Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node

The optimum marrow ablative regimen for preparing recipients of bone marrow transplantation (BMT) has not been established. gamma- Irradiation, but not busulfan, produces a characteristic microvascular injury pattern which results in depressed capacity of normal lymphocytes to localize into the lymph nodes of syngeneic murine BMT recipients. Since peripheral lymph nodes are important sites for initiation and amplification of immune responses, the preparative regimen might delay recovery of regionally compartmentalized immune functions after BMT. We evaluated the effects of busulfan and gamma- irradiation on the phenotypic and functional reconstitution of helper T- cell function within the peripheral lymph nodes of BMT recipients. Both marrow ablative regimens caused a protracted delay in regeneration of peripheral lymph node CD4+ T cells. Specific helper T-cell functions, such as contact hypersensitivity and alloantigen responses, remained significantly depressed in the lymph nodes of irradiated mice for prolonged periods (up to 60 weeks). These responses recovered more rapidly in busulfan-treated BMT recipients. In contrast, the capacity of peripheral lymph node T cells to provide “help” for antigen-specific immunoglobulin production was only transiently depressed by either preparative regimen. Our experiments confirm the hypothesis that the marrow ablative regimen, particularly gamma-irradiation, may contribute to the period of immunodeficiency which follows BMT. The pattern of immune recovery observed suggests that preparative total body irradiation (TBI) may selectively depress the regional recovery of the TH1 [interleukin-2 (IL-2) and gamma-interferon (gamma-IFN) secreting] lymphocyte subset.

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CCR4 Expression in Hodgkin Lymphoma

Blood ◽

10.1182/blood.v118.21.2626.2626 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2626-2626

Author(s):

Lydia Visser ◽

Myrna van West ◽

Bea Rutgers ◽

Sibrand Poppema ◽

Anke Van Den Berg

Keyword(s):

Lymph Node ◽

T Cell ◽

Hodgkin Lymphoma ◽

Tumor Cells ◽

Conflicts Of Interest ◽

Treg Cells ◽

Cd4 T Cell ◽

Th2 Cells ◽

Follicular Hyperplasia ◽

Reactive Lymph Node

Abstract Abstract 2626 In Hodgkin lymphoma (HL) a minority (<1%) of tumor cells is found in a reactive background. The tumor cells shape their environment by the production of several chemokines and cytokines. Production of the chemokine TARC will lead to the attraction of Th2 and Treg cells specifically to involved lymph nodes. Although Treg and Th2 cells are prominent in the infiltrate the expression of its receptor CCR4 is not very high in lymphocytes surrounding the tumor cells. We hypothesized that this is due to internalization of the receptor. We analyzed in which specific compartment of lymphocytes CCR4 is expressed and if CCR4 expression can be recovered when TARC and MDC levels are low. We analyzed 11 lymph node suspensions involved with HL and 11 with follicular hyperplasia (RLN) for expression of CD4, CD26, FoxP3 and CCR4 at t=0 and t=24 hours. We tested the effect of TARC and MDC on CCR4 expression and the mechanism of internalization on normal PBMCs. At t=0 the CD4+ T cell compartment was significantly lower for CD26 in HL (49% vs 68% in RLN, p<0.01) (Table 1). In the comparison between CD26+ and CD26- cells no difference was seen in CCR4 expression in HL but in RLN CCR4 in CD26- cells was significantly lower than in CD26+ cells (p<0.01).Recovery of CCR4 (in average %) after 24 hours was significantly lower in CD26+ cells and FoxP3+ cells in RLN (p<0.01 and p<0.001). Recovery of CCR4 as factor change is significantly higher in HL than in RLN for CCR4 as well as the 3 subpopulations (Table 2). Generally, internalization of CCR4 on lymphocytes is higher with MDC (54 to 90% internalization with 10 and 500ng/ml MDC) than TARC (28 to 48% with 10 and 1000ng/ml TARC) after 2 hours. Internalization occurs through the lipid raft/caveolae dependent pathway as filipin III could inhibit internalization completely and not by clathrin-mediated endocytosis since no effect of inhibition by sucrose was seen. Recovery of CCR4 back on the membrane is fast and by exocytosis since it can be disrupted by exocytosis inhibitor Brefeldin A.Table 1:Percentages subpopulations CD4+ T cells in Hodgkin lymphoma and reactive lymph node by flowcytometry on cell suspensionsHLRLNpCD264968<0.01CCR44137nsFoxP34.41.8nsCCR4/CD26+1925nsCCR4/CD26-2212nsCCR4/FoxP3+5560nsTable 2:Factor of CCR4 recovery after 24 hours in CD4+ subpopulations in Hodgkin lymphoma and reactive lymph node cell suspensionsHLRLNpCCR41.70.9<0.05CCR4 in CD26+1.30.8<0.05CCR4 in CD26-2.91.1<0.05CCR4 in FoxP3+1.60.8<0.05 In conclusion, CD26 expression is significantly lower in HL than RLN. CCR4 expression is equally divided over CD26+ and CD26- cells in HL, but in RLN less is found in CD26-. Recovery of CCR4 expression after culture for 24 hours is lower in RLN than in HL. More CCR4 is recovered in HL especially in the CD26- CD4+ T cell population that is surrounding the tumor cells in HL. Disclosures: No relevant conflicts of interest to declare.

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Peripheral lymph node helper T-cell recovery after syngeneic bone marrow transplantation in mice prepared with either gamma-irradiation or busulfan

Blood ◽

10.1182/blood.v74.4.1436.1436 ◽

1989 ◽

Vol 74 (4) ◽

pp. 1436-1445 ◽

Cited By ~ 13

Author(s):

WE Samlowski ◽

BA Araneo ◽

MO Butler ◽

MC Fung ◽

HM Johnson

Keyword(s):

Bone Marrow ◽

Lymph Node ◽

Bone Marrow Transplantation ◽

T Cell ◽

Lymph Nodes ◽

Gamma Irradiation ◽

Peripheral Lymph Node ◽

Helper T Cell ◽

Peripheral Lymph ◽

Preparative Regimen

Abstract The optimum marrow ablative regimen for preparing recipients of bone marrow transplantation (BMT) has not been established. gamma- Irradiation, but not busulfan, produces a characteristic microvascular injury pattern which results in depressed capacity of normal lymphocytes to localize into the lymph nodes of syngeneic murine BMT recipients. Since peripheral lymph nodes are important sites for initiation and amplification of immune responses, the preparative regimen might delay recovery of regionally compartmentalized immune functions after BMT. We evaluated the effects of busulfan and gamma- irradiation on the phenotypic and functional reconstitution of helper T- cell function within the peripheral lymph nodes of BMT recipients. Both marrow ablative regimens caused a protracted delay in regeneration of peripheral lymph node CD4+ T cells. Specific helper T-cell functions, such as contact hypersensitivity and alloantigen responses, remained significantly depressed in the lymph nodes of irradiated mice for prolonged periods (up to 60 weeks). These responses recovered more rapidly in busulfan-treated BMT recipients. In contrast, the capacity of peripheral lymph node T cells to provide “help” for antigen-specific immunoglobulin production was only transiently depressed by either preparative regimen. Our experiments confirm the hypothesis that the marrow ablative regimen, particularly gamma-irradiation, may contribute to the period of immunodeficiency which follows BMT. The pattern of immune recovery observed suggests that preparative total body irradiation (TBI) may selectively depress the regional recovery of the TH1 [interleukin-2 (IL-2) and gamma-interferon (gamma-IFN) secreting] lymphocyte subset.

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