81 research outputs found
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Constitutive CD8 expression allows inefficient maturation of CD4+ helper T cells in class II major histocompatibility complex mutant mice.
Although mature CD4+ T cells bear T cell receptors (TCRs) that recognize class II major histocompatibility complex (MHC) and mature CD8+ T cells bear TCRs that recognize class I MHC, it is possible that the initial commitment of an immature thymocyte to a CD4 or CD8 lineage is made without regard to the specificity of the TCR. According to this model, CD4+ cells with class I TCR do not mature because the CD8 coreceptor is required for class I MHC recognition and positive selection. If this model is correct, constitutive expression of CD8 should allow CD4+ T cells with class I-specific TCRs to develop. In this report, we show that mature peripheral CD4+ cells are present in class II MHC-deficient mice that express a constitutive CD8.1 transgene. These cells share a number of properties with the major class II MHC-selected CD4 population, including the ability to express CD40 ligand upon activation. Although mature CD4 cells are also detectable in the thymus of class II MHC mutant/CD8.1 transgenic mice, they represent a small fraction of the mature CD4 cells found in mice that express class II MHC. These results indicate that some T cells choose the CD4 helper lineage independent of their antigen receptor specificity; however, the inefficiency of generating class I-specific CD4 cells leaves open the possibility that an instructive signal generated upon MHC recognition may bias lineage commitment
Dynamic Behavior of T Cells and Thymocytes in Lymphoid Organs as Revealed by Two-Photon Microscopy
AbstractThe initial application of two-photon imaging to the study of lymphoid tissues has provided a dramatic glimpse into how cells of the immune system move and interact in their native environments. In this review we summarize what we have learned so far and point out areas for future investigation using this approach
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The cytoplasmic domain of CD4 promotes the development of CD4 lineage T cells.
Thymocytes must bind major histocompatibility complex (MHC) proteins on thymic epithelial cells in order to mature into either CD8+ cytotoxic T cells or CD4+ helper T cells. Thymic precursors express both CD8 and CD4, and it has been suggested that the intracellular signals generated by CD8 or CD4 binding to class I or II MHC, respectively, might influence the fate of uncommitted cells. Here we test the notion that intracellular signaling by CD4 directs the development of thymocytes to a CD4 lineage. A hybrid protein consisting of the CD8 extracellular and transmembrane domains and the cytoplasmic domain of CD4 (CD884) should bind class I MHC but deliver a CD4 intracellular signal. We find that expression of a hybrid CD884 protein in thymocytes of transgenic mice leads to the development of large numbers of class I MHC-specific, CD4 lineage T cells. We discuss these results in terms of current models for CD4 and CD8 lineage commitment
Mice Infected with Low-virulence Strains of Toxoplasma gondii Lose their Innate Aversion to Cat Urine, Even after Extensive Parasite Clearance
Toxoplasma gondii chronic infection in rodent secondary hosts has been
reported to lead to a loss of innate, hard-wired fear toward cats, its primary
host. However the generality of this response across T. gondii strains and the
underlying mechanism for this pathogen mediated behavioral change remain
unknown. To begin exploring these questions, we evaluated the effects of
infection with two previously uninvestigated isolates from the three major
North American clonal lineages of T. gondii, Type III and an attenuated strain
of Type I. Using an hour-long open field activity assay optimized for this
purpose, we measured mouse aversion toward predator and non-predator urines. We
show that loss of innate aversion of cat urine is a general trait caused by
infection with any of the three major clonal lineages of parasite.
Surprisingly, we found that infection with the attenuated Type I parasite
results in sustained loss of aversion at times post infection when neither
parasite nor ongoing brain inflammation were detectable. This suggests that T.
gondii-mediated interruption of mouse innate aversion toward cat urine may
occur during early acute infection in a permanent manner, not requiring
persistence of parasitecysts or continuing brain inflammation.Comment: 14 pages, 3 figure
The Ins and Outs of CCR7 in the Thymus
Although it is widely supposed that chemokines play a role in the thymus, most existing evidence is circumstantial. In this issue, two groups provide direct evidence that the chemokine receptor CCR7 is required for normal thymocyte migration (Ueno, T., F. Saito, D. Gray, S. Kuse, K. Hieshima, H. Nakano, T. Kakiuchi, M. Lipp, R. Boyd, and Y. Takahama. 2004. J. Exp. Med. 200:493β505; Misslitz, A., O. Pabst, G. Hintzen, L. Ohl, E. Kremmer, H. T. Petrie, and R. Forster. 2004. J. Exp. Med. 200:481β491). The two papers focus on distinct and opposite migration events, an early outward migration and a later inward migration. Together these papers provide a fascinating picture of the complex role of CCR7 in orchestrating thymocyte migration
3D quantitative imaging of unprocessed live tissue reveals epithelial defense against bacterial adhesion and subsequent traversal requires MyD88.
While a plethora of in vivo models exist for studying infectious disease and its resolution, few enable factors involved in the maintenance of health to be studied in situ. This is due in part to a paucity of tools for studying subtleties of bacterial-host interactions at a cellular level within live organs or tissues, requiring investigators to rely on overt outcomes (e.g. pathology) in their research. Here, a suite of imaging technologies were combined to enable 3D and temporal subcellular localization and quantification of bacterial distribution within the murine cornea without the need for tissue processing or dissection. These methods were then used to demonstrate the importance of MyD88, a central adaptor protein for Toll-Like Receptor (TLR) mediated signaling, in protecting a multilayered epithelium against both adhesion and traversal by the opportunistic bacterial pathogen Pseudomonas aeruginosa ex vivo and in vivo
Dynamic Repositioning of CD4 and CD8 Genes during T Cell Development
Although stable repression of CD4 and CD8 genes is a central feature of T cell lineage commitment, we lack detailed information about the timing and mechanism of this repression. Stable gene repression has been linked to the position of genes within the nucleus. Therefore, information about the nuclear position of CD4 and CD8 genes during T cell development could provide insights into both the mechanism of regulation of CD4 and CD8 genes, and the process of lineage commitment. Here, we report that lineage-specific repression of CD4 and CD8 genes is associated with the repositioning of alleles close to heterochromatin. We also provide evidence that the relocalization of CD4 and CD8 genes to heterochromatin can occur as an early response to positive selection signals. We discuss our results in terms of our current knowledge of CD4 and CD8 gene regulation and CD4 versus CD8 lineage commitment
Toxoplasma gondiiβinfected natural killer cells display a hypermotility phenotype in vivo
Toxoplasma gondii is a highly prevalent intracellular protozoan parasite that causes severe disease in congenitally infected or immunocompromised hosts. T. gondii is capable of invading immune cells and it has been suggested that the parasite harnesses the migratory pathways of these cells to spread through the body. Although in vitro evidence suggests that the parasite further enhances its spread by inducing a hypermotility phenotype in parasitized immune cells, in vivo evidence for this phenomenon is scarce. Here we use a physiologically relevant oral model of T. gondii infection, in conjunction with twoβphoton laser scanning microscopy, to address this issue. We found that a small proportion of natural killer (NK) cells in mesenteric lymph nodes contained parasites. Compared with uninfected βbystanderβ NK cells, these infected NK cells showed faster, more directed and more persistent migratory behavior. Consistent with this, infected NK cells showed impaired spreading and clustering of the integrin, LFAβ1, when exposed to plated ligands. Our results provide the first evidence for a hypermigratory phenotype in T. gondiiβinfected NK cells in vivo, providing an anatomical context for understanding how the parasite manipulates immune cell motility to spread through the host
The promiscuous development of an unconventional Qa1b-restricted T cell population
MHC-E restricted CD8 T cells show promise in vaccine settings, but their development and specificity remain poorly understood. Here we focus on a CD8 T cell population reactive to a self-peptide (FL9) bound to mouse MHC-E (Qa-1b) that is presented in response to loss of the MHC I processing enzyme ERAAP, termed QFL T cells. We find that mature QFL thymocytes are predominantly CD8Ξ±Ξ²+CD4-, show signs of agonist selection, and give rise to both CD8Ξ±Ξ± and CD8Ξ±Ξ² intraepithelial lymphocytes (IEL), as well as memory phenotype CD8Ξ±Ξ² T cells. QFL T cells require the MHC I subunit Ξ²-2 microglobulin (Ξ²2m), but do not require Qa1b or classical MHC I for positive selection. However, QFL thymocytes do require Qa1b for agonist selection and full functionality. Our data highlight the relaxed requirements for positive selection of an MHC-E restricted T cell population and suggest a CD8Ξ±Ξ²+CD4- pathway for development of CD8Ξ±Ξ± IELs
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