35 research outputs found
Phenotype, effector function, and tissue localization of PD-1-expressing human follicular helper T cell subsets
<p>Abstract</p> <p>Background</p> <p>It is well established that PD-1 is expressed by follicular T cells but its function in regulation of human T helper cells has been unclear. We investigated the expression modality and function of PD-1 expressed by human T cells specialized in helping B cells.</p> <p>Results</p> <p>We found that PD-1-expressing T cells are heterogeneous in PD-1 expression. We identified three different PD-1-expressing memory T cell subsets (i.e. PD-1<sup>low (+)</sup>, PD-1<sup>medium (++)</sup>, and PD-1<sup>high (+++) </sup>cells). PD-1<sup>+++ </sup>T cells expressed CXCR5 and CXCR4 and were localized in the rim of germinal centers. PD-1<sup>+ </sup>or PD-1<sup>++ </sup>cells expressed CCR7 and were present mainly in the T cell area or other parts of the B cell follicles. Utilizing a novel antigen density-dependent magnetic sorting (ADD-MS) method, we isolated the three T cell subsets for functional characterization. The germinal center-located PD-1<sup>+++ </sup>T cells were most efficient in helping B cells and in producing IL-21 and CXCL13. Other PD-1-expressing T cells, enriched with Th1 and Th17 cells, were less efficient than PD-1<sup>+++ </sup>T cells in these capacities. PD-1<sup>+++ </sup>T cells highly expressed Ki-67 and therefore appear active in cell activation and proliferation in vivo. IL-2 is a cytokine important for proliferation and survival of the PD-1<sup>+++ </sup>T cells. In contrast, IL-21, while a major effector cytokine produced by the PD-1-expressing T helper cells, had no function in generation, survival, or proliferation of the PD-1-expressing helper T cells at least in vitro. PD-1 triggering has a suppressive effect on the proliferation and B cell-helping function of PD-1<sup>+++ </sup>germinal center T cells.</p> <p>Conclusion</p> <p>Our results revealed the phenotype and effector function of PD-1-expressing T helper cell subsets and indicate that PD-1 restrains the B cell-helping function of germinal center-localized T cells to prevent excessive antibody response.</p
Human CD57(+ )germinal center-T cells are the major helpers for GC-B cells and induce class switch recombination
BACKGROUND: The function of CD57(+ )CD4(+ )T cells, constituting a major subset of germinal center T (GC-Th) cells in human lymphoid tissues, has been unclear. There have been contradictory reports regarding the B cell helping function of CD57(+ )GC-Th cells in production of immunoglobulin (Ig). Furthermore, the cytokine and co-stimulation requirement for their helper activity remains largely unknown. To clarify and gain more insight into their function in helping B cells, we systematically investigated the capacity of human tonsil CD57(+ )GC-Th cells in inducing B cell Ig synthesis. RESULTS: We demonstrated that CD57(+ )GC-Th cells are highly efficient in helping B cell production of all four subsets of Ig (IgM, IgG, IgA and IgE) compared to other T-helper cells located in germinal centers or interfollicular areas. CD57(+ )GC-Th cells were particularly more efficient than other T cells in helping GC-B cells but not naïve B cells. CD57(+ )GC-Th cells induced the expression of activation-induced cytosine deaminase (AID) and class switch recombination in developing B cells. IgG1-3 and IgA1 were the major Ig isotypes induced by CD57(+ )GC-Th cells. CD40L, but not IL-4, IL-10 and IFN-γ, was critical in CD57(+ )GC-Th cell-driven B cell production of Ig. However, IL-10, when added exogenously, significantly enhanced the helper activity of CD57(+ )GC-Th cells, while TGF-β1 completely and IFN-γ partially suppressed the CD57(+ )GC-Th cell-driven Ig production. CONCLUSIONS: CD57(+)CD4(+ )T cells in the germinal centers of human lymphoid tissues are the major T helper cell subset for GC-B cells in Ig synthesis. Their helper activity is consistent with their capacity to induce AID and class switch recombination, and can be regulated by CD40L, IL-4, IL-10 and TGF-β
Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells.
Regulatory T cells (Tregs) can potentially migrate to the B cell areas of secondary lymphoid tissues and suppress T cell-dependent B cell Ig response. T cell-dependent Ig response requires B cell stimulation by Th cells. It has been unknown whether Tregs can directly suppress B cells or whether they must suppress Th cells to suppress B cell response. We report here that Foxp3+ Tregs are found in T-B area borders and within germinal centers of human lymphoid tissues and can directly suppress B cell Ig response. Although Tregs can effectively suppress T cells, they can also directly suppress B cell response without the need to first suppress Th cells. The direct suppression of B cell Ig production by Tregs is accompanied by inhibition of Ig class switch recombination
Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3(+) regulatory T cells
It is a question of interest whether Th17 cells express trafficking receptors unique to this Th cell lineage and migrate specifically to certain tissue sites. We found several Th17 cell subsets at different developing stages in a human secondary lymphoid organ (tonsils) and adult, but not in neonatal, blood. These Th17 cell subsets include a novel in vivo-stimulated tonsil IL17(+) T cell subset detected without any artificial stimulation in vitro. We investigated in depth the trafficking receptor phenotype of the Th17 cell subsets in tonsils and adult blood. The developing Th17 cells in tonsils highly expressed both Th1- (CCR2, CXCR3, CCR5, and CXCR6) and Th2-associated (CCR4) trafficking receptors. Moreover, Th17 cells share major non-lymphoid tissue trafficking receptors, such as CCR4, CCR5, CCR6, CXCR3, and CXCR6, with FOXP3(+) T regulatory cells. In addition, many Th17 cells express homeostatic chemokine receptors (CD62L, CCR6, CCR7, CXCR4, and CXCR5) implicated in T cell migration to and within lymphoid tissues. Expression of CCR6 and CCR4 by some Th17 cells is not a feature unique to Th17 cells but shared with FOXP3(+) T cells. Interestingly, the IL17(+)IFN-gamma(+) Th17 cells have the features of both IL17(-)IFN-gamma(+) Th1 and IL17(+)IFN-gamma(-) Th17 cells in expression of trafficking receptors. Taken together, our results revealed that Th17 cells are highly heterogeneous, in terms of trafficking receptors, and programmed to share major trafficking receptors with other T cell lineages. These findings have important implications in their distribution in the human body in relation to other regulatory T cell subsets
An Engineering Aerodynamic Heating Method For Hypersonic Flow
A capability to calculate surface heating rates has been incorporated in an approximate three-dimensional inviscid technique. Surface streamlines are calculated from the inviscid solution, and the axisymmetric analog is then used along with a set of approximate convectiveheating equations to compute the surface heat transfer. The method is applied to blunted axisymmetric and three-dimensional ellipsoidal cones at angle of attack for the laminar flow of a perfect gas. The method is also applicable to turbulent and equilibrium-air conditions. The present technique predicts surface heating rates that compare favorably with experimental (ground-test and flight) data and numerical solutions of the Navier-Stokes (NS) and viscous shock-layer (VSL) equations. The new technique represents a significant improvement over current engineering aerothermal methods with only a modest increase in computational effort. Nomenclature A; B; D; J geometric factors e ¯ s ; e¯ t tangential unit vectors on b..
Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell–driven B cell responses
How Tregs migrate to GCs, and whether they regulate the helper activity of the T cells in GCs (GC-Th cells) remains poorly understood. We found a T cell subset in human tonsils that displays potent suppressive activities toward GC-Th cell–dependent B cell responses. These Tregs with the surface phenotype of CD4(+)CD25(+)CD69(–) migrate well to CCL19, a chemokine expressed in the T cell zone, but poorly to CXCL13, a chemokine expressed in the B cell zone. This migration toward the T cell–rich zone rapidly changes to trafficking toward B cell follicles upon T cell activation. This change in chemotactic behavior upon activation of T cells is consistent with their switch in the expression of the 2 chemokine receptors CXCR5 and CCR7. CD4(+)CD25(+)CD69(–) Tregs suppress GC-Th cells and GC-Th cell–induced B cell responses such as Ig production, survival, and expression of activation-induced cytosine deaminase. Our results have identified a subset of Tregs that is physiologically relevant to GC-Th cell–dependent B cell responses and a potential regulation mechanism for the trafficking of these Tregs to GCs