Biomedical subjects

William T Lee

Publications and source records attributed to William T Lee.

7 recordsLinked to original sources

PubMed2004

Ferroelastic phase transitions: structure and microstructure.

Landau-type theories describe the observed behaviour of phase transitions in ferroelastic and co-elastic minerals and materials with a high degree of accuracy. In this review, the derivation of the Landau potential G=1/2AthetaS [coth(thetaS/T)-coth(thetaS/TC)]Q2 + 1/4BQ4 + ... is derived as a solution of the general phi4 model. The coupling between the order parameter and spontaneous strain of a phase transition brings the behaviour of many phase transitions to the mean-field limit, even when the atomistic mechanism of the transition is spin-like. Strain coupling is also a common mechanism for the coupling between multiple order parameters in a single system. As well as changes on the crystal structure scale, phase transitions modify the microstructure of materials, leading to anomalous mesoscopic features at domain boundaries. The mesostructure of a domain wall is studied experimentally using X-ray diffraction, and interpreted theoretically using Ginzburg-Landau theory. One important consequence of twin mesostructures is their modified transport properties relative to the bulk. Domain wall motion also provides a mechanism for superelastic behaviour in ferroelastics. At surfaces, the relaxations that occur can be described in terms of order parameters and Landau theory. This leads to an exponential profile of surface relaxations. This in turn leads to an exponential interaction energy between surfaces, which can, if large enough, destabilize symmetrical morphologies in favour of a platelet morphology. Surface relaxations may also affect the behaviour of twin walls as they intersect surfaces, since the surface relaxation may lead to an incompatibility of the two domains at the surface, generating large strains at the relaxation. Landau theory may also be extended to describe the kinetics of phase transitions. Time-dependent Landau theory may be used to describe the kinetics of order-disorder phase transitions in which the order parameter is homogeneous. However, the time-dependent Landau theory equations also have microstructural solutions, explaining the formation of microstructures such as tweed.

Journal Article↗

PubMed2004

Differences in signaling molecule organization between naive and memory CD4+ T lymphocytes.

The immunological synapse is a highly organized complex formed at the junction between Ag-specific T cells and APCs as a prelude to cell activation. Although its exact role in modulating T cell signaling is unknown, it is commonly believed that the immunological synapse is the site of cross-talk between the T cell and APC (or target). We have examined the synapses formed by naive and memory CD4 cells during Ag-specific cognate interactions with APCs. We show that the mature immunological synapse forms more quickly during memory T cell activation. We further show that the composition of the synapse found in naive or memory cell conjugates with APCs is distinct with the tyrosine phosphatase, CD45, being a more integral component of the mature synapses formed by memory cells. Finally, we show that signaling molecules, including CD45, are preassociated in discrete, lipid-raft microdomains in resting memory cells but not in naive cells. Thus, enhanced memory cell responses may be due to intrinsic properties of signaling molecule organization.

Animals↗

PubMed2004

Antigen-specific CD4 T cell clonal expansion and differentiation in the aged lymphoid microenvironment. II. The memory T cell response is diminished.

We investigated the ability of the aged host environment to support a memory CD4 T cell response to a secondary immunization with a specific antigen. Using an adoptive transfer model, we previously reported that young CD4 T cells, transferred into the young or the aged lymphoid microenvironment, clonally expand and differentiate in a similar fashion after primary immunization with a specific antigen. In this report, we have monitored the clonal expansion of the donor-derived memory CD4 T population following a secondary challenge with the specific antigen. We show that antigen-specific memory T cell clonal expansion is diminished in the aged hosts. However, upon in vitro re-stimulation, antigen-specific CD4 T cells isolated from young and from aged hosts were equally responsive to antigen, thus indicating an inhibitory effect in the aged host environment. We provide evidence that factors specifically present in previously immunized aged hosts must be responsible for the diminished response of otherwise functional, antigen-specific memory CD4 T cells. Our results suggest that the decline in immunologic memory to foreign antigens may be due not only to intrinsic defects in aged T cells, but also to age-related differences in the lymphoid microenvironment of previously immunized hosts.

Adoptive Transfer↗

PubMed2004

Antigen-specific CD4 T cell clonal expansion and differentiation in the aged lymphoid microenvironment. I. The primary T cell response is unaffected.

Aging is associated with changes in the immune system that lead to decreased immunity in the elderly. Prior studies from humans and mice have shown that aged T cells exhibit numerous defects, including decreased proliferation following in vitro stimulation, suggesting that intrinsic defects exist within aged T cells, leading to defective T cell activation and clonal expansion. In vivo, however, cellular and soluble factors in the lymphoid microenvironment influence T cell function. To investigate the effects of the aged lymphoid microenvironment on T cell function, we monitored the immune response of CD4 T cells from DO11.10 TCR transgenic mice following adoptive transfer into young and aged hosts. After immunization with specific antigen similar rates of donor DO11.10 T cell division were observed in the two host types. However, at the peak of the response, greater numbers of DO11.10 T cells were found in the aged hosts. Regardless of the age of the host, the donor DO11.10 T cell population differentiated into functional effector cells. Despite the increased CD4 T cell growth in aged hosts, similar numbers of memory DO11.10 T cells were found in young and in aged hosts. As CD4 T cell clonal expansion and differentiation is not impaired in the aged microenvironment, our data suggest that diminished T cell immunity during aging is largely due to intrinsic T cell defects, rather than to extrinsic influences associated with the aged lymphoid microenvironment.

Aging↗

PubMed2003

Staphylococcal enterotoxin B induces anergy to conventional peptide in memory T cells.

Microbial superantigens can alter host immunity through aberrant activation and subsequent anergy of responding naive T cells. We show here that the superantigen, staphylococcal enterotoxin B (SEB), directly induces tolerance in memory CD4 T cells. Murine naive and memory CD4(+) T cells were labeled with the fluorescent dye CFSE and the cells were exposed to SEB before they were cultured with specific peptide antigen. Memory, but not naive, T cells became anergic and did not respond to their cognate peptide antigen. The extent and duration of T cell receptor (TCR) clustering was similar to promote naive T cell activation and memory T cell anergy, suggesting similar TCR-SEB interactions led to distinct intracellular signaling processes in the two cell types. Like SEB, soluble anti-CD3 mAb does not stimulate memory cell proliferation. However, unlike SEB, soluble anti-CD3 mAbs did not induce anergy to cognate peptide. Anergy was directly visualized in vivo. CD4(+) memory T cells were identified in mice that had been administered SEB. The cells failed to proliferate in response to subsequent immunization with their cognate recall antigen. Hence, one mode of pathogen survival is the modulation of host immunity through selective elimination of memory T cell responses.

Animals↗

PubMed2003

Exogenous interleukin-12 protects against lethal infection with coxsackievirus B4.

Infections with the group B coxsackieviruses either can be asymptomatic or can lead to debilitating chronic diseases. To elucidate the mechanism by which these viruses cause chronic disease, we developed a mouse model of chronic pancreatitis by using a virulent variant of coxsackievirus B4, CVB4-V. Infection with CVB4-V results in an early, severe pancreatitis, which can lead to mortality or progress to chronic pancreatitis. Chronic pancreatitis, in this model, is due to immunopathological mechanisms. We investigated whether interleukin-12 (IL-12) could modulate the outcome of CVB4-V infection. Eighty-five percent of the infected mice treated with 500 ng of IL-12 survived, whereas all untreated mice succumbed. To understand the mechanism underlying the beneficial effect of IL-12, we investigated the role of gamma interferon (IFN-gamma). Three lines of evidence suggest that the protective effect of IL-12 is due to IFN-gamma. First, administration of IL-12 increased the production of endogenous IFN-gamma in CVB4-V-infected mice. Both NK and NKT cells were identified as the source of IFN-gamma. Second, IFN-gamma knockout mice treated with IL-12 succumbed to infection with CVB4-V. Third, wild-type mice treated with IFN-gamma survived infection with CVB4-V. Due to the antiviral effects of IFN-gamma, we examined whether IL-12 treatment affected viral replication. Administration of IL-12 did not decrease viral replication in the pancreas, but it did prevent extensive tissue damage and the subsequent development of chronic pancreatitis. The data suggest that IL-12 treatment during CVB4-V infection is able to suppress the immunopathological mechanisms that lead to chronic disease.

Animals↗

PubMed2002

Continued antigen stimulation is not required during CD4(+) T cell clonal expansion.

Peptide Ag initiates CD4(+) T cell proliferation, but the subsequent effects of Ag on clonal expansion are not fully known. In this study, murine CD4(+) T cells were labeled with the fluorescent dye CFSE and were stimulated with specific peptide Ag. Activation occurred, as CFSE-associated fluorescence was reduced 2-fold with each cell division. Separation of proliferating cells based upon CFSE fluorescence intensity showed that daughter cells from each cell division proliferate even after removal of Ag. A limited exposure (2 h) to peptide programmed the cells to proliferate independently of Ag. Although not required for cell division, Ag increased the survival of proliferating cells and increased the total number of cell divisions in the expansion process. These results indicate that Ag exposure begins a program of cell division that does not require but is modified by further TCR stimulation.

Animals↗