Abstract
Follicular regulatory T (Tfr) cells play various roles in immune responses, contributing to both positive and negative regulation of foreign antigen-specific B cell responses, control over ...autoreactive antibody responses and autoimmunity, and B cell class-switching to IgE and allergy development. Studies conducted on mice uncovered various subsets of CXCR5+FoxP3+CD4+ Tfr cells that could differently contribute to immune regulation. Moreover, recent studies of human Tfr cells revealed similar complexity with various subsets of follicular T cells of different origins and immunosuppressive and/or immunostimulatory characteristics. In this review we will overview and compare Tfr subsets currently identified in mice and humans and will discuss their origins and antigen specificity, as well as potential modes of action and contribution to the control of the autoimmune and allergic reactions.
Graphical Abstract
Graphical Abstract
The splenic marginal zone is a unique microenvironment where resident immune cells are exposed to the open blood circulation. Even though it has an important role in responses against blood-borne ...antigens, lymphocyte migration in the marginal zone has not been intravitally visualized due to challenges associated with achieving adequate imaging depth in this abdominal organ. Here we develop a two-photon microscopy procedure to study marginal zone and follicular B-cell movement in the live mouse spleen. We show that marginal zone B cells are highly motile and exhibit long membrane extensions. Marginal zone B cells shuttle between the marginal zone and follicles with at least one-fifth of the cells exchanging between compartments per hour, a behaviour that explains their ability to deliver antigens rapidly from the open blood circulation to the secluded follicles. Follicular B cells also transit from follicles to the marginal zone, but unlike marginal zone B cells, they fail to undergo integrin-mediated adhesion, become caught in fluid flow and are carried into the red pulp. Follicular B-cell egress via the marginal zone is sphingosine-1-phosphate receptor-1 (S1PR1)-dependent. This study shows that marginal zone B cells migrate continually between marginal zone and follicles and establishes the marginal zone as a site of S1PR1-dependent B-cell exit from follicles. The results also show how adhesive differences of similar cells critically influence their behaviour in the same microenvironment.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent studies have identified cortical sinuses as sites of sphingosine-1-phosphate receptor-1 (S1P₁)-dependent T- and B-cell egress from the lymph node (LN) parenchyma. However, the distribution of ...cortical sinuses in the entire LN and the extent of lymph flow within them has been unclear. Using 3D reconstruction and intravital two-photon microscopy we describe the branched organization of the cortical sinus network within the inguinal LN and show that lymphocyte flow begins within blunt-ended sinuses. Many cortical sinuses are situated adjacent to high endothelial venules, and some lymphocytes access these sinuses within minutes of entering a LN. However, upon entry to inflamed LNs, lymphocytes rapidly up-regulate CD69 and are prevented from accessing cortical sinuses. Using the LN reconstruction data and knowledge of lymphocyte migration and cortical sinus entry dynamics, we developed a mathematical model of T-cell egress from LNs. The model suggests that random walk encounters with lymphatic sinuses are the major factor contributing to LN transit times. A slight discrepancy between predictions of the model and the measured transit times may be explained by lymphocytes undergoing a few rounds of migration between the parenchyma and sinuses before departing from the LN. Because large soluble antigens gain rapid access to cortical sinuses, such parenchyma—sinus shuttling may facilitate antibody responses.
Modern vaccines must be designed to generate long-lasting, high-affinity, and broadly neutralizing Ab responses against pathogens. The diversity of B cell clones recruited into germinal center (GC) ...responses is likely to be important for the Ag-neutralization potential of the Ab-secreting cells and memory cells generated upon immunization. However, the factors that influence the diversity of B cell clones recruited into GCs are unclear. As recirculating naive Ag-specific B cells arrive in Ag-draining secondary lymphoid organs, they may join the ongoing GC response. However, the factors that limit their entry are not well understood, and it is not known how that depends on the stage of the ongoing follicular T cell and GC B cell response. In this article, we show that, in mice, naive B cells have a limited window of time during which they can undergo Ag-driven activation and join ongoing immunization-induced GC responses. However, preloading naive B cells with even a threshold-activating amount of Ag is sufficient to rescue their entry into the GC response during its initiation, peak, and contraction. Based on these results, we suggest that productive acquisition of Ag may be one of the main factors limiting entry of new B cell clones into ongoing immunization-triggered GC responses.
Diverse B cell responses are important for generating antibody‐mediated protection against highly variable pathogens. While some antigens can trigger T‐independent B cell proliferation and short‐term ...antibody production, development of long‐term humoral immunity requires T‐dependent B cell responses. The “two‐signal” model of B cell activation has long been invoked to explain alternate B cell recruitment into immune response to foreign antigens vs. induction of tolerance to self‐antigens. However, a number of other factors appear to influence the fate of mature B cells responding to antigen in vivo. In this review, we will discuss how various spatiotemporal scenarios of antigen access into secondary lymphoid organs, antigen valency and cellular environment of antigen acquisition by B cells, duration of B cell access to antigen and the timing of T cell help may affect follicular B cell fate, including death, survival, anergy, and recruitment into T‐dependent responses. We will also highlight unresolved questions related to B cell activation and tolerance in vivo that may have important implications for vaccine development and autoimmunity.
Follicular regulatory T cells (Tfr) restrict development of autoantibodies and autoimmunity while supporting high-affinity foreign antigen-specific humoral response. However, whether Tfr can directly ...repress germinal center (GC) B cells that acquire autoantigens is unclear. Moreover, TCR specificity of Tfr to self-antigens is not known. Our study suggests that nuclear proteins contain antigens specific to Tfr. Targeting of these proteins to antigen-specific B cells in mice triggers rapid accumulation of Tfr with immunosuppressive characteristics. Tfr then exert negative regulation of GC B cells with predominant inhibition of the nuclear protein-acquiring GC B cells, suggesting an important role of direct cognate Tfr-GC B cells interactions for the control of effector B cell response.
Follicular regulatory T cells (Tfr) can play opposite roles in the regulation of germinal center (GC) responses. Depending on the studies, Tfr suppress or support GC and B cell affinity maturation. ...However, which factors determine positive vs. negative effects of Tfr on the GC B cell is unclear. In this study, we show that GC centrocytes that express MYC up-regulate expression of CCL3 chemokine that is needed for both the positive and negative regulation of GC B cells by Tfr. B cell-intrinsic expression of CCL3 contributes to Tfr-dependent positive selection of foreign Ag-specific GC B cells. At the same time, expression of CCL3 is critical for direct Tfr-mediated suppression of GC B cells that acquire cognate to Tfr nuclear proteins. Our study suggests that CCR5 and CCR1 receptors promote Tfr migration to CCL3 and highlights
expression on the Tfr subset that expresses
. Based on our findings and previous studies, we suggest a model of chemotactically targeted checkpoint control of B cells undergoing positive selection in GCs by Tfr, where Tfr directly probe and license foreign antigen-specific B cells to complete their positive selection in GCs but, at the same time, suppress GC B cells that present self-antigens cognate to Tfr.
Previous studies and our findings suggest upregulated expression of proinflammatory chemokines CCL3/4 in germinal center (GC) centrocytes. However, the role of CCL3/4 for centrocyte interactions with ...follicular T cells and regulation of humoral immunity is poorly understood. We found that CCL3 promotes chemotaxis of Tfr cells
. Two-photon imaging revealed that B cells-intrinsic production of CCL3 promotes their probing by follicular regulatory T cells (Tfr) within GCs of murine lymph nodes. Overall this study suggests that CCL3 facilitates direct interactions of foreign antigen-specific GC B cells and their negative regulation with Tfr cells
.
The cellular dynamics of the egress of lymphocytes from lymph nodes are poorly defined. Here we visualized the branched organization of lymph node cortical sinuses and found that after entry, some T ...cells were retained, whereas others returned to the parenchyma. T cells deficient in sphingosine 1-phosphate receptor type 1 probed the sinus surface but failed to enter the sinuses. In some sinuses, T cells became rounded and moved unidirectionally. T cells traveled from cortical sinuses into macrophage-rich sinus areas. Many T cells flowed from medullary sinuses into the subcapsular space. We propose a multistep model of lymph node egress in which cortical sinus probing is followed by entry dependent on sphingosine 1-phosphate receptor type 1, capture of cells in a sinus region with flow, and transport to medullary sinuses and the efferent lymph.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To explore scenarios that permit transcription regulation by activator recruitment of RNA polymerase and σ competition in vivo, we used an equilibrium model of RNA polymerase binding to DNA ...constrained by the values of total RNA polymerase (E) and $\sigma^{70}$ per cell measured in this work. Our numbers of E and $\sigma^{70}$ per cell, which are consistent with most of the primary data in the literature, suggest that in vivo (I) only a minor fraction of RNA polymerase (<20%) is involved in elongation and (ii) $\sigma^{70}$ is in excess of total E. Modeling the partitioning of RNA polymerase between promoters, nonspecific DNA binding sites, and the cytoplasm suggested that even weak promoters will be saturated with $\sigma^{70}$ in vivo unless nonspecific DNA binding by $E\sigma^{70}$ is rather significant. In addition, the model predicted that as compete for binding to E only when their total number exceeds the total amount of RNA polymerase (excluding that involved in elongation) and that weak promoters will be preferentially subjected to a competition.
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