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Biomedical subjects

Michael J Bevan

Publications and source records attributed to Michael J Bevan.

At least 19 recordsLinked to original sources
PubMed2004

Shortening the infectious period does not alter expansion of CD8 T cells but diminishes their capacity to differentiate into memory cells.

Following a primary immune response, a portion of effector T cells gives rise to long-lived memory cells. Although primary expansion and differentiation of effector CD8 T cells is dictated by a brief exposure to Ag, it is unclear whether full memory differentiation is also programmed within the same short window. By carefully modulating the kinetics of Listeria monocytogenes infection, we analyzed the requirements for the programming of effector and memory T cell development in vivo. We find that although limiting the infectious period to the first 24-48 h does not impact the size of the primary CD8 response, the ensuing memory population is significantly diminished. This effect is particularly pronounced in the development of tissue-homing memory cells and is inversely proportional to the initial infectious dose. In contrast to CD8 responses, the differentiation of primary CD4 responses was highly dependent on the continued presence of the infection. Shortening the duration of the infection greatly reduced the development of CD4 effector responses in the spleen and prevented their trafficking to peripheral sites of infection. We propose that the stimulus received by CD8 T cells during the early stages of infection largely contribute to the differentiation of CD8 effector cells, whereas continued or distinct signals received at later stages influence their ability to differentiate into memory cells.

Administration, Oral↗
PubMed2004

Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation.

Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs.

Animals↗
PubMed2004

Notch ligands Delta 1 and Jagged1 transmit distinct signals to T-cell precursors.

Signaling through the Notch pathway plays an essential role in inducing T-lineage commitment and promoting the maturation of immature thymocytes. Using an in vitro culture system, we show that 2 different classes of Notch ligands, Jagged1 or Delta1, transmit distinct signals to T-cell progenitors. OP9 stromal cells expressing either Jagged1 or Delta1 inhibit the differentiation of DN1 thymocytes into the B-cell lineage, but only the Delta1-expressing stromal cells promote the proliferation and maturation of T-cell progenitors through the early double-negative (DN) stages of thymocyte development. Whereas the majority of bone marrow-derived stem cells do not respond to Jagged1 signals, T-cell progenitors respond to Jagged1 signals during a brief window of their development between the DN1 and DN3 stages of thymic development. During these stages, Jagged1 signals can influence the differentiation of immature thymocytes along the natural killer (NK) and gamma delta T-cell lineages.

Animals↗
PubMed2004

CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection.

Immunization in the absence of CD4(+) T cell help results in defective CD8(+) T cell memory, deficient recall responses and diminished protective immunity. Here we investigated at what stage during the immune response to pathogen CD4(+) T cells are essential in the promotion of functional CD8(+) T cell memory. Memory CD8(+) T cell numbers decreased gradually in the absence of CD4(+) T cells despite the presence of similar numbers of memory cell precursors at the peak of the effector phase. Adoptive transfer of effector or memory CD8(+) T cells into wild-type or CD4(+) T cell-deficient mice demonstrated that the presence of CD4(+) T cells was important only after, not during, the early CD8(+) T cell programming phase. In the absence of CD4(+) T cells, memory CD8(+) T cells became functionally impaired and decreased in quantity over time. We conclude that in the context of an acute infection, CD4(+) T cells are required only during the maintenance phase of long-lived memory CD8(+) T cells.

Adoptive Transfer↗
PubMed2004

The Gads (GrpL) adaptor protein regulates T cell homeostasis.

Little is known about the role of the Gads (GrpL) adaptor protein in mature T cell populations. In this study we show that the effects of Gads deficiency on murine CD4(+) and CD8(+) T cells are markedly different. Gads(-/-) CD4(+) T cells were markedly deficient in the spleen and had an activated phenotype and a rapid turnover rate. When transferred into a wild-type host, Gads(-/-) CD4(+) T cells continued to proliferate at a higher rate than wild-type CD4(+) T cells, demonstrating a defect in homeostatic proliferation. Gads(-/-) CD8(+) T cells had a memory-like phenotype, produced IFN-gamma in response to ex vivo stimulation, and underwent normal homeostatic proliferation in wild-type hosts. Gads(-/-) T cells had defective TCR-mediated calcium responses, but had normal activation of ERK. Gads(-/-) CD4(+) T cells, but not CD8(+) T cells, had a severe block of TCR-mediated proliferation and a high rate of spontaneous cell death and were highly susceptible to CD95-induced apoptosis. This suggests that the rapid turnover of Gads(-/-) CD4(+) T cells is due to a defect in cell survival. The intracellular signaling pathways that regulate homeostasis in CD4(+) and CD8(+) T cells are clearly different, and the Gads adaptor protein is critical for homeostasis of CD4(+) T cells.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Cellular and humoral immunity against vaccinia virus infection of mice.

Despite the widespread use of vaccinia virus (VV) as a vector for other Ags and as the smallpox vaccine, there is little information available about the protective components of the immune response following VV infection. In this study, protection against wild-type VV was evaluated in mice with respect to the relative contributions of CD8(+) T cells vs that of CD4(+) T cells and Ab. C57BL/6 mice primed with the Western Reserve strain of VV mount significant IgM and IgG Ab responses, specific cytotoxic T cell responses, IFN-gamma responses in CD4(+) and CD8(+) T cells, and effectively clear the virus. This protection was abrogated by in vivo depletion of CD4(+) T cells or B cells in IgH(-/-) mice, but was not sensitive to CD8(+) T cell depletion alone. However, a role for CD8(+) T cells in primary protection was demonstrated in MHC class II(-/-) mice, where depleting CD8(+) T cells lead to increase severity of disease. Unlike control MHC class II(-/-) mice, the group depleted of CD8(+) T cells developed skin lesions on the tail and feet and had adrenal necrosis. Adoptive transfer experiments also show CD8(+) T cells can mediate protective memory. These results collectively show that both CD4(+) and CD8(+) T cell-mediated immunity can contribute to protection against VV infection. However, CD4(+) T cell-dependent anti-virus Ab production plays a more important role in clearing virus following acute infection, while in the absence of Ab, CD8(+) T cells can contribute to protection against disease.

Animals↗
PubMed2004

Driven to autoimmunity: the nod mouse.

In the lymphoid system, T cells respond to space or under-crowding by dividing to maintain their numbers. In this issue of Cell, evidence is provided that this homeostatic proliferation, coupled with excess production of a cytokine, IL-21, is a key factor in susceptibility to autoimmune diabetes.

Animals↗
PubMed2004

Cutting edge: long-lived CD8 memory and protective immunity in the absence of CD40 expression on CD8 T cells.

CD8 T cells need CD4 T cells to develop into long-lived, functional memory cells that provide protection against pathogen rechallenge. We investigated whether signaling via CD40 expressed on the CD8 cells themselves is involved in this cooperation. In murine responses to Listeria monocytogenes and lymphocytic choriomeningitis virus, we found no evidence of any requirement for CD40-CD40 ligand interaction at this level. No differences were observed between CD40(-/-) and CD40(+/+) CD8 T cells that had matured in the same environment when comparing their expansion in a primary or secondary response, their contribution to memory, and their ability to enter nonlymphoid tissues such as the liver. Thus, we find no evidence that CD40 ligand-expressing CD4 T cells are required to activate CD40 on CD8 T cells directly for the full differentiation of the cytotoxic T cell response.

Animals↗
PubMed2004

The CD8 population in CD4-deficient mice is heavily contaminated with MHC class II-restricted T cells.

In experiments to study the impact of deficiency in CD4+ T cell help on the magnitude of CD8+ cytotoxic T cell response to pathogens, it was noted that in CD4 gene knockout mice, the CD8 population made significant responses to several nominally major histocompatibility complex (MHC) class II-restricted epitopes in addition to the expected responses to MHC class I-restricted epitopes. A similar response by CD8+ T cells to class II-restricted epitopes was not observed in wild-type mice, or in mice that had been acutely depleted of CD4+ T cells just before the immunization. Coincident with this unexpected response to class II-restricted epitopes, it was also observed that the CD8+ response to the class I-restricted epitopes was consistently lower in CD4-/- mice than in wild-type mice. Further experiments suggested that these two observations are linked and that the CD8 population in CD4-/- mice may contain a majority of T cells that were actually selected by recognition of MHC class II molecules in the thymus. These results have implications for understanding CD4 versus CD8 lineage commitment in the thymus, and for the practical use of CD4-/- mice as models of helper deficiency.

Animals↗
PubMed2004

The human and mouse orthologous LIM-only proteins respectively encoded in chromosome 6 and 17 show a different expression pattern.

Thymocytes interact with various subpopulations of thymic epithelial cells (TECs) at different stages of their development. To identify new molecules specifically expressed in TECs and/or thymic nurse cells (TNCs), we used representational difference analysis. We identified a LIM protein located on mouse chromosome 17 (m17TLP) and belonging to the family of the LIM-only proteins (LIMo). We found a new splice variant in addition to the two described A and B isoforms. The three alternative species of m17TLP are found strictly in the thymic stroma. This protein is expressed on a subpopulation of TECs and TNCs. Strikingly, we found that the human ortholog of m17TLP, located on chromosome 6 (h6LIMo), is expressed in most tissues, but not in skeletal muscle. We have identified four human splice variants of h6LIMo which differ in their carboxy-terminal regions. The sequence comprising the genomic structure suggests that CRP2 is the closest known relative of m17TLP. Although the human and mouse nucleotide sequences are 88-97% homologous, this homology is reduced to 47% in the promoter regions, which strongly suggests that their differential expression is related to their promoter regulatory activity.

Alternative Splicing↗
PubMed2003

The extracellular matrix protein mindin is a pattern-recognition molecule for microbial pathogens.

Microbial pathogens use a variety of their surface molecules to bind to host extracellular matrix (ECM) components to establish an effective infection. However, ECM components can also serve as an integral part of the innate immunity. Mice lacking expression of mindin (spondin 2), a highly conserved ECM protein, have an impaired ability to clear bacterial infection, and mindin-deficient macrophages show defective responses to a broad spectrum of microbial stimuli. Moreover, mindin binds directly to bacteria and their components and functions as an opsonin for macrophage phagocytosis of bacteria. Thus, mindin is essential in the initiation of the innate immune response and represents a unique pattern-recognition molecule in the ECM for microbial pathogens.

Amino Acid Sequence↗
PubMed2003

Promiscuity of MHC class Ib-restricted T cell responses.

Murine infection with the Gram-positive intracellular bacterium Listeria monocytogenes activates CD8(+) T cells that recognize bacterially derived N-formyl methionine peptides in the context of H2-M3 MHC class Ib molecules. Three peptides, fMIGWII, fMIVIL, and fMIVTLF, are targets of L. monocytogenes-specific CD8(+) T cells. To investigate epitope cross-recognition by H2-M3-restricted CD8(+) T cells, we deleted the sequence encoding fMIGWII from a virulent strain of L. monocytogenes. Infection with fMIGWII-deficient L. monocytogenes unexpectedly primed CD8(+) T cells that stain with fMIGWII/H2-M3 tetramers and lyse fMIGWII-coated target cells in vivo. Because the fMIGWII sequence is nonredundant, we speculated that other bacterially derived Ags are priming these responses. HPLC peptide fractionation of bacterial culture supernatants revealed several distinct L. monocytogenes-derived peptides that are recognized by fMIGWII-specific T cells. Our results demonstrate that the dominant H2-M3-restricted CD8(+) T cell population, although reactive with fMIGWII, is primed by other, non-fMIGWII peptides derived from L. monocytogenes. Although this degree of Ag receptor promiscuity is unusual for the adaptive immune system, it may be a more common feature of T cell responses restricted by nonpolymorphic MHC class Ib molecules.

Animals↗
PubMed2003

B7h is required for T cell activation, differentiation, and effector function.

T helper (Th) cell activation, differentiation, and immune function are regulated by costimulatory molecules. Inducible costimulator (ICOS) is a recently identified costimulatory receptor expressed on activated T cells. A ligand for ICOS, B7h, is expressed on B cells and other types of antigen-presenting cells (APC). Although ICOS has been shown to be essential in T cell activation and differentiation, the regulatory roles of B7h at different stages of T cell immune responses have not been examined genetically. In this study, we generated and analyzed B7h-deficient mice. We present evidence that B7h is the only ligand for ICOS, and ICOS, its only corresponding receptor. Th cells, when activated with B7h-deficient APC, exhibited reduced proliferation and IL-2 production. In addition, Th cells produced significantly reduced amounts of IL-4 and -13 after differentiation at the presence of B7h-/- APC. This cytokine defect was associated with a deficiency in c-Maf expression and could be rescued completely by c-Maf overexpression in T cells. Furthermore, we showed that effector T cells, when restimulated in the presence of B7h-deficient APC, exhibited reduced Th2 cytokine production. Therefore, B7h is required for proper Th cell activation, differentiation, and effector cytokine expression.

Animals↗
PubMed2003

Surface expression of Notch1 on thymocytes: correlation with the double-negative to double-positive transition.

Notch1 plays a critical role in regulating T lineage commitment during the differentiation of lymphoid precursors. The physiological relevance of Notch1 signaling during subsequent stages of T cell differentiation has been more controversial. This is due in part to conflicting data from studies examining the overexpression or targeted deletion of Notch1 and to difficulties in distinguishing between the activities of multiple Notch family members and their ligands, which are expressed in the thymus. We employed a polyclonal antiserum against the extracellular domain of Notch1 to study surface expression during thymopoiesis. We found high levels of Notch1 on the cell surface only on double negative (DN) stage 2 through the immature single-positive stage of thymocyte development, before the double-positive (DP) stage. The Notch signaling pathway, as read out by Deltex1 expression levels, is highly active in DN thymocytes. When an active Notch1 transgene, Notch1IC, is exogenously introduced into thymocytes of recombinase-activating gene 2-deficient mice, it promotes proliferation and development to the DP stage following anti-CD3 treatment without apparently affecting the intensity of pre-TCR signaling. In addition, a stromal cell line expressing the Notch ligand, Delta-like-1, promotes the in vitro expansion of wild-type DN3 thymocytes in vitro. Consistent with other recent reports, these data suggest a role for Notch1 during the DN to DP stage of thymocyte maturation and suggest a cellular mechanism by which Notch1IC oncogenes could contribute to thymoma development and maintenance.

Animals↗