scholarly journals Jagged-1 regulates Foxp3 expression and cytokine production in CD4+ T cells

2019 ◽  
Author(s):  
Soichiro Kimura ◽  
Ronald Allen ◽  
Melissa Scola ◽  
Nicholas W Lukacs ◽  
Steven L. Kunkel ◽  
...  
Keyword(s):  
T Cells ◽  
Cytokine Production ◽  
Foxp3 Expression ◽  
Bacille Calmette Guerin ◽  
Altered Expression ◽  
Effector Cells ◽  
T Cell Regulation ◽  
Notch Ligands ◽  
Draining Lymph Nodes

AbstractNotch ligands are present during the interactions between T cells and dendritic cells (DC) and induce a myriad of effects that facilitate the activation of T cells, including the induction of T cell regulation, survival, and cytokine production. Although the ligands Delta-like 4 and Delta-like 1 are expressed as a function of DC activation, the notch ligand Jagged-1 is constitutively expressed on DC. We sought to determine the role of Jagged-1 in the interactions between CD4+ T cells and DC. We observed that Jagged-1 regulates Foxp3 expression, and Cd11cCre+Jaggedff mice have an altered expression of Foxp3 in effector cells that arise as a result of infection with the mycobacterium Bacille Calmette-Guerin. The observed changes in Foxp3 expression were correlated with an increase in cytokine production from cultures of antigen-stimulated draining lymph nodes.

scholarly journals Gastric Hyperplasia and Increased Proliferative Responses of Lymphocytes in Mice Lacking the COOH-terminal Ankyrin Domain of NF-κB2

1997 ◽  
Vol 186 (7) ◽  
pp. 999-1014 ◽  
Author(s):  
Hideaki Ishikawa ◽  
Daniel Carrasco ◽  
Estefania Claudio ◽  
Rolf-Peter Ryseck ◽  
Rodrigo Bravo
Keyword(s):  
T Cells ◽  
Lymphocyte Proliferation ◽  
Cytokine Production ◽  
Cell Types ◽  
Homozygous Deletion ◽  
Binding Activity ◽  
Activated T Cells ◽  
Physiological Relevance

The nfkb2 gene encodes the p100 precursor which produces the p52 protein after proteolytic cleavage of its COOH-terminal domain. Although the p52 product can act as an alternative subunit of NF-κB, the p100 precursor is believed to function as an inhibitor of Rel/NF-κB activity by cytoplasmic retention of Rel/NF-κB complexes, like other members of the IκB family. However, the physiological relevance of the p100 precursor as an IκB molecule has not been understood. To assess the role of the precursor in vivo, we generated, by gene targeting, mice lacking p100 but still containing a functional p52 protein. Mice with a homozygous deletion of the COOH-terminal ankyrin repeats of NF-κB2 (p100−/−) had marked gastric hyperplasia, resulting in early postnatal death. p100−/− animals also presented histopathological alterations of hematopoietic tissues, enlarged lymph nodes, increased lymphocyte proliferation in response to several stimuli, and enhanced cytokine production in activated T cells. Dramatic induction of nuclear κB–binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes. Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-κB complexes in various cell types and its absence cannot be efficiently compensated for by other IκB proteins.

Autologous Gamma-Delta T (GD-T) Cells in Acute Myeloid Leukemia (AML): Potential Immune Effector Cells for Minimal Disease?.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2538-2538
Author(s):  
Joerg M. Aswald ◽  
Xing-Hua Wang ◽  
Sandra Aswald ◽  
Loralyn A. Benoit ◽  
Mark Minden ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interferon Gamma ◽  
Residual Disease ◽  
Blast Cell ◽  
Healthy Controls ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells

Abstract Prolonging event-free survival of AML with autologous activated immune cells is a promising concept. GD-T cells are a rare circulating lymphocyte population (1%) and a component of the innate immune system capable of exerting anti-neoplastic activity. Their role as potential anti-cancer immune effector cells deserves further exploration. It is noteworthy that GD-T cells are over-represented in reactive regions surrounding melanoma lesions. While patients with an accumulation of GD-T cells showed a survival benefit over those who did not, such increases were not present in patients with metastatic disease and high tumor cell burden (Bachelez, J. Invest. Dermatol.98:369,1992). Little is known about the role of GD-T cells as immuno-effectors, their absolute numbers in peripheral blood or the feasibility of purifying functional GD-T cells from patients with AML. We are interested in testing the clinical feasibility of using GD-T cells freshly purified from PB against minimal residual disease in AML. As a first step towards achieving this goal, we compared circulating GD-T cell levels sequentially in 33 AML patients with 20 healthy adult volunteers. We used ultra-low volume multi-color flow-cytometry and microbeads to measure absolute numbers of GD-T cells in PB. Functional studies were done by the chromium release assay and single-cell intra-cellular interferon-gamma detection. We observed that AML patients with a high leukemic blast cell burden (e.g. prior to chemotherapy) had marginally decreased GD-T cell levels compared with healthy controls: median 38/μl, Q1-Q3, 27–86/μl, versus median 83/μl, Q1-Q3, 45–122/μl, respectively, p= 0.051. We re-examined the AML patients at several time points after induction therapy and observed significantly increased numbers of GD-T cells in patients with lower but detectable residual disease (either molecular maker positive or borderline bone marrow blast infiltration by morphology) compared to patients with persistently high blast cell burden: median 105/μl, Q1-Q3, 105–133/μl versus median, 7/μl, Q1-Q3, 6–15/μl; p=0.008. Patients with residual disease also showed significantly higher numbers of absolute GD-T cells per microliter blood compared to those retested after they had achieved complete remission (CR); p=0.0025. In CR, GD-T cell counts remained lower than those of healthy individuals: median 33/μl, Q1-Q3, 22–35/μl versus median 83/μl, Q1-Q3, 45–122/μl; p=0.030. Interestingly, we found a sharp increase (on average, 4.9-fold higher than values obtained in CR) in GD-T levels at the time of very early morphologic (n=3) or molecular relapse (n=2). Hence, we were interested in studying the functional properties of the GD-T cells from AML patients. We were able to isolate functional GD-T cells from the PB of patients with AML in CR-1 in sufficient numbers and purity to assay for interferon-gamma and found that similar numbers of GD-T cells expressed the Th1 cytokine compared with healthy controls: 84% versus 93% of all GD-T cells, respectively. We also showed that GD-T cells were able to kill leukemic target cells (AML-OCI2) in vitro more efficiently than CD3+ T cells. Our data suggest that further studies to investigate the potential therapeutic role of autologous GD-T cells in patients with AML in CR are warranted.

The Role of ERK5 Signaling in Tolerance Induction by Veto CTLs.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3302-3302
Author(s):  
Shlomit Reich-Zeliger ◽  
Tamar Hanoch ◽  
Rony Seger ◽  
Yair Reisner
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cellular Systems ◽  
Class I ◽  
Spleen Cells ◽  
Effector Cells ◽  
Cd8 Cells ◽  
Veto Cells ◽  
Specific Inhibitors

Abstract Several bone marrow cells and lymphocyte subpopulations, known as ‘veto cells’, were shown to induce transplantation tolerance across major histocompatibility antigens. Recently, it has been suggested that anti-3rd party CTLs depleted of alloreactivity against the host are endowed with marked veto activity and can facilitate bone marrow allografting. The veto mechanism is still obscure. While early studies emphasized the role of CD8 mediated apoptosis, we showed that the veto activity of anti-3rd party CD8+ CTLs is dependent upon the simultaneous expression of both CD8 and FasL. Thus, it seems that although Fas is upregulated on the effector T cells upon engagement of their TCR by class I of the veto cells, the presence of FasL on the veto cells cannot result in apoptosis of the effector cells unless CD8 on the veto cells is available and can interact with class 1 on the effector cells. Thus, the interaction of CD8 on the veto cells with class I on the effector cells seems to be associated with an increased susceptability of the effector cells to FasL killing. To further delineate the mechanism of the veto effect we have now studied the role of different signaling pathways using specific inhibitors. Spleen CD8 T cells from 2C mice (H2b) bearing TCR transgene directed against (H2d) were used as effector cells and anti FVB (H2q, third party) CTLs generated from Balb/c spleen cells (H2d) were used as veto cells. The addition of the latter cells to MLR of 2C against Balb/c (H2d) simulators, leads to deletion of the 2C effector CD8 cells within 72 hrs. Deletion monitored by FACS analysis of cells stained with anti-TCR transgene antibody (1B2+) revealed reduction from 46%±11% 1B2+CD8+ cells to 6%±3% 1B2+CD8+ cells in 6 different experiments. In contrast, veto CTLs generated from SJL (H2s) spleen cells that do not display the H2 recognized by the 2C effector cells, did not result in a significant deletion of the effector cells (42%±12% 1B2+CD8+ cells in 6 different experiments). The specific deletion exhibited by veto CTLs of Balb/c origin, can be inhibited by MEK1/2/5 inhibitors such as U0126, reducing the veto activity from 85.5%±7% to 16%±14% in 6 different experiments. The effective concentration of U0126 was relatively high (10μM), and lower concentration of this drug (1μM) had no response, indicating a potential involvement of the MEK5/ERK5 cascade rather than the MEK1/2-ERK1/2 cascade, in the veto effect. In addition, no inhibition of veto activity could be found with specific inhibitors of other signaling molecules such as JNK, P38, PI3K or PKC. Considering that Fas expression on the effector cells is critical for the veto activity, it is interesting that the ERK inhibitor didn’t affect the level of Fas on the effectors (93%±3% of 1B2+CD8+ upregulate FAS in the presence of U0126 in 7 different experiments). Also, this inhibition is not likely mediated by affecting the veto CTLs, as pretreatment of the latter cells with ERK inhibitor didn’t diminish the veto effect. The pro-apoptotic effects of MEK5-ERK5 cascade in this system is intriguing because these kinases are usually thought to promote proliferation and survival in most cellular systems. Therefore, the veto cells exhibit a unique signaling system, which utilizes ERK5 cascade to induce apoptosis. Further studies are directed at the potential links between the ERK5 cascade, the Fas system and the rest of the apoptotic machinery.

Novel Chimeric Antigen Receptor T Cells for the Treatment of CD19-Negative Relapses Occurring after CD19-Targeted Immunotherapies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 966-966 ◽  
Author(s):  
Marco Ruella ◽  
David Barrett ◽  
Saad S. Kenderian ◽  
Olga Shestova ◽  
Ted J. Hofmann ◽  
...  
Keyword(s):  
T Cells ◽  
Chimeric Antigen Receptor ◽  
Research Funding ◽  
Cytokine Production ◽  
Term Survival ◽  
Long Term Survival ◽  
Nsg Mice

Abstract Relapsing/refractory (r/r) B-cell Acute Lymphoblastic Leukemia (ALL) is associated with a poor prognosis in both pediatric and adult patients. Novel therapies targeting CD19 on leukemic blasts, such as anti-CD19 Chimeric Antigen Receptor T cells (CART19, CTL019) or bi-specific anti-CD19/CD3 antibodies (blinatumomab) induce significant responses in this population. However, CD19-negative relapses have been reported in 5-10% of patients following CART19 or blinatumomab therapies. This is likely due to selective pressure on leukemia sub-clones by these potent anti-CD19 agents. Hence, novel effective immunotherapies are needed in order to treat these patients. In order to identify potential additional B-ALL antigens, samples from 20 r/r patients (including two that relapsed with CD19-negative disease after treatment with CART19 therapy) were screened using a custom Quantigene RNA panel (Affymetrix) and expression on cell surface was confirmed by multiparametric flow cytometry. The IL-3 receptor α (CD123) was one of the most highly and homogeneously expressed antigens in the blasts of 16/20 r/r ALL patients, and 2/2 CD19-negative relapses. Therefore, we sought to investigate the role of CART targeting CD123 (CART123) against r/r B-ALL, focusing on treating patients with CD19-negative relapses after prior anti-CD19 directed therapy. CART123 was shown to be effective in eradicating acute myeloid leukemia in xenograft mouse models but its role in ALL has not been investigated (Gill et al, Blood, 2014). We used a 2nd generation CAR123 construct that comprised a 4-1BB (CD137) co-stimulatory domain. T cells were lentivirally transduced and expanded using anti-CD3/CD28 beads. Head-to-head in vitro comparisons between CART123 and CART19 revealed similar rates of proliferation, CD107a degranulation, cytokine production and cytotoxicity when CART were co-cultured with the CD19+CD123+ B-ALL cell line NALM-6 and with primary B-ALL blasts. For in vivo evaluation, we utilized the primary ALL model that was developed by our group (Barrett et al, Blood, 2011). In this model, primary blasts obtained from ALL patients were passaged in NOD-SCID-γ chain KO (NSG) mice, and transduced with GFP/luciferase. We injected NSG mice with 2 million primary ALL blasts i.v. (CD19+, CD123+) and after engraftment, mice were treated with CART19, CART123 or control untransduced T cells (1 million i.v.). Mice treated with control T cells succumbed quickly to disease, while mice treated with either CART19 or CART123 showed tumor eradication and long term survival (Figure 1). We then evaluated the role of CART123 in the treatment of leukemia obtained from an ALL patient that relapsed with CD19-negative disease after CART19 treatment. Both CART123 and CART19 were incubated with CD19-negative ALL blasts; CART123, but not CART19 resulted in significant degranulation, robust cytokine production, and potent cytotoxicity. To confirm these results in vivo, we established a unique model of CD19-negative B-ALL xenograft. We used primary CD19-negative blasts obtained from a pediatric patient that relapsed after CART19 therapy; CD19-negative blasts were passaged in vivo in NSG mice and stably transduced with GFP/luciferase. Importantly, the blasts retained their CD19-negative phenotype. After engraftment, mice were treated with CART19, CART123 or control T cells. CART19 and control T cells had no anti-tumor activity, while CART123 resulted in a complete eradication of the disease and long term survival in these mice (Figure 2). In conclusion, CART123 represents an important additional approach to treating B-ALL, in particular due to its activity against CD19-negative relapses. Since we have previously shown that treatment with CART123 can lead to myelosuppression, CART123 should be employed to eradicate disease prior to allogeneic transplantation. Future direction may include combining CART123 with CART19 preemptively in order to avoid CD19 antigen escapes. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Ruella: Novartis: Research Funding. Kenderian:Novartis: Research Funding. Shestova:Novartis: Research Funding. Scholler:Novartis: Research Funding. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Nazimuddin:Novartis: Research Funding. Kalos:Novartis: CTL019 Patents & Royalties, Research Funding. Porter:Novartis: Research Funding. June:Novartis: Patents & Royalties, Research Funding. Grupp:Novartis: Consultancy, Research Funding. Gill:Novartis: Research Funding.

The Prognostic Role of CD68 and FoxP3 Expression in Primary Central Nervous System Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1457-1457 ◽  
Author(s):  
Soo-Jeong Kim ◽  
Hyunsung Park ◽  
Hyunsoo Cho ◽  
Yu Ri Kim ◽  
Jung Yeon Lee ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Multivariate Analysis ◽  
Central Nervous System Lymphoma ◽  
Foxp3 Expression ◽  
Prognostic Role ◽  
Median Level ◽  
The Difference

Abstract Background The prognostic role of CD68+ tumor-associated macrophages (TAMs) and tumor infiltrating T-cells including FoxP3+ regulatory T-cells (Tregs) has been extensively evaluated in areas of lymphoma research, however their expression and prognostic role have little been explored in primary central nervous system lymphoma (PCNSL). Therefore, we investigated CD68 and FoxP3 expression in tumor microenvironment of PCNSL and evaluated its prognostic role. Methods Seventy-six consecutive immunocompetent patients diagnosed with PCNSL between December 2004 and April 2015 treated homogenously with high-dose methotrexate (HD-MTX)-based chemotherapy as an initial treatment in Severance Hospital, Seoul, S. Korea and for whom archived formalin-fixed and paraffin-embedded (FFPE) tissue blocks for initial diagnosis were available were retrospectively identified. We studied CD68 and FoxP3 expression by immunohistochemical staining on FFPE biopsy specimen and evaluated correlations of their expression with obtained clinical data, treatment response depending on the upfront ASCT, and survival of the patients. The cut-off value for the expression of CD68+ TAMs and FoxP3+ Tregs were evaluated by the area under curve (AUC) of the receiver operating characteristic (ROC) curve for analysis purposes, and we established cut-offs of 55 cells/high power field (HPF) for CD68 and 15 cells/HPF for FoxP3. We stratified patients based on CD68 and FoxP3 expression according to the cut-off values we determined from the AUC. The overall survival (OS) and progression-free survival (PFS) were plotted using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional-hazards regression model was used in both univariate and multivariate analyses. Results The median age of the patients was 57 (range 33-79) years. The median follow-up duration for survivors was 23.2 months (range, 2.4-128.5). Sixteen (21.1%) patients underwent upfront ASCT, after median 4 (range 2-4) cycles of HD-MTX based chemotherapy. The 2-year OS and PFS rates for all patients were 75.2% and 43.3%, respectively. The patients did not reach median OS, and the median PFS was 17.9 months (95% confidence interval [CI], 9.4-26.4). The median level of expression for CD68+ TAM/HPF was 25 (range, 5-80) and the median level of expression for FoxP3+ Tregs/HPF was 0 (range, 0-68). The difference in OS and PFS between the high and low CD68 groups was significant in the univariate (hazard ratio [HR] = 2.79, 95% CI: 0.97-8.03, P = 0.058 for OS, and HR = 2.17, 95% CI: 1.03-4.58, P = 0.043 for PFS), as well as in the multivariate analysis (HR = 3.71, 95% CI: 1.25-11.02, P = 0.018 for OS, and HR = 4.83, 95% CI: 1.91-12.27, P = 0.001 for PFS). The patients with high CD68 expression exhibited 2-year OS and PFS rates of 42.9%, and 10.0%, respectively, in comparison to 81.5%, and 50.7% for those with low CD68 expression (P = 0.048 for OS, and P = 0.035 for PFS) (Figure 1A, 1B). In a subgroup analysis of 60 patients who did not receive upfront ASCT, high CD68 expression was associated with inferior OS and PFS compared to low CD68 expression (P = 0.014 for OS, and P = 0.016 for PFS) (Figure 1C, 1D). The difference in OS and PFS between the high and low CD68 expression groups in the non-upfront ASCT subgroup (n = 60) was significant in the univariate (HR = 3.63, 95% CI: 1.21-10.88, P = 0.021 for OS, and HR = 2.60, 95% CI: 1.15-5.86, P = 0.021 for PFS) as well as in the multivariate analysis (HR = 4.05, 95% CI: 1.35-12.16, P = 0.013 for OS, and HR = 5.80, 95% CI: 2.25-14.95, P < 0.001 for PFS). However, the OS and PFS in the upfront ASCT cohort (n = 16) were similar between the high and low CD68 expression groups (P = 0.426 and P = 0.848, respectively) (Figure 1E, 1F). There were no differences in OS and PFS according to the expression level of FoxP3 in all patients as well as in subgroup of patients who did not receive upfront ASCT. Conclusion High level of CD68 expression in patients with PCNSL was significantly associated with inferior OS and PFS, especially in non-upfront ASCT treated subgroup of patients. FoxP3 expression level was also not associated with survival in this study. We suggest CD68 as a potential biomarker at initial PCNSL diagnosis and upfront ASCT consolidative strategy might improve survival in PCNSL patients by overcoming negative impact of high CD68 expression. Further validation studies are warranted. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Glucocorticoid hormone treatment enhances the cytokine production of regulatory T cells by upregulation of Foxp3 expression

Immunobiology ◽  
2018 ◽  
Vol 223 (4-5) ◽  
pp. 422-431 ◽  
Author(s):  
Emese Ugor ◽  
Lilla Prenek ◽  
Ramóna Pap ◽  
Gergely Berta ◽  
Dávid Ernszt ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cytokine Production ◽  
Foxp3 Expression ◽  
Hormone Treatment ◽  
Glucocorticoid Hormone

scholarly journals T-cell regulation of antibody responses: demonstration of allotype-specific helper T cells and their specific removal by suppressor T cells.

1976 ◽  
Vol 144 (2) ◽  
pp. 330-344 ◽  
Author(s):  
L A Herzenberg ◽  
K Okumura ◽  
H Cantor ◽  
V L Sato ◽  
F W Shen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antibody Responses ◽  
Helper T Cells ◽  
Spleen Cells ◽  
Suppressor T Cells ◽  
Effector Cells ◽  
T Cell Regulation ◽  
The Difference

Allotype suppressor T cells (Ts) generated in SJL X BALB/c mice specifically suppress production of antibodies marked with the Ig-1a allotype. The studies presented here show that allotypes Ts suppress by specifically removing helper T cell (Th) activity required to facilitate differentiation and expansion of B cells to Ig-1b antibody-forming cells. We show first that Ts and Th belong to different T-cell subclasses as defined by Ly surface antigens. Ts are Ly2+Lyl- and thus belong to the same subclass as cytotoxic precursor and effector cells; Th are Lyl+Ly2- cells and thus belong to the subclass containing cells which can exert helper functions and initiate delayed hypersensitivity reactions. Placing these cells in these two subclasses shows that Th are different from Ts and suggests that they play different roles in regulating antibody responses. The difference in these roles is defined by the evidence presented here showing that Ts attack Th and regulate the antibody response by specifically regulating the availability of Th activity. We show that in allotype suppressed mice, Ts which suppress Ig-1b antibody production have completely removed the Th activity of helping Ig-1b cells without impairing Th activity which helps other IgB B cells. These findings imply the existence of allotype-specific Th for Ig-1b cells (Ig-1b Th). We directly establish that Ig-1b cells require such help by showing that carrier-primed spleen cells from Iga/Iga congenic hybrids help Ig-1a B cells from hapten-primed Igb/Iga donors but do not help Ig-1b B cells from the same donor in the same adoptive recipient.

scholarly journals Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells

2010 ◽  
Vol 207 (7) ◽  
pp. 1381-1391 ◽  
Author(s):  
Yohsuke Harada ◽  
Yasuyo Harada ◽  
Chris Elly ◽  
Ge Ying ◽  
Ji-Hye Paik ◽  
...  
Keyword(s):  
T Cells ◽  
Ring Finger ◽  
Foxp3 Expression ◽  
Proximal Region ◽  
Binding Motif ◽  
Mechanistic Insight ◽  
T Cell Regulation ◽  
And Function ◽  
Deficient Mice ◽  
Insight Into

The transcription factor Foxp3 is essential for optimal regulatory T (T reg) cell development and function. Here, we show that CD4+ T cells from Cbl-b RING finger mutant knockin or Cbl-b–deficient mice show impaired TGF-β–induced Foxp3 expression. These T cells display augmented Foxo3a phosphorylation, but normal TGF-β signaling. Expression of Foxo3a rescues Foxp3 expression in Cbl-b–deficient T cells, and Foxo3a deficiency results in defective TGF-β–driven Foxp3 induction. A Foxo3a-binding motif is present in a proximal region of the Foxp3 promoter, and is required for Foxo3a association. Foxo1 exerts similar effects as Foxo3a on Foxp3 expression. This study reveals that Foxo factors promote transcription of the Foxp3 gene in induced T reg cells, and thus provides new mechanistic insight into Foxo-mediated T cell regulation.

scholarly journals Requirement for vasoactive amines for production of delayed-type hypersensitvity skin reactions.

1975 ◽  
Vol 142 (3) ◽  
pp. 732-747 ◽  
Author(s):  
R K Gershon ◽  
P W Askenase ◽  
M D Gershon
Keyword(s):  
T Cells ◽  
Mast Cells ◽  
Suppressive Effect ◽  
Delayed Type Hypersensitivity ◽  
Postcapillary Venule ◽  
Skin Reactions ◽  
Effector Cells ◽  
Homologous Antigen ◽  
T Cell Regulation ◽  
Pass Through

The skin sites of the mouse where delayed-type hypersensitivity (DTH) reactions are most easily elicited (foot pads and ears) are particularly rich in 5-hydroxytryptamine (5-HT)-containing mast cells. Since mice are deficient in circulating basophils, which play a role in at least some DTH reactions, we investigated the possibility that the mast cells were playing an important role in the evolution of the skin reactions of DTH in mice. We found that reserpine, a drug which depletes mast cells of 5-HT, abolished the ability of the mouse to make DTH reactions in the skin. The suppressive effect of reserpine could be partially blocked by monoamine oxidase inhibitors which prevent the degradation of 5-HT in the cytosol of the mast cell. Spleen cells of immune, reserpine-treated mice transferred DTH reactions to nonimmune mice normally, indicating that the reserpine treatment did not affect immune T cells. DTH reactions could not be transferred into reserpine-treated mice. We suggest that T cells are continually emigrating from the blood, through postcapillary venule endothelium, by a mechanism which does not depend on vasoactive amines. If they are appropriately immune and meet the homologous antigen in the tissue, they induce mast cells to release vasoactive amines which cause postcapillary venule endothelial cells to separate, allowing the egress from the blood of cells which ordinarily do not recirculate. The secondarily arriving vasoactive amine-dependent cells are responsible for the micro- and macroscopic lesions of DTH reactions. Chemotactic factors may also be involved in bringing cells to the DTH reaction sites but we propose that T-cell regulation of vasoactive amine-containing cells allows the effector cells to pass through the endothelial gates after they are called.

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