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

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. 200:493–505; Misslitz, A., O. Pabst, G. Hintzen, L. Ohl, E. Kremmer, H. T. Petrie, and R. Forster. 2004. J. Exp. Med. 200:481–491). 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

Toxoplasma gondii‐infected 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 two‐photon 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 ‘bystander’ 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, LFA‐1, when exposed to plated ligands. Our results provide the first evidence for a hypermigratory phenotype in T. gondii‐infected 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 CD8αβ+CD4-, show signs of agonist selection, and give rise to both CD8αα and CD8αβ intraepithelial lymphocytes (IEL), as well as memory phenotype CD8αβ T cells. QFL T cells require the MHC I subunit β-2 microglobulin (β2m), 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 CD8αβ+CD4- pathway for development of CD8αα IELs