| 1. |
- Akeus, Paulina, et al.
(författare)
-
Regulatory T cells reduce endothelial neutral sphingomyelinase 2 to prevent T-cell migration into tumors
- 2021
-
Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 51:9, s. 2317-2329
-
Tidskriftsartikel (refereegranskat)abstract
- Endothelial cells are key regulators of transendothelial migration and their secretion of chemokines and expression of adhesion molecules facilitates lymphocyte entry into tissues. Previously, we demonstrated that Tregs can reduce transendothelial migration of T cells into tumors by decreasing endothelial CXCL10 secretion, but the mechanism by which this occurs is still not known. In this study, we aimed to define how Tregs decrease transendothelial migration into tumors. mRNA sequencing of intestinal tumor endothelial cells from Treg depleted mice identified neutral sphingomyelinase 2 (nSMase2) as a gene downregulated in the presence of Tregs. nSMase2 is expressed in human umbilical vein endothelial cells (HUVECs) and was decreased after coculture with Tregs. Furthermore, blocking of nSMase2 activity in vitro decreased VCAM1, CX3CL1, and CXCL10 expression in HUVECs, mirroring the same decrease found in Treg cocultures. In the APC(min/+) mouse model of intestinal cancer, nSMase2 is lower in tumor endothelial cells than in unaffected small intestine and chronic treatment with a nSMase2 inhibitor suppressed the increased migration that is otherwise seen in the absence of Tregs. We conclude that nSMase2 is an important mediator in endothelial cells supporting transendothelial migration, which may be targeted by Tregs to reduce T-cell migration into tumors.
|
|
| 2. |
- Akeus, Paulina, et al.
(författare)
-
Treg-cell depletion promotes chemokine production and accumulation of CXCR3(+) conventional T cells in intestinal tumors.
- 2015
-
Ingår i: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 45:6, s. 1654-66
-
Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is one of the most prevalent tumor types worldwide and tumor-infiltrating T cells are crucial for anti-tumor immunity. We previously demonstrated that Treg cells from CRC patients inhibit transendothelial migration of conventional T cells. However, it remains unclear if local Treg cells affect lymphocyte migration into colonic tumors. By breeding APC(Min/+) mice with depletion of regulatory T cells mice, expressing the diphtheria toxin receptor under the control of the FoxP3 promoter, we were able to selectively deplete Treg cells in tumor-bearing mice, and investigate the impact of these cells on the infiltration of conventional T cells into intestinal tumors. Short-term Treg-cell depletion led to a substantial increase in the frequencies of T cells in the tumors, attributed by both increased infiltration and proliferation of T cells in the Treg-cell-depleted tumors. We also demonstrate a selective increase of the chemokines CXCL9 and CXCL10 in Treg-cell-depleted tumors, which were accompanied by accumulation of CXCR3(+) T cells, and increased IFN-γ mRNA expression. In conclusion, Treg-cell depletion increases the accumulation of conventional T cells in intestinal tumors, and targeting Treg cells could be a possible anti-tumor immunotherapy, which not only affects T-cell effector functions, but also their recruitment to tumors.
|
|
| 3. |
- Enarsson, Karin, 1975, et al.
(författare)
-
CD4+ CD25high regulatory T cells reduce T cell transendothelial migration in cancer patients.
- 2007
-
Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 37:1, s. 282-91
-
Tidskriftsartikel (refereegranskat)abstract
- Cell-mediated immunity is thought to be the main mechanism of anti-tumour responses of the host, but it is not known if cancer disease affects T cell recruitment from blood to tissues. Therefore, we compared Heliobacter pylori-induced T cell transendothelial migration (TEM) in H. pylori-infected gastric carcinoma patients, colon and lung carcinoma patients and healthy volunteers. H. pylori induced significant T cell migration from all groups. However, there was a dramatic reduction of T cell TEM in gastric carcinoma patients (80%) compared to healthy individuals. A similarly reduced transmigration was also seen in colon and lung carcinoma patients. We found significantly increased frequencies of T(reg) cells in the blood of gastric carcinoma patients compared to healthy individuals, and depletion of T(reg) cells from the blood of these patients prior to TEM restored T cell migration. The effect of T(reg) cells was largely dependent on cell-cell contact, but not on IL-10 or TGF-beta. In addition, the presence of T(reg) cells led to reduced T cell attachment to endothelium and decreased production of T cell-recruiting chemokines during TEM. In conclusion, T(reg) cell-mediated reduction of T cell TEM may reduce T cell recruitment in patients with epithelial malignancies, thereby hampering anti-tumour responses.
|
|
| 4. |
- Sundström, Patrik, et al.
(författare)
-
Human IgA-secreting cells induced by intestinal, but not systemic, immunization respond to CCL25 (TECK) and CCL28 (MEC).
- 2008
-
Ingår i: European journal of immunology. - : Wiley. - 0014-2980. ; 38:12, s. 3327-38
-
Tidskriftsartikel (refereegranskat)abstract
- Organ-specific homing of lymphoid cells depends on the expression of tissue-specific adhesion molecules and production of specific chemokines. CCL25 (TECK) and CCL28 (MEC) have been reported to direct circulating memory/effector B cells to mucosal tissues. Here, we examined if differential responsiveness to mucosal and systemic chemokines could explain the differential migration pattern of circulating human antibody-secreting cells (ASC), induced by mucosal and systemic immunization. There was a robust migration of specific IgA- and IgM-ASC induced by Salmonella vaccination toward the mucosal chemokines CCL25 and CCL28. In contrast, tetanus-specific ASC migrated to the systemic chemokine CXCL12 (SDF-1alpha) and showed no response to CCL25 or CCL28, not even tetanus-specific IgA-ASC. Cell sorting experiments demonstrated that Salmonella-specific ASC co-expressed CCR9 and CCR10. Our results show that induction site, rather than isotype commitment, determines the chemokine responsiveness and migration pattern of human effector B cells.
|
|
