells to young hosts, there was significantly reduced expansion and germinal center (GC) differentiation of the antigen-specific B cell population after immunization. This reduced cognate helper function was seen at all time points and over a wide range of donor cell numbers. In hosts receiving aged CD4 cells, there were also dramatically lower levels of antigen-specific IgG. These age-related defects were not due to defects in migration of the aged CD4 T cells, but may be attributable to reduced CD154 (CD40L) expression. Furthermore, we found that there was no difference in B cell expansion and differentiation or in IgG production when young CD4 T cells were transferred to young or aged hosts. Our results show that, in this model, age-related reductions in the cognate helper function of CD4 T cells contribute significantly to defects in humoral responses observed in aged individuals.

Aging↗
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↗
PubMed2003

CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly.

Age-related declines in immune function have an impact on both primary and memory responses. In this study, we have examined the ability of naive CD4 T cells from young and aged T cell receptor transgenic mice to establish functional memory. We found that memory cells generated from young CD4 T cells responded well to antigen, even a year after generation, whereas memory cells derived from CD4 T cells from aged mice responded poorly both ex vivo and in vivo. Memory cells generated from aged naive cells proliferate less, produce reduced levels of cytokines, and exhibit reduced cognate helper function, compared with memory cells generated by using young naive cells. These results indicate that it is the age of the naive T cell when it first encounters antigen, rather than the age when it reencounters antigen, that is critical for good memory CD4 T cell function.

Aging↗
PubMed2002

Reliable generation and use of MHC class II:gamma2aFc multimers for the identification of antigen-specific CD4(+) T cells.

MHC tetramers have proven to be powerful reagents for the analysis of MHC class I-restricted T cells. However, generating similarly reliable reagents for MHC class II-restricted T cells has been elusive. Here we evaluated the utility of MHC class II:gamma2aFc multimers, which contain the MHC class II extracellular domains, with or without recombinantly attached peptides, dimerized via a fos-jun leucine zipper and attached to the hinge of murine IgG2a. We have successfully generated 24 multimers in either myeloma or Drosophila melanogaster S2 cells, with an average yield of 7 mg/L. 'Empty' MHC class II:gamma2aFc multimers were effectively used in peptide binding assays. Similar versions that contained recombinantly attached peptides stimulated T cells in an antigen-specific, MHC-restricted manner, and identified antigen-specific nai;ve and effector T cells by flow cytometry. Furthermore, we have successfully used these reagents to stain T cells generated following viral infection. Thus, MHC class II:gamma2aFc multimers are robust and reliable reagents for the analysis of MHC class II-restricted T cells.

Amino Acid Sequence↗
PubMed2002

The biological outcome of CD40 signaling is dependent on the duration of CD40 ligand expression: reciprocal regulation by interleukin (IL)-4 and IL-12.

CD40 ligand (CD154) expression on activated T cells can be separated into an early TCR-dependent phase, which occurs between 0 and 24 h after activation, and a later extended phase, which occurs after 24 h and is reciprocally regulated by the cytokines IL-4 and IL-12. IL-4 represses, whereas IL-12 sustains CD154 expression. Consistent with this, Th1, but not Th2, cells express CD154 for extended periods. Differences in the duration of CD154 expression have important biological consequences because sustained, but not transient, expression of CD154 on activated T cells can prevent B cell terminal differentiation. Thus, the differential ability of Th cells to sustain CD154 expression is an important part of their helper function and should influence the activities of other CD40-expressing cell types.

Animals↗