| 1. |
- Alsén, Samuel, et al.
(författare)
-
Antigen-Presenting B Cells Program the Efferent Lymph T Helper Cell Response
- 2022
-
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- B cells interact with T follicular helper (Tfh) cells in germinal centers (GCs) to generate high-affinity antibodies. Much less is known about how cognate T-B-cell interactions influence Th cells that enter circulation and peripheral tissues. Therefore, we generated mice lacking MHC-II expressing B cells and, by thoracic duct cannulation, analyzed Th cells in the efferent lymph at defined intervals post-immunization. Focusing on gut-draining mesenteric lymph nodes (MLNs), we show that antigen-specific alpha(4)beta(+)(7) gut-homing effector Th cells enter the circulation prior to CXCR5(+)PD-1(+) Tfh-like cells. B cells appear to have no or limited impact on the early generation and egress of gut-homing Th cells but are critical for the subsequent appearance of Tfh-like cells that peak in the lymph before GCs have developed. At this stage, antigen-presenting B cells also reduce the proportion of alpha(4)beta(+)(7) Th cells in the MLN and efferent lymph. Furthermore, cognate B-cell interaction drives a broad transcriptional program in Th cells, including IL-4 that is confined to the Tfh cell lineage. The IL-4-producing Tfh-like cells originate from Bcl6(+) precursors in the LNs and have gut-homing capacity. Hence, B cells program the efferent lymph Th cell response within a limited window of time after antigenic challenge.
|
|
| 2. |
- Carlsson, Michael, et al.
(författare)
-
Galectin-3 guides intracellular trafficking of some human serotransferrin glycoforms
- 2013
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 288:39, s. 28398-28408
-
Tidskriftsartikel (refereegranskat)abstract
- Transferrin internalization via clathrin-mediated endocytosis and subsequent recycling after iron delivery has been extensively studied. Here we demonstrate a previously unrecognized parameter regulating this recycling -the binding of galectin-3 to particular glycoforms of transferrin. Two fractions of transferrin, separated by affinity chromatography based on their binding or not to galectin-3, are targeted to kinetically different endocytic pathways in HFL-1 cells expressing galectin-3 but not in SKBR3 cells lacking galectin-3; the SKBR3 cells, however can acquire the ability to target these transferrin glycoforms differently after preloading with exogenously added galectin-3. In all, this study provides the first evidence of a functional role for transferrin glycans, in intracellular trafficking after uptake. Moreover, the galectin-3 bound glycoform increased in cancer, suggesting a pathophysiological regulation. These are novel aspects of transferrin cell biology, which has previously considered only degree of iron loading, but not other forms of heterogeneity.
|
|
| 3. |
- Cucak, Helena
(författare)
-
THE ROLE OF DENDRITIC CELLS AND TYPE I INTERFERON IN THE GENERATION AND FUNCTION OF T FOLLICULAR HELPER CELLS
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Generation of long-lived plasma cells and memory B cells of high affinity takes place in germinal centers and depends on help from a specialized CD4+ T cell subset termed T follicular helper (Tfh) cells. These processes are crucial for long-term protection upon natural infection or in settings of vaccination, however they are also responsible for development of antibody-mediated autoimmune disease. Targeting of Tfh cells may therefore be of importance both in the development of new vaccines and in treatment of autoimmune conditions associated with pathologic autoantibody production. The aim of this thesis was to examine the molecular and cellular interactions in the generation and function of Tfh cells. First we wanted to determine if CXCR5+ Tfh cells are developmentally distinct from peripheral gut homing Th cells, and if they differ in terms of lymph node egress. We could observe that CXCR5+ Tfh cells and α4β7+ gut-homing Th cells are generated as two separate subsets and that majority of CXCR5+ Tfh cells were retained within the lymph node whereas the majority of α4β7+ Th cells exited. Second we looked at the role of type I interferon and dendritic cells in the generation and function of Tfh cells. We observed that type I interferon signaling in DCs is important for development of Tfh cells in response to antigen and TLR3 or TLR4 agonists and suggested that it functioned by inducing IL-6 production. We have also demonstrated that conventional CD11c DCs at least partially through their robust co-stimulation via CD28 provide unique signals essential for development of functional Tfh cells. A deeper knowledge of these processes would undoubtedly be valuable for the development of new vaccines as well as for advances in treatment of autoimmune diseases.
|
|
| 4. |
- Cucak, Helena, et al.
(författare)
-
Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells.
- 2009
-
Ingår i: Immunity. - : Elsevier BV. - 1097-4180 .- 1074-7613. ; 31:3, s. 491-501
-
Tidskriftsartikel (refereegranskat)abstract
- T follicular helper (Tfh) cells represent a recently defined CD4(+) T cell subset characterized by the expression of the chemokine receptor CXCR5 and an enhanced ability to support B cells to mount antibody responses. Here, we demonstrate that lymph-node-resident CXCR5(+) Tfh cells and gut-homing integrin alpha(4)beta(7)-expressing T helper cells are generated as separate subsets in the gut-draining mesenteric lymph nodes. Type I interferon signaling in dendritic cells and in nonhematopoietic cells selectively stimulates Tfh cell development in response to antigen in conjunction with Toll-like receptor (TLR)3 or TLR4 agonists. Consistent with this, the ability of dendritic cells to produce the cytokine IL-6, required for in vivo Tfh differentiation, and antibody affinity maturation are both reduced in absence of type I interferon signaling. Thus, our results identify type I interferon as a natural adjuvant that selectively supports the generation of lymph node resident Tfh cells.
|
|
| 5. |
- Dahlgren, Madelene, et al.
(författare)
-
T Follicular Helper, but Not Th1, Cell Differentiation in the Absence of Conventional Dendritic Cells
- 2015
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 194:11, s. 5187-5199
-
Tidskriftsartikel (refereegranskat)abstract
- Development of long-lived humoral immunity is dependent on CXCR5-expressing T follicular helper (Tfh) cells, which develop concomitantly to effector Th cells that support cellular immunity. Conventional dendritic cells (cDCs) are critical APCs for initial priming of naive CD4(+) T cells but, importantly, also provide accessory signals that govern effector Th cell commitment. To define the accessory role of cDCs during the concurrent development of Tfh and effector Th1 cells, we performed high-dose Ag immunization in conjunction with the Th1-biased adjuvant polyinosinic: polycytidylic acid (pI:C). In the absence of cDCs, pI: C failed to induce Th1 cell commitment and IgG2c production. However, cDC depletion did not impair Tfh cell differentiation or germinal center formation, and long-lived IgG1 responses of unaltered affinity developed in mice lacking cDCs at the time point for immunization. Thus, cDCs are required for the pI: C-driven Th1 cell fate commitment but have no crucial accessory function in relation to Tfh cell differentiation.
|
|
| 6. |
- Stenstad, Hanna, et al.
(författare)
-
Differential homing mechanisms regulate regionalized effector CD8alphabeta+ T cell accumulation within the small intestine.
- 2007
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:24, s. 10122-7
-
Tidskriftsartikel (refereegranskat)abstract
- The CC chemokine receptor (CCR)9 is expressed on the majority of small intestinal, but few colonic, T cells, whereas its ligand CCL25 is constitutively expressed by small intestinal epithelial cells. As such, CCR9/CCL25 have been proposed to play a central role in regulating small intestinal but not colonic immune responses and thus to organize regionalized immunity within the intestinal mucosa. Here, we demonstrate that CCL25 is expressed at reduced levels by epithelial cells in the distal compared with proximal small intestine, which correlated with less efficient CCR9-dependent effector CD8alphabeta+ T cell entry into the ileal epithelium. In vitro-generated alpha4beta7+ effector CD8alphabeta+ T cell entry into the lamina propria was less dependent on CCR9 than entry into the epithelium along the entire length of the small intestine and in particular in the ileum. CCR9-independent alpha4beta7+ effector CD8alphabeta+ T cell entry was pertussis toxin-sensitive, suggesting a role for additional Galpha(I)-linked G protein-coupled receptors. Finally, in vivo-primed effector CD8alphabeta+ T cells displayed regionalized differences in their entry to the small intestinal epithelium with enhanced CCR9-independent entry to the ileum. These results highlight a hitherto underappreciated compartmentalization of immune responses within the small intestine and have direct implications for targeting strategies aimed at regulating T cell localization to the small intestinal mucosa.
|
|
